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1
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Goto Y. Immunomodulation by Leishmania parasites: Potential for controlling other diseases. Parasitol Int 2025; 104:102987. [PMID: 39515578 DOI: 10.1016/j.parint.2024.102987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 11/01/2024] [Accepted: 11/02/2024] [Indexed: 11/16/2024]
Abstract
In the mammalian hosts, Leishmania parasites survive and proliferate within phagolysosomes of macrophages. To avoid being killed by the immune cells, Leishmania parasites utilize their molecules to manipulate macrophages' functions for survival. Targets of such immunomodulatory molecules are not limited to macrophages, as Leishmania-derived molecules sometimes show influence on other immune cells such as neutrophils, dendritic cells, T cells and B cells. This review covers research on immunomodulation of host immunity by Leishmania parasites and introduces some examples of parasite-derived molecules participating in the immunomodulation. For example, Leishmania cell surface lipophosphoglycan (LPG) can modulate TLR2 signaling and PI3K/Akt axis in macrophages leading to induction of Th2 cells. Because chronic secretion of inflammatory cytokines is one of the causes of immune-mediated diseases such as atherosclerosis, Crohn's disease, and rheumatoid arthritis, LPG may be useful as a drug to suppress the inflammatory conditions. The unique characteristics of leishmanial molecules pose a promise as a source of immunomodulatory drugs for controlling diseases other than leishmaniasis.
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Affiliation(s)
- Yasuyuki Goto
- Laboratory of Molecular Immunology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Japan.
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2
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Jafarzadeh A, Gurjar D, Bodhale N, Jafarzadeh S, Nemati M, Sharifi I, Saha B. Aberrant expression of SOCS impairs the anti-leishmanial immune response. Cytokine 2024; 174:156461. [PMID: 38065046 DOI: 10.1016/j.cyto.2023.156461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 11/27/2023] [Accepted: 11/30/2023] [Indexed: 01/01/2024]
Abstract
Establishing a balance between Th1 and Th2 subsets and M1- and M2-type macrophages is essential for the control of Leishmania infection. The suppressors of cytokine secretion (SOCS) proteins, particularly SOCS1 and SOCS3, play a significant role in regulating cytokine-triggered signaling pathways, thereby impacting the macrophage-and effector T-cell mediated antileishmanial immune response. In addition to the pro-inflammatory cytokines, Leishmania-derived lipophosphoglycan (LPG) and CpG-DNA interact with TLR2 and TLR9 to trigger SOCS expression. The aberrant levels of SOCS1 and SOCS3 expression in Leishmania-infected macrophages impair macrophage-T-cell interaction perturbing the balance in macrophage subsets polarization. This hinders macrophage apoptosis and macrophage-mediated leishmanicidal activity, both support the establishment of infection and parasite replication. Furthermore, aberrant SOCS3 levels in T-cells disrupt Th1 differentiation and aid in parasite replication, lesion development, and pathological immune responses. Strategically, selective modulation of SOCS expression and function in immune effector cells may reduce parasite survival and prevent disease progression.
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Affiliation(s)
- Abdollah Jafarzadeh
- Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran; Molecular Medicine Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
| | - Dhiraj Gurjar
- National Centre for Cell Science, Pune 411007, India
| | | | - Sara Jafarzadeh
- Student Research Committee, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Maryam Nemati
- Molecular Medicine Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Department of Hematology and Laboratory Sciences, School of Para-Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Iraj Sharifi
- Leishmaniasis Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Bhaskar Saha
- National Centre for Cell Science, Pune 411007, India; Student Research Committee, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran.
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3
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Bretscher P. What Determines the Class of Immunity an Antigen Induces? A Foundational Question Whose Rational Consideration Has Been Undermined by the Information Overload. BIOLOGY 2023; 12:1253. [PMID: 37759652 PMCID: PMC10525557 DOI: 10.3390/biology12091253] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 09/15/2023] [Accepted: 09/16/2023] [Indexed: 09/29/2023]
Abstract
Activated CD4 T helper cells are required to activate B cells to produce antibody and CD8 T cells to generate cytotoxic T lymphocytes. In the absence of such help, antigens inactivate B cells and CD8 T cells. Thus, the activation or inactivation of CD4 T cells determines whether immune responses are generated, or potentially ablated. Most consider that the activation of CD4 T cells requires an antigen-dependent signal, signal 1, as well as a critical costimulatory signal, initiated when a pattern recognition receptor (PRR) engages with a danger- or pathogen-associated molecular pattern (DAMP or PAMP). Most also envisage that the nature of the DAMP/PAMP signal determines the Th subset predominantly generated and so the class of immunity predominantly induced. I argue that this framework is implausible as it is incompatible with diverse observations of the variables of immunization affecting the class of immunity induced. An alternative framework, the threshold hypothesis, posits that different levels of antigen mediated CD4 T cell interactions lead to the generation of different Th subsets and so different classes of immunity, that it is compatible with these observations. This alternative supports a rational approach to preventing and treating diverse clinical conditions associated with infectious disease and, more speculatively, with cancer.
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Affiliation(s)
- Peter Bretscher
- Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
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4
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Saidi N, Blaizot R, Prévot G, Aoun K, Demar M, Cazenave PA, Bouratbine A, Pied S. Clinical and immunological spectra of human cutaneous leishmaniasis in North Africa and French Guiana. Front Immunol 2023; 14:1134020. [PMID: 37575260 PMCID: PMC10421664 DOI: 10.3389/fimmu.2023.1134020] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 03/10/2023] [Indexed: 08/15/2023] Open
Abstract
Cutaneous leishmaniasis (CL) caused by infection with the parasite Leishmania exhibits a large spectrum of clinical manifestations ranging from single healing to severe chronic lesions with the manifestation of resistance or not to treatment. Depending on the specie and multiple environmental parameters, the evolution of lesions is determined by a complex interaction between parasite factors and the early immune responses triggered, including innate and adaptive mechanisms. Moreover, lesion resolution requires parasite control as well as modulation of the pathologic local inflammation responses and the initiation of wound healing responses. Here, we have summarized recent advances in understanding the in situ immune response to cutaneous leishmaniasis: i) in North Africa caused by Leishmania (L.) major, L. tropica, and L. infantum, which caused in most cases localized autoresolutives forms, and ii) in French Guiana resulting from L. guyanensis and L. braziliensis, two of the most prevalent strains that may induce potentially mucosal forms of the disease. This review will allow a better understanding of local immune parameters, including cellular and cytokines release in the lesion, that controls infection and/or protect against the pathogenesis in new world compared to old world CL.
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Affiliation(s)
- Nasreddine Saidi
- Univ. Lille, Univ. French Guiana, CNRS UMR 9017-INSERM U1019, Center for Infection and Immunity of Lille-CIIL, Institut Pasteur de Lille, Lille, France
- Laboratoire de Recherche, LR 16-IPT-06, Parasitoses Médicales, Biotechnologies et Biomolécules, Institut Pasteur de Tunis, Université Tunis El-Manar, Tunis, Tunisia
| | - Romain Blaizot
- Univ. Lille, Univ. French Guiana, CNRS UMR 9017-INSERM U1019, Center for Infection and Immunity of Lille-CIIL, Institut Pasteur de Lille, Lille, France
- Centre National de Référence des Leishmanioses, Laboratoire Associé, Hôpital Andrée Rosemon, Cayenne, French Guiana, France
- Service de Dermatologie, Hôpital de Cayenne, Cayenne, French Guiana, France
| | - Ghislaine Prévot
- Univ. Lille, Univ. French Guiana, CNRS UMR 9017-INSERM U1019, Center for Infection and Immunity of Lille-CIIL, Institut Pasteur de Lille, Lille, France
| | - Karim Aoun
- Laboratoire de Recherche, LR 16-IPT-06, Parasitoses Médicales, Biotechnologies et Biomolécules, Institut Pasteur de Tunis, Université Tunis El-Manar, Tunis, Tunisia
- Service de Parasitologie-Mycologie, Institut Pasteur de Tunis, Tunis, Tunisia
| | - Magalie Demar
- Univ. Lille, Univ. French Guiana, CNRS UMR 9017-INSERM U1019, Center for Infection and Immunity of Lille-CIIL, Institut Pasteur de Lille, Lille, France
- Centre National de Référence des Leishmanioses, Laboratoire Associé, Hôpital Andrée Rosemon, Cayenne, French Guiana, France
- Service de Dermatologie, Hôpital de Cayenne, Cayenne, French Guiana, France
| | - Pierre André Cazenave
- Univ. Lille, Univ. French Guiana, CNRS UMR 9017-INSERM U1019, Center for Infection and Immunity of Lille-CIIL, Institut Pasteur de Lille, Lille, France
| | - Aida Bouratbine
- Laboratoire de Recherche, LR 16-IPT-06, Parasitoses Médicales, Biotechnologies et Biomolécules, Institut Pasteur de Tunis, Université Tunis El-Manar, Tunis, Tunisia
- Service de Parasitologie-Mycologie, Institut Pasteur de Tunis, Tunis, Tunisia
| | - Sylviane Pied
- Univ. Lille, Univ. French Guiana, CNRS UMR 9017-INSERM U1019, Center for Infection and Immunity of Lille-CIIL, Institut Pasteur de Lille, Lille, France
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5
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Murphy KM. "Doubt No More": Two Sizes Fit All. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 211:3-5. [PMID: 37339405 DOI: 10.4049/jimmunol.2300198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/22/2023]
Abstract
This Pillars of Immunology article is a commentary on “Differing lymphokine profiles of functional subsets of human CD4 and CD8 T cell clones,” a pivotal article written by P. Salgame, J. S. Abrams, C. Clayberger, H. Goldstein, J. Convit, R. L. Modlin, and B. R. Bloom, and published in Science, in 1991. https://www.science.org/doi/10.1126/science.254.5029.279.
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Affiliation(s)
- Kenneth M Murphy
- Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO
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6
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Goto Y, Mizobuchi H. Pathological roles of macrophages in Leishmania infections. Parasitol Int 2023; 94:102738. [PMID: 36738983 DOI: 10.1016/j.parint.2023.102738] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 01/31/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023]
Abstract
Macrophages are the major host cells for Leishmania parasites, and determine the fate of infection by either limiting or allowing growth of the parasites, resulting in development or control of leishmaniasis, respectively. They also play important roles in causing pathological outcomes during Leishmania infection. The pathophysiology is complex and include a wide variety of molecular and cellular responses including enhancement of inflammatory responses by releasing cytokines, causing damages to surrounding cells by reactive oxygen species, or disordered phagocytosis of other cells. It is of note that disease severity in leishmaniasis sometimes does not correlate with parasite burdens, indicating that pathological roles of macrophages are not necessarily linked to their parasite-killing activities that are often defined by M1/M2 status. Here, we review the roles of macrophages in leishmaniasis with a focus on their pathological mechanisms in disease development.
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Affiliation(s)
- Yasuyuki Goto
- Laboratory of Molecular Immunology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
| | - Haruka Mizobuchi
- Laboratory of Molecular Immunology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
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7
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Antczak M, Cañete PF, Chen Z, Belle C, Yu D. Evolution of γ chain cytokines: Mechanisms, methods and applications. Comput Struct Biotechnol J 2022; 20:4746-4755. [PMID: 36147674 PMCID: PMC9465101 DOI: 10.1016/j.csbj.2022.08.050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 08/21/2022] [Accepted: 08/22/2022] [Indexed: 11/12/2022] Open
Abstract
The common γ chain family of cytokines and their receptors play fundamental roles in the immune system. Evolutionary studies of γ chain cytokines have elegantly illustrated how the immune system adapts to ever-changing environmental conditions. Indeed, these studies have revealed the uniqueness of cytokine evolution, which exhibits strong positive selection pressure needed to adapt to rapidly evolving threats whilst still conserving their receptor binding capabilities. In this review, we summarise the evolutionary mechanisms that gave rise to the characteristically diverse family of γ chain cytokines. We also speculate on the benefits of studying cytokine evolution, which may provide alternative ways to design novel cytokine therapeutic strategies. Additionally, we discuss current evolutionary models that elucidate the emergence of distinct cytokines (IL-4 and IL-13) and cytokine receptors (IL-2Rα and IL-15Rα). Finally, we address and reflect on the difficulties associated with evolutionary studies of rapidly evolving genes and describe a variety of computational methods that have revealed numerous aspects of cytokine evolution.
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Affiliation(s)
- Magdalena Antczak
- The University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Pablo F. Cañete
- The University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Zhian Chen
- The University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Clémence Belle
- The University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Di Yu
- The University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
- Ian Frazer Centre for Children’s Immunotherapy Research, Child Health Research Centre, Faculty of Medicine, The University of Queensland, Brisbane, Australia
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8
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Sechi A, Neri I, Patrizi A, Di Altobrando A, Clinca R, Caro RDC, Leuzzi M, Misciali C, Gaspari V. Ultrasound patterns of localized cutaneous leishmaniasis and clinical correlations. J Ultrasound 2022; 25:343-348. [PMID: 33527311 PMCID: PMC9148356 DOI: 10.1007/s40477-020-00537-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Accepted: 10/22/2020] [Indexed: 11/24/2022] Open
Abstract
A single-center retrospective study reviewed the following sonographic features of 18 confirmed cases of localized cutaneous leishmaniasis to identify shared presentation patterns: echotexture, lesion borders, hypodermal involvement, soft-tissue changes, and vascular pattern. A second objective was to correlate these patterns with clinical characteristics, including sex, age, anatomical location, nodule vs. plaque presentation, raised borders, granulation tissue, swelling, hyperkeratotic crusting, disease onset, and healing time. Two main patterns were identified with high-frequency ultrasonography. The first pattern was characterized by a high level of inflammation and deep hypodermal involvement, while the second variant showed involvement limited to the dermis, with minimal inflammation. The "inflammatory pattern" showed ill-defined borders, mixed echotexture, prominent vascularity with central distribution, and was correlated with clinical signs of ulceration, granulation tissue, raised borders, and longer healing time (p < 0.05). The "pauci-inflammatory pattern" presented a well-defined structure with decreased echogenicity, reduced or absent vascularity with minimal soft-tissue changes, and was associated with a shorter healing time (p < 0.05).
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Affiliation(s)
- Andrea Sechi
- Division of Dermatology, Department of Experimental, Diagnostic and Specialty Medicine, University Hospital of Bologna Sant' Orsola-Malpighi Polyclinic, Via Massarenti, 1, 40138, Bologna, Italy.
| | - Iria Neri
- Division of Dermatology, Department of Experimental, Diagnostic and Specialty Medicine, University Hospital of Bologna Sant' Orsola-Malpighi Polyclinic, Via Massarenti, 1, 40138, Bologna, Italy
| | - Annalisa Patrizi
- Division of Dermatology, Department of Experimental, Diagnostic and Specialty Medicine, University Hospital of Bologna Sant' Orsola-Malpighi Polyclinic, Via Massarenti, 1, 40138, Bologna, Italy
| | - Ambra Di Altobrando
- Division of Dermatology, Department of Experimental, Diagnostic and Specialty Medicine, University Hospital of Bologna Sant' Orsola-Malpighi Polyclinic, Via Massarenti, 1, 40138, Bologna, Italy
| | - Roberta Clinca
- Radiology Unit, University Hospital of Bologna Sant' Orsola-Malpighi Polyclinic, Bologna, Italy
| | | | - Miriam Leuzzi
- Division of Dermatology, Department of Experimental, Diagnostic and Specialty Medicine, University Hospital of Bologna Sant' Orsola-Malpighi Polyclinic, Via Massarenti, 1, 40138, Bologna, Italy
| | - Cosimo Misciali
- Division of Dermatology, Department of Experimental, Diagnostic and Specialty Medicine, University Hospital of Bologna Sant' Orsola-Malpighi Polyclinic, Via Massarenti, 1, 40138, Bologna, Italy
| | - Valeria Gaspari
- Division of Dermatology, Department of Experimental, Diagnostic and Specialty Medicine, University Hospital of Bologna Sant' Orsola-Malpighi Polyclinic, Via Massarenti, 1, 40138, Bologna, Italy
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9
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Seth A, Kar S. Host-directed antileishmanial interventions: Harvesting unripe fruits to reach fruition. Int Rev Immunol 2022; 42:217-236. [PMID: 35275772 DOI: 10.1080/08830185.2022.2047670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Leishmaniasis is an exemplary paradigm of immune evasion, fraught with the perils of limited clinical assistance, escalating costs of treatment and made worse with the lack of suitable vaccine. While drugs remain central to large-scale disease control, the growing emergence of parasite resistance necessitates the need for combination therapy involving host-directed immunological agents. Also, since prolonged disease progression is associated with strong immune suppression of the host, augmentation of host immunity via restoration of the immunoregulatory circuit involving antigen-presenting cells and T-cells, activation of macrophage function and/or CD4+ T helper 1 cell differentiation may serve as an ideal approach to resolve severe cases of leishmaniasis. As such, therapies that embody a synergistic approach that involve direct killing of the parasite in addition to elevating host immunity are likely to pave the way for widespread elimination of leishmaniasis in the future. With this review, we aim to recapitulate the various immunotherapeutic agents found to hold promise in antileishmanial treatment both in vitro and in vivo. These include parasite-specific antigens, dendritic cell-targeted therapy, recombinant inhibitors of various components intrinsic to immune cell signaling and agonists or antagonists to immune cells and cytokines. We also summarize their abilities to direct therapeutic skewing of the host cell-immune response and review their potential to combat the disease either alone, or as adjunct modalities.
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Affiliation(s)
- Anuradha Seth
- Division of Molecular Microbiology and Immunology, CSIR-Central Drug Research Institute, Lucknow, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India
| | - Susanta Kar
- Division of Molecular Microbiology and Immunology, CSIR-Central Drug Research Institute, Lucknow, India
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10
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Bretscher PA. Facing the Increased Prevalence of Antibiotic-Resistant M. tuberculosis: Exploring the Feasibility of Realising Koch’s Aspiration of Immunotherapy of Tuberculosis. Antibiotics (Basel) 2022; 11:antibiotics11030371. [PMID: 35326834 PMCID: PMC8944510 DOI: 10.3390/antibiotics11030371] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 03/08/2022] [Accepted: 03/08/2022] [Indexed: 01/25/2023] Open
Abstract
Koch attempted to treat tuberculosis in the late 1800s by administering an antigenic extract derived from the pathogen to patients. He hoped to bolster the patient’s protective immunity. The treatment had diverse results. In some, it improved the patient’s condition and in others led to a worsening state and even to death. Koch stopped giving his experimental treatment. I consider here three issues pertinent to realizing Koch’s vision. Rational immunotherapy requires a knowledge of what constitutes protective immunity; secondly, how on-going immune responses are regulated, so the patient’s immunity can be modulated to become optimally protective; thirdly, a simple methodology by which treatment might be realized. I deliberately cast my account in simple terms to transcend barriers due to specialization. The proposed immunotherapeutic treatment, if realizable, would significantly contribute to overcoming problems of treatment posed by antibiotic resistance of the pathogen.
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Affiliation(s)
- Peter A Bretscher
- Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Heath Sciences Building, 105 Wiggins Road, Saskatoon, SK S5N 5E5, Canada
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11
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Russler-Germain EV, Jung J, Miller AT, Young S, Yi J, Wehmeier A, Fox LE, Monte KJ, Chai JN, Kulkarni DH, Funkhouser-Jones LJ, Wilke G, Durai V, Zinselmeyer BH, Czepielewski RS, Greco S, Murphy KM, Newberry RD, Sibley LD, Hsieh CS. Commensal Cryptosporidium colonization elicits a cDC1-dependent Th1 response that promotes intestinal homeostasis and limits other infections. Immunity 2021; 54:2547-2564.e7. [PMID: 34715017 DOI: 10.1016/j.immuni.2021.10.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 06/01/2021] [Accepted: 10/05/2021] [Indexed: 12/17/2022]
Abstract
Cryptosporidium can cause severe diarrhea and morbidity, but many infections are asymptomatic. Here, we studied the immune response to a commensal strain of Cryptosporidium tyzzeri (Ct-STL) serendipitously discovered when conventional type 1 dendritic cell (cDC1)-deficient mice developed cryptosporidiosis. Ct-STL was vertically transmitted without negative health effects in wild-type mice. Yet, Ct-STL provoked profound changes in the intestinal immune system, including induction of an IFN-γ-producing Th1 response. TCR sequencing coupled with in vitro and in vivo analysis of common Th1 TCRs revealed that Ct-STL elicited a dominant antigen-specific Th1 response. In contrast, deficiency in cDC1s skewed the Ct-STL CD4 T cell response toward Th17 and regulatory T cells. Although Ct-STL predominantly colonized the small intestine, colon Th1 responses were enhanced and associated with protection against Citrobacter rodentium infection and exacerbation of dextran sodium sulfate and anti-IL10R-triggered colitis. Thus, Ct-STL represents a commensal pathobiont that elicits Th1-mediated intestinal homeostasis that may reflect asymptomatic human Cryptosporidium infection.
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Affiliation(s)
- Emilie V Russler-Germain
- Department of Internal Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Jisun Jung
- Department of Internal Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Aidan T Miller
- Department of Internal Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Shannon Young
- Department of Internal Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Jaeu Yi
- Department of Internal Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Alec Wehmeier
- Department of Internal Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Lindsey E Fox
- Department of Internal Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Kristen J Monte
- Department of Internal Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Jiani N Chai
- Department of Internal Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Devesha H Kulkarni
- Department of Internal Medicine, Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Lisa J Funkhouser-Jones
- Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Georgia Wilke
- Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Vivek Durai
- Department of Pathology, Division of Immunobiology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Bernd H Zinselmeyer
- Department of Pathology, Division of Immunobiology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Rafael S Czepielewski
- Department of Pathology, Division of Immunobiology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Suellen Greco
- Division of Comparative Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Kenneth M Murphy
- Department of Pathology, Division of Immunobiology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Rodney D Newberry
- Department of Internal Medicine, Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - L David Sibley
- Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
| | - Chyi-Song Hsieh
- Department of Internal Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO 63110, USA.
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12
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Bretscher PA. The role of cytokines in determining the Th1/Th2 phenotype of an immune response: Coherence of the T cell response and the Cytokine Implementation Hypothesis. Scand J Immunol 2021. [PMCID: PMC9286540 DOI: 10.1111/sji.13110] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
The widely accepted Cytokine Milieu Hypothesis proposes that the cytokine milieu, in which antigen activates CD4 T cells, from a non‐T cell source, primarily determines the Th subset to which the ensuing effector Th cells belong. We focus on the generation of Th1 and Th2 cells. We briefly restate the grounds for the Threshold Hypothesis we favour for how the Th1/Th2 phenotype of a response is primarily determined: tentative and robust thresholds of antigen‐mediated CD4 T cell interactions lead to the generation of Th1 and Th2 cells. The component antigens of pathogens are present in different amounts. It is expected, within the context of the threshold mechanism that, although there is often an initial predominance of Th1 or Th2 cells, some Th cells of the opposing type are initially generated. An initially somewhat heterogeneous Th response is known to become with time more ‘coherent’ in its Th1/Th2 phenotype. I propose The Cytokine Implementation Hypothesis as a mechanism for how coherence is achieved. Most cytokines made by Th cells of one subset tend to facilitate the further generation of Th cells of this subset and/or inhibit the generation of Th cells of opposing subsets, accounting for how coherence may be achieved. Many observations on which The Cytokine Milieu Hypothesis is based are accounted for by this alternative hypothesis. We outline predictions of the new hypothesis and discuss the importance of coherence of immune responses for their efficacy in protecting against foreign invaders.
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Affiliation(s)
- Peter A. Bretscher
- Department of Biochemistry, Microbiology and Immunology Saskatoon Saskatchewan Canada
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Rodríguez-Serrato MA, Salinas-Carmona MC, Limón-Flores AY. Immune response to Leishmania mexicana: the host-parasite relationship. Pathog Dis 2020; 78:5917983. [PMID: 33016312 DOI: 10.1093/femspd/ftaa060] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 10/01/2020] [Indexed: 11/12/2022] Open
Abstract
Leishmaniosis is currently considered a serious public health problem and it is listed as a neglected tropical disease by World Health Organization (WHO). Despite the efforts of the scientific community, it has not been possible to develop an effective vaccine. Current treatment consists of antimonials that is expensive and can cause adverse effects. It is essential to fully understand the immunopathogenesis of the disease to develop new strategies to prevent, treat and eradicate the disease. Studies on animal models have shown a new paradigm in the resolution or establishment of infection by Leishmania mexicana where a wide range of cytokines, antibodies and cells are involved. In recent years, the possibility of a new therapy with monoclonal antibodies has been considered, where isotype, specificity and concentration are critical for effective therapy. Would be better to create/generate a vaccine to induce host protection or produce passive immunization with engineering monoclonal antibodies to a defined antigen? This review provides an overview that includes the current known information on the immune response that are involved in the complex host-parasite relationship infection caused by L. mexicana.
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Affiliation(s)
- Mayra A Rodríguez-Serrato
- Universidad Autónoma de Nuevo León, Facultad de Medicina y Hospital Universitario Dr. Jose Eleuterio González, Servicio y Departamento de Inmunología, Av. Madero y Av. Gonzalitos s/n, Colonia Mitras Centro, Monterrey, Nuevo León, México
| | - Mario C Salinas-Carmona
- Universidad Autónoma de Nuevo León, Facultad de Medicina y Hospital Universitario Dr. Jose Eleuterio González, Servicio y Departamento de Inmunología, Av. Madero y Av. Gonzalitos s/n, Colonia Mitras Centro, Monterrey, Nuevo León, México
| | - Alberto Yairh Limón-Flores
- Universidad Autónoma de Nuevo León, Facultad de Medicina y Hospital Universitario Dr. Jose Eleuterio González, Servicio y Departamento de Inmunología, Av. Madero y Av. Gonzalitos s/n, Colonia Mitras Centro, Monterrey, Nuevo León, México
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14
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Mirzaei A, Maleki M, Masoumi E, Maspi N. A historical review of the role of cytokines involved in leishmaniasis. Cytokine 2020; 145:155297. [PMID: 32972825 DOI: 10.1016/j.cyto.2020.155297] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 09/07/2020] [Accepted: 09/09/2020] [Indexed: 02/06/2023]
Abstract
Leishmaniasis is an infectious disease caused by the Leishmania genus, affecting millions of persons in the world. Despite increased studies, no vaccine has been developed against leishmaniasis, and drug resistance is evolving in some Leishmania species (spp). Innate and acquired immune cells and their associated cytokines interplay together to determine the immune responses related outcomes in leishmaniasis. Interferon (IFN)-γ or macrophage activating factor (MAF) is the first effective lymphokine (LK), with a related function to leishmaniasis, discovered in 1979. This review article discussed the history of cytokines involved in Leishmania infection, and it is the first report demonstrating the involvement in the disease by focusing on cutaneous leishmaniasis. Up to now, the role of many cytokines has been determined and the literature review showed that IL-35 is the latest known cytokine involved in leishmaniasis. This review revealed that the cytokines have pleiotropic effects, depending upon the cytokine environment, generated during the infection and the host genetic background or infecting Leishmania spp. Overall, advances in our knowledge of immune cells and their secreted cytokines, contributing to the protection or pathological process of leishmaniasis may help to reach new approaches for immunotherapy.
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Affiliation(s)
- Asad Mirzaei
- Department of Parasitology, School of Paramedicine, Ilam University of Medical Sciences, Ilam, Iran; Zoonotic Diseases Research Center, Ilam University of Medical Sciences, Ilam, Iran
| | - Maryam Maleki
- Department of Physiology, School of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Elham Masoumi
- Zoonotic Diseases Research Center, Ilam University of Medical Sciences, Ilam, Iran; Research Committee, School of Medicine, Ilam University of Medical Sciences, Ilam, Iran; Department of Medical Immunology, School of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Nahid Maspi
- Department of Parasitology, School of Paramedicine, Ilam University of Medical Sciences, Ilam, Iran; Zoonotic Diseases Research Center, Ilam University of Medical Sciences, Ilam, Iran.
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15
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Poudel B, Yorek MS, Mazgaeen L, Brown SA, Kanneganti TD, Gurung P. Acute IL-4 Governs Pathogenic T Cell Responses during Leishmania major Infection. Immunohorizons 2020; 4:546-560. [PMID: 32948646 PMCID: PMC7640617 DOI: 10.4049/immunohorizons.2000076] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 09/01/2020] [Indexed: 11/19/2022] Open
Abstract
Leishmania spp. infection is a global health problem affecting more than 2 million people every year with 300 million at risk worldwide. It is well established that a dominant Th1 response (IFN-γ, a hallmark Th1 cytokine) provides resistance, whereas a dominant Th2 response (IL-4, a hallmark Th2 cytokine) confers susceptibility during infection. Given the important role of IL-4 during L. major infection, we used IL-4-neutralizing Abs to investigate the cellular and molecular events regulated by IL-4 signaling. As previously published, neutralization of IL-4 in L. major-infected BALB/c mice (a Leishmania susceptible strain) provided protection when compared with control L. major-infected BALB/c mice. Despite this protection, IFN-γ production by T cells was dramatically reduced. Temporal neutralization of IL-4 revealed that acute IL-4 produced within the first days of infection is critical for not only programming IL-4-producing Th2 CD4+ T cells, but for promoting IFN-γ produced by CD8+ T cells. Mechanistically, IL-4 signaling enhances anti-CD3-induced Tbet and IFN-γ expression in both CD4+ and CD8+ T cells. Given the pathogenic role of IFN-γ-producing CD8+ T cells, our data suggest that IL-4 promotes cutaneous leishmaniasis pathology by not only promoting Th2 immune responses but also pathogenic CD8+ T cell responses. Our studies open new research grounds to investigate the unsuspected role of IL-4 in regulating both Th1 and Th2 responses.
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Affiliation(s)
- Barun Poudel
- Iowa Inflammation Program, University of Iowa, Iowa City, IA 52242.,Department of Internal Medicine, University of Iowa, Iowa City, IA 52242
| | - Matthew S Yorek
- Iowa Inflammation Program, University of Iowa, Iowa City, IA 52242.,Department of Internal Medicine, University of Iowa, Iowa City, IA 52242
| | - Lalita Mazgaeen
- Iowa Inflammation Program, University of Iowa, Iowa City, IA 52242.,Department of Internal Medicine, University of Iowa, Iowa City, IA 52242.,Interdisciplinary Graduate Program in Human Toxicology, University of Iowa, Iowa City, IA 52242
| | - Scott A Brown
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105
| | | | - Prajwal Gurung
- Iowa Inflammation Program, University of Iowa, Iowa City, IA 52242; .,Department of Internal Medicine, University of Iowa, Iowa City, IA 52242.,Interdisciplinary Graduate Program in Human Toxicology, University of Iowa, Iowa City, IA 52242.,Immunology Graduate Program, University of Iowa, Iowa City, IA 52242; and.,Center for Immunology and Immune Based Disease, University of Iowa, Iowa City, IA 52242
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16
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In Vitro Modulator Effect of Total Extract from the Endophytic Paenibacillus polymyxa RNC-D in Leishmania (Leishmania) amazonensis and Macrophages. Int J Microbiol 2020; 2020:8895308. [PMID: 32908533 PMCID: PMC7474380 DOI: 10.1155/2020/8895308] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 07/22/2020] [Accepted: 08/05/2020] [Indexed: 01/07/2023] Open
Abstract
Leishmaniases are diseases with high epidemiological relevance and wide geographical distribution. In Brazil, Leishmania (Leishmania) amazonensis is related to the tegumentary form of leishmaniasis. The treatment for those diseases is problematic as the available drugs promote adverse effects in patients. Therefore, it is important to find new therapeutic targets. In this regard, one alternative is the study of biomolecules produced by endophytic microorganisms. In this study, the total extract produced by the endophytic Paenibacillus polymyxa RNC-D was used to evaluate the leishmanicidal, nitric oxide, and cytokines production using RAW 264.7 macrophages. The results showed that, in the leishmanicidal assay with L. amazonensis, EC50 values at the periods of 24 and 48 hours were 0.624 mg/mL and 0.547 mg/mL, respectively. Furthermore, the cells treated with the extract presented approximately 25% of infected cells with an average of 3 amastigotes/cell in the periods of 24 and 48 hours. Regarding the production of cytokines in RAW 264.7 macrophages infected/treated with the extract, a significant increase in TNF-α was observed at the periods of 24 and 48 hours in the treated cells. The concentrations of IFN-γ and IL-12 showed significant increase in 48 hours. A significant decrease in IL-4 was observed in all cells treated with the extract in 24 hours. It was observed in the treated cells that the NO production by RAW 264.7 macrophages increased between 48 and 72 hours. The endophytic Paenibacillus polymyxa RNC-D extract modulates the mediators of inflammation produced by RAW 264.7 macrophages promoting L. amazonensis death. The immunomodulatory effects might be a promising target to develop new immunotherapeutic and antileishmanial drugs.
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A Laboratory Strain of Leishmania major: Protective Effects on Experimental Leishmaniasis. Acta Parasitol 2019; 64:645-651. [PMID: 31111360 DOI: 10.2478/s11686-019-00068-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Accepted: 05/06/2019] [Indexed: 11/20/2022]
Abstract
PURPOSE Leishmaniasis, as one of the most important vector-borne and zoonotic diseases, can be seen in different forms and is more prevalent in developing countries worldwide. Due to the absence of effective strategies in its prevention, treatment, and control, investigation of effective control strategies against the disease is necessary. In this research, we evaluated the immunogenicity of a cold-adapted laboratory strain of Leishmania major (LMC) in the mouse model. METHODS Twenty BALB/c mice were divided into two groups. LMC group received 4 × 106 of LMC strain in 0.5 ml DMEM, and VLM group, as the control group, received 0.5 ml Dulbecco's modified Eagle's medium. Both groups were challenged with virulent L. major 3 weeks after inoculation. RESULTS The data obtained from the analysis of immune responses and histopathological changes interestingly revealed protection against L. major in immunized mice. Compared with the VLM group, the mice immunized with LMC strain of L. major in the LMC group showed a significant increase in IFN-γ and IgG2a levels (P < 0.05) which are important indexes for Th1-related immune responses. Additionally, significant differences in concentration of IgG1 and IgG total before and after the challenge was observed in LMC group (P < 0.05). Furthermore, the immunized mice showed a significant reduction in mean sizes of skin lesion and liver damage compared to the VLM group. CONCLUSION Based on the present findings on immunogenicity of LMC strain, it seems this strain is able to induce both humoral and cellular immunity and a significant protection against L. major in the mouse model.
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18
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Hu C, Zhao L, Li L. Current understanding of adipose-derived mesenchymal stem cell-based therapies in liver diseases. Stem Cell Res Ther 2019; 10:199. [PMID: 31287024 PMCID: PMC6613269 DOI: 10.1186/s13287-019-1310-1] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The liver, the largest organ with multiple synthetic and secretory functions in mammals, consists of hepatocytes, cholangiocytes, hepatic stellate cells (HSCs), sinusoidal endothelial cells, Kupffer cells (KCs), and immune cells, among others. Various causative factors, including viral infection, toxins, autoimmune defects, and genetic disorders, can impair liver function and result in chronic liver disease or acute liver failure. Mesenchymal stem cells (MSCs) from various tissues have emerged as a potential candidate for cell transplantation to promote liver regeneration. Adipose-derived MSCs (ADMSCs) with high multi-lineage potential and self-renewal capacity have attracted great attention as a promising means of liver regeneration. The abundance source and minimally invasive procedure required to obtain ADMSCs makes them superior to bone marrow-derived MSCs (BMMSCs). In this review, we comprehensively analyze landmark studies that address the isolation, proliferation, and hepatogenic differentiation of ADMSCs and summarize the therapeutic effects of ADMSCs in animal models of liver diseases. We also discuss key points related to improving the hepatic differentiation of ADMSCs via exposure of the cells to cytokines and growth factors (GFs), extracellular matrix (ECM), and various physical parameters in in vitro culture. The optimization of culturing methods and of the transplantation route will contribute to the further application of ADMSCs in liver regeneration and help improve the survival rate of patients with liver diseases. To this end, ADMSCs provide a potential strategy in the field of liver regeneration for treating acute or chronic liver injury, thus ensuring the availability of ADMSCs for research, trial, and clinical applications in various liver diseases in the future.
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Affiliation(s)
- Chenxia Hu
- 0000 0004 1759 700Xgrid.13402.34Kidney Disease Center, First Affiliated Hospital, College of Medicine, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang People’s Republic of China
| | - Lingfei Zhao
- 0000 0004 1759 700Xgrid.13402.34Kidney Disease Center, First Affiliated Hospital, College of Medicine, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang People’s Republic of China
| | - Lanjuan Li
- 0000 0004 1759 700Xgrid.13402.34Kidney Disease Center, First Affiliated Hospital, College of Medicine, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang People’s Republic of China
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19
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Bretscher P. On Analyzing How the Th1/Th2 Phenotype of an Immune Response Is Determined: Classical Observations Must Not Be Ignored. Front Immunol 2019; 10:1234. [PMID: 31231378 PMCID: PMC6560152 DOI: 10.3389/fimmu.2019.01234] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Accepted: 05/15/2019] [Indexed: 12/18/2022] Open
Abstract
How an antigen interacts differently with lymphocytes and other cells of the immune system, to result in the generation of distinct classes of immunity, is one of the most basic questions of immune regulation. Understanding the nature of these "decision criteria" is central to developing effective medical interventions. Clinical observations lead to the recognition that much disease is due to an inappropriate class of immunity being generated, inappropriate because damaging, as in autoimmunity and allergies, or inappropriate because ineffective, against pathogens and cancer. I argue that the prevalent, contemporary conceptual frameworks, employed to analyze the nature of the decision criterion controlling the Th1/Th2 phenotype of the immune response, are implausible, as they ignore pertinent, classical observations. I outline reasons for favoring a different framework, that takes these observations into account, and explore its pertinence to the design of strategies of medical intervention.
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Affiliation(s)
- Peter Bretscher
- Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK, Canada
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20
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Abdossamadi Z, Taheri T, Seyed N, Montakhab-Yeganeh H, Zahedifard F, Taslimi Y, Habibzadeh S, Gholami E, Gharibzadeh S, Rafati S. Live Leishmania tarentolae secreting HNP1 as an immunotherapeutic tool against Leishmania infection in BALB/c mice. Immunotherapy 2018; 9:1089-1102. [PMID: 29032739 DOI: 10.2217/imt-2017-0076] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
AIM Several disadvantages about chemotherapy for leishmaniasis has reinforced discovery of novel therapeutic agents especially immunotherapeutics. HNP1, as a member of the mammalian antimicrobial peptides family, is an attractive molecule due to its broad functional spectrum. Here, the in vivo potency of HNP1 in transgenic Leishmania tarentolae as an immunotherapy tool against Leishmania major-infected BALB/c mice was examined. METHODS & RESULTS 3 weeks after infection with L. major, the treatment effect of L. tarentolae-HNP1-EGFP was pursued. The results were promising in respect to parasite load control and Th1 immune response polarization compared with controls. CONCLUSION Immunotherapy by live L. tarentolae secreting HNP1 can elicit cellular immune response in a susceptible mouse model in order to control L. major infection.
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Affiliation(s)
- Zahra Abdossamadi
- Department of Immunotherapy & Leishmania Vaccine Research, Pasteur Institute of Iran, Tehran, Iran, 13194
| | - Tahereh Taheri
- Department of Immunotherapy & Leishmania Vaccine Research, Pasteur Institute of Iran, Tehran, Iran, 13194
| | - Negar Seyed
- Department of Immunotherapy & Leishmania Vaccine Research, Pasteur Institute of Iran, Tehran, Iran, 13194
| | - Hossein Montakhab-Yeganeh
- Department of Immunotherapy & Leishmania Vaccine Research, Pasteur Institute of Iran, Tehran, Iran, 13194
| | - Farnaz Zahedifard
- Department of Immunotherapy & Leishmania Vaccine Research, Pasteur Institute of Iran, Tehran, Iran, 13194
| | - Yasaman Taslimi
- Department of Immunotherapy & Leishmania Vaccine Research, Pasteur Institute of Iran, Tehran, Iran, 13194
| | - Sima Habibzadeh
- Department of Immunotherapy & Leishmania Vaccine Research, Pasteur Institute of Iran, Tehran, Iran, 13194
| | - Elham Gholami
- Department of Immunotherapy & Leishmania Vaccine Research, Pasteur Institute of Iran, Tehran, Iran, 13194
| | - Safoora Gharibzadeh
- Department of Epidemiology & Biostatistics, Pasteur institute of Iran, Tehran, Iran
| | - Sima Rafati
- Department of Immunotherapy & Leishmania Vaccine Research, Pasteur Institute of Iran, Tehran, Iran, 13194
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Zimara N, Chanyalew M, Aseffa A, van Zandbergen G, Lepenies B, Schmid M, Weiss R, Rascle A, Wege AK, Jantsch J, Schatz V, Brown GD, Ritter U. Dectin-1 Positive Dendritic Cells Expand after Infection with Leishmania major Parasites and Represent Promising Targets for Vaccine Development. Front Immunol 2018; 9:263. [PMID: 29535708 PMCID: PMC5834765 DOI: 10.3389/fimmu.2018.00263] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Accepted: 01/30/2018] [Indexed: 12/31/2022] Open
Abstract
Resistant mouse strains mount a protective T cell-mediated immune response upon infection with Leishmania (L.) parasites. Healing correlates with a T helper (Th) cell-type 1 response characterized by a pronounced IFN-γ production, while susceptibility is associated with an IL-4-dependent Th2-type response. It has been shown that dermal dendritic cells are crucial for inducing protective Th1-mediated immunity. Additionally, there is growing evidence that C-type lectin receptor (CLR)-mediated signaling is involved in directing adaptive immunity against pathogens. However, little is known about the function of the CLR Dectin-1 in modulating Th1- or Th2-type immune responses by DC subsets in leishmaniasis. We characterized the expression of Dectin-1 on CD11c+ DCs in peripheral blood, at the site of infection, and skin-draining lymph nodes of L. major-infected C57BL/6 and BALB/c mice and in peripheral blood of patients suffering from cutaneous leishmaniasis (CL). Both mouse strains responded with an expansion of Dectin-1+ DCs within the analyzed tissues. In accordance with the experimental model, Dectin-1+ DCs expanded as well in the peripheral blood of CL patients. To study the role of Dectin-1+ DCs in adaptive immunity against L. major, we analyzed the T cell stimulating potential of bone marrow-derived dendritic cells (BMDCs) in the presence of the Dectin-1 agonist Curdlan. These experiments revealed that Curdlan induces the maturation of BMDCs and the expansion of Leishmania-specific CD4+ T cells. Based on these findings, we evaluated the impact of Curdlan/Dectin-1 interactions in experimental leishmaniasis and were able to demonstrate that the presence of Curdlan at the site of infection modulates the course of disease in BALB/c mice: wild-type BALB/c mice treated intradermally with Curdlan developed a protective immune response against L. major whereas Dectin-1-/- BALB/c mice still developed the fatal course of disease after Curdlan treatment. Furthermore, the vaccination of BALB/c mice with a combination of soluble L. major antigens and Curdlan was able to provide a partial protection from severe leishmaniasis. These findings indicate that the ligation of Dectin-1 on DCs acts as an important checkpoint in adaptive immunity against L. major and should therefore be considered in future whole-organism vaccination strategies.
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Affiliation(s)
- Nicole Zimara
- Regensburg Center for Interventional Immunology (RCI), Institute of Immunology, University Medical Center Regensburg, University of Regensburg, Regensburg, Germany
| | - Menberework Chanyalew
- Armauer Hansen Research Institute, Leishmaniasis Research Laboratory, Addis Ababa, Ethiopia
| | - Abraham Aseffa
- Armauer Hansen Research Institute, Leishmaniasis Research Laboratory, Addis Ababa, Ethiopia
| | - Ger van Zandbergen
- Federal Institute for Vaccines and Biomedicines, Division of Immunology, Paul Ehrlich Institute, Langen, Germany
| | - Bernd Lepenies
- University of Veterinary Medicine Hannover, Immunology Unit, Research Center for Emerging Infections and Zoonoses (RIZ), Hannover, Germany
| | - Maximilian Schmid
- Department of Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Regensburg, Germany
| | - Richard Weiss
- Department of Molecular Biology, Division of Allergy and Immunology, University of Salzburg, Salzburg, Austria
| | - Anne Rascle
- Regensburg Center for Interventional Immunology (RCI), Institute of Immunology, University Medical Center Regensburg, University of Regensburg, Regensburg, Germany
| | - Anja Kathrin Wege
- Department of Gynecology and Obstetrics, University Medical Center Regensburg, Regensburg, Germany
| | - Jonathan Jantsch
- Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg, University of Regensburg, Regensburg, Germany
| | - Valentin Schatz
- Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg, University of Regensburg, Regensburg, Germany
| | - Gordon D. Brown
- MRC Centre for Medical Mycology, University of Aberdeen, Aberdeen, United Kingdom
| | - Uwe Ritter
- Regensburg Center for Interventional Immunology (RCI), Institute of Immunology, University Medical Center Regensburg, University of Regensburg, Regensburg, Germany
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Chauhan P, Shukla D, Chattopadhyay D, Saha B. Redundant and regulatory roles for Toll-like receptors in Leishmania infection. Clin Exp Immunol 2017; 190:167-186. [PMID: 28708252 PMCID: PMC5629438 DOI: 10.1111/cei.13014] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/13/2017] [Indexed: 01/07/2023] Open
Abstract
Toll-like receptors (TLRs) are germline-encoded, non-clonal innate immune receptors, which are often the first receptors to recognize the molecular patterns on pathogens. Therefore, the immune response initiated by TLRs has far-reaching consequences on the outcome of an infection. As soon as the cell surface TLRs and other receptors recognize a pathogen, the pathogen is phagocytosed. Inclusion of TLRs in the phagosome results in quicker phagosomal maturation and stronger adaptive immune response, as TLRs influence co-stimulatory molecule expression and determinant selection by major histocompatibility complex (MHC) class II and MHC class I for cross-presentation. The signals delivered by the TCR-peptide-MHC complex and co-stimulatory molecules are indispensable for optimal T cell activation. In addition, the cytokines induced by TLRs can skew the differentiation of activated T cells to different effector T cell subsets. However, the potential of TLRs to influence adaptive immune response into different patterns is severely restricted by multiple factors: gross specificity for the molecular patterns, lack of receptor rearrangements, sharing of limited number of adaptors that assemble signalling complexes and redundancy in ligand recognition. These features of apparent redundancy and regulation in the functioning of TLRs characterize them as important and probable contributory factors in the resistance or susceptibility to an infection.
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Affiliation(s)
- P. Chauhan
- Pathogenesis and Cellular Response Division, National Centre for Cell ScienceGaneshkhind, PuneIndia
| | - D. Shukla
- Pathogenesis and Cellular Response Division, National Centre for Cell ScienceGaneshkhind, PuneIndia
| | | | - B. Saha
- National Institute of Traditional MedicineBelagaviIndia
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23
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Khadem F, Jia P, Mou Z, Feiz Barazandeh A, Liu D, Keynan Y, Uzonna JE. Pharmacological inhibition of p110δ subunit of PI3K confers protection against experimental leishmaniasis. J Antimicrob Chemother 2016; 72:467-477. [DOI: 10.1093/jac/dkw448] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Revised: 09/15/2016] [Accepted: 09/22/2016] [Indexed: 01/17/2023] Open
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Abstract
Leishmaniasis is a vector-borne infectious disease caused by multiple Leishmania (L.) species with diverse clinical manifestations. There is currently no vaccine against any form of the disease approved in humans, and chemotherapy is the sole approach for treatment. Unfortunately, treatment options are limited to a small number of drugs, partly due to high cost and significant adverse effects. The other obstacle in leishmaniasis treatment is the potential for drug resistance, which has been observed in multiple endemic countries. Immunotherapy maybe another important avenue for controlling leishmaniasis and could help patients control the disease. There are different approaches for immunotherapy in different infectious diseases, generally with low-cost, limited side-effects and no possibility to developing resistance. In this paper, different immunotherapy approaches as alternatives to routine drug treatment will be reviewed against leishmaniasis.
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25
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Miahipour A, Haji-Fatahaliha M, Keshavarz H, Gharavi MJ, Mohamadi H, Babaloo Z, Rafati S, Younesi V, Hosseini M, Yousefi M. T Helper 1 (Th1), Th2, and Th17 Responses to Leishmania major Lipophosphoglycan 3. Immunol Invest 2016; 45:692-702. [PMID: 27611455 DOI: 10.1080/08820139.2016.1208217] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Leishmania major is the main causal agent of cutaneous leishmaniasis (CL) that remains a serious public health concern in many tropical and subtropical countries. A long-lasting protective vaccine against leishmaniasis remains as a medical unmet need. Lipophosphoglycan 3 (LPG3) is one of the class II LPG genes from HSP90 family involved in the host immune responses. The aim of the present study is to investigate the capability of recombinant LPG3 (rLPG3) to induce Th1, Th2, Th17 responses. The results showed that rLPG3 in moderate and high concentrations significantly induced expression of Th1 lineage-specific transcription factor (T-bet) and cytokine (IFN-γ)(P < 0.05). Moreover, the Th1-stimulating effect of rLPG3 was confirmed by significant induction of IFN-γ secretion from treated T cells (P < 0.01). However, no significant effect of rLPG3 on Th2 and Th17 lineage cells was observed even in high concentration. Our findings demonstrate that rLPG3 induces Th1, but not Th2 and Th17, lineage responses. Further studies are needed to investigate adjuvant properties of rLPG3 for leishmania therapy.
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Affiliation(s)
- Abolfazl Miahipour
- a Department of Medical Parasitology and Mycology , School of Medicine, Alborz University of Medical Sciences , Karaj , Iran
| | - Mostafa Haji-Fatahaliha
- b Drug Applied Research Center , Tabriz University of Medical Sciences , Tabriz , Iran
- c Immunology Research Center , Tabriz University of Medical Sciences , Tabriz , Iran
- d Department of Immunology, Faculty of Medicine , Tabriz University of Medical Sciences , Tabriz , Iran
| | - Hossein Keshavarz
- e Department of Medical Parasitology and Mycology, School of Public Health , Tehran University of Medical Sciences , Tehran , Iran
- f Center for Research of Endemic Parasites of Iran (CREPI) , Tehran University of Medical Sciences , Tehran , Iran
| | - Mohammad Javad Gharavi
- a Department of Medical Parasitology and Mycology , School of Medicine, Alborz University of Medical Sciences , Karaj , Iran
| | - Hamed Mohamadi
- b Drug Applied Research Center , Tabriz University of Medical Sciences , Tabriz , Iran
- c Immunology Research Center , Tabriz University of Medical Sciences , Tabriz , Iran
- d Department of Immunology, Faculty of Medicine , Tabriz University of Medical Sciences , Tabriz , Iran
| | - Zohre Babaloo
- b Drug Applied Research Center , Tabriz University of Medical Sciences , Tabriz , Iran
- c Immunology Research Center , Tabriz University of Medical Sciences , Tabriz , Iran
- d Department of Immunology, Faculty of Medicine , Tabriz University of Medical Sciences , Tabriz , Iran
| | - Sima Rafati
- g Molecular Immunology and Vaccine Research Lab , Pasteur Institute of Iran , Tehran , Iran
| | - Vahid Younesi
- a Department of Medical Parasitology and Mycology , School of Medicine, Alborz University of Medical Sciences , Karaj , Iran
| | - Maryam Hosseini
- b Drug Applied Research Center , Tabriz University of Medical Sciences , Tabriz , Iran
- c Immunology Research Center , Tabriz University of Medical Sciences , Tabriz , Iran
- d Department of Immunology, Faculty of Medicine , Tabriz University of Medical Sciences , Tabriz , Iran
| | - Mehdi Yousefi
- b Drug Applied Research Center , Tabriz University of Medical Sciences , Tabriz , Iran
- c Immunology Research Center , Tabriz University of Medical Sciences , Tabriz , Iran
- d Department of Immunology, Faculty of Medicine , Tabriz University of Medical Sciences , Tabriz , Iran
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26
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Maspi N, Abdoli A, Ghaffarifar F. Pro- and anti-inflammatory cytokines in cutaneous leishmaniasis: a review. Pathog Glob Health 2016; 110:247-260. [PMID: 27660895 DOI: 10.1080/20477724.2016.1232042] [Citation(s) in RCA: 153] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Cutaneous leishmaniasis (CL) is caused by different species of the genus Leishmania. Pro- and anti-inflammatory cytokines play different roles in resistance/susceptibility and the immunopathogenesis of Leishmania infection. The balance and dynamic changes in cytokines may control or predict clinical outcome. T helper 1 (Th1) inflammatory cytokines (especially interferon-γ, tumor necrosis factor-α and interleukin-12) are the crucial factors in the initiation of protective immunity against L. major infection, whereas T helper 2 cytokines including IL-5, IL-4, and IL-13 facilitate the persistence of parasites by downregulating the Th1 immune response. On the other hand, aggravation of inflammatory reactions leads to collateral tissue damage and formation of ulcer. For this reason, immunity system such as T regulatory cells produce regulatory cytokines such as transforming growth factor-β and IL-10 to inhibit possible injures caused by increased inflammatory responses in infection site. In this article, we review the role of pro- and anti-inflammatory cytokines in the immunoprotection and immunopathology of CL.
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Affiliation(s)
- Nahid Maspi
- a Faculty of Medical Sciences, Department of Parasitology , Tarbiat Modares University , Tehran , Iran
| | - Amir Abdoli
- a Faculty of Medical Sciences, Department of Parasitology , Tarbiat Modares University , Tehran , Iran
| | - Fathemeh Ghaffarifar
- a Faculty of Medical Sciences, Department of Parasitology , Tarbiat Modares University , Tehran , Iran
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Abstract
Cutaneous leishmaniasis is a major public health problem and causes a range of diseases from self-healing infections to chronic disfiguring disease. Currently, there is no vaccine for leishmaniasis, and drug therapy is often ineffective. Since the discovery of CD4(+) T helper 1 (TH1) cells and TH2 cells 30 years ago, studies of cutaneous leishmaniasis in mice have answered basic immunological questions concerning the development and maintenance of CD4(+) T cell subsets. However, new strategies for controlling the human disease have not been forthcoming. Nevertheless, advances in our knowledge of the cells that participate in protection against Leishmania infection and the cells that mediate increased pathology have highlighted new approaches for vaccine development and immunotherapy. In this Review, we discuss the early events associated with infection, the CD4(+) T cells that mediate protective immunity and the pathological role that CD8(+) T cells can have in cutaneous leishmaniasis.
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28
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Fromm PD, Kling JC, Remke A, Bogdan C, Körner H. Fatal Leishmaniasis in the Absence of TNF Despite a Strong Th1 Response. Front Microbiol 2016; 6:1520. [PMID: 26834705 PMCID: PMC4722107 DOI: 10.3389/fmicb.2015.01520] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Accepted: 12/17/2015] [Indexed: 01/28/2023] Open
Abstract
Induction of inducible nitric oxide synthase in mononuclear phagocytes by IFN-γ and innate tumor necrosis factor (TNF) provide the basis for an effective immune response to the intracellular parasite Leishmania (L.) major. In previous experiments, we observed a fatal visceral form of leishmaniasis in L. major-infected C57BL/6 TNF-/- mice. To further delineate the protective function of TNF and its receptor requirements, we comparatively assessed L. major-infected C57BL/6 mice that were either deficient for membrane and soluble TNF (Tnf-/-), for soluble TNF alone (memTnfΔ/Δ), or the TNF receptors type 1 (Tnfr1-/-) or type 2 (Tnfr2-/-). We detected locally and systemically increased levels of the cytokine IFN-γ in the absence of the TNF-TNFR1-signaling pathway. An analysis of transcription factors and cytokines revealed that activated Tnf-/- CD4+ T cells displayed a highly active Th1 phenotype with a strong usage of the T cell receptor Vβ5.1/2. From these data we conclude that the fatal outcome of L. major infection in Tnf-/- mice does not result from a skewed or deficient Th1 differentiation.
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Affiliation(s)
- Phillip D Fromm
- Comparative Genomics Centre, James Cook University, Townsville QN, Australia
| | - Jessica C Kling
- Menzies Institute for Medical Research Tasmania, HobartTAS, Australia; Blumenthal Group, The University of Queensland Diamantina Institute, Translational Research Institute, WoolloongabbaQLD, Australia
| | - Annika Remke
- Menzies Institute for Medical Research Tasmania, Hobart TAS, Australia
| | - Christian Bogdan
- Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Friederich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen Erlangen, Germany
| | - Heinrich Körner
- Menzies Institute for Medical Research Tasmania, Hobart TAS, Australia
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29
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Carneiro MBH, Lopes MEDM, Vaz LG, Sousa LMA, dos Santos LM, de Souza CC, Campos ACDA, Gomes DA, Gonçalves R, Tafuri WL, Vieira LQ. IFN-γ-Dependent Recruitment of CD4(+) T Cells and Macrophages Contributes to Pathogenesis During Leishmania amazonensis Infection. J Interferon Cytokine Res 2015; 35:935-47. [PMID: 26401717 PMCID: PMC4683564 DOI: 10.1089/jir.2015.0043] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Accepted: 06/09/2015] [Indexed: 12/21/2022] Open
Abstract
Interferon gamma (IFN-γ) is a key factor in the protection of hosts against intracellular parasites. This cytokine induces parasite killing through nitric oxide and reactive oxygen species production by phagocytes. Surprisingly, during Leishmania amazonensis infection, IFN-γ plays controversial roles. During in vitro infections, IFN-γ induces the proliferation of the amastigote forms of L. amazonensis. However, this cytokine is not essential at the beginning of an in vivo infection. It is not clear why IFN-γ does not mediate protection during the early stages of infection. Thus, the aim of our study was to investigate the role of IFN-γ during L. amazonensis infection. We infected IFN-γ(-/-) mice in the footpad and followed the development of leishmaniasis in these mice compared with that in WT mice. CD4(+) T lymphocytes and macrophages migrated earlier to the site of infection in the WT mice, and the earlier migration of these 2 cell types was associated with lesion development and parasite growth, respectively. These differences in the infiltrate populations were explained by the increased expression of chemokines in the lesions of the WT mice. Thus, we propose that IFN-γ plays a dual role during L. amazonensis infection; it is an important inducer of effector mechanisms, particularly through inducible nitric oxide synthase expression, and conversely, it is a mediator of inflammation and pathogenesis through the induction of the expression of chemokines. Our data provided evidence for a pathogenic effect of IFN-γ production during leishmaniasis that was previously unknown.
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Affiliation(s)
- Matheus Batista Heitor Carneiro
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Mateus Eustáquio de Moura Lopes
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Leonardo Gomes Vaz
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Louisa Maria Andrade Sousa
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Liliane Martins dos Santos
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Carolina Carvalho de Souza
- Departamento de Patologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Ana Carolina de Angelis Campos
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Dawidson Assis Gomes
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Ricardo Gonçalves
- Departamento de Patologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Wagner Luiz Tafuri
- Departamento de Patologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Leda Quercia Vieira
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
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30
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Al-Qadhi BN, Musa IS, Al-Mulla Hummadi YMK. Comparative immune study on cutaneous leishmaniasis patients with single and multiple sores. J Parasit Dis 2015; 39:361-70. [PMID: 26345036 PMCID: PMC4554559 DOI: 10.1007/s12639-013-0368-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2013] [Accepted: 10/18/2013] [Indexed: 11/26/2022] Open
Abstract
Ninety-five Iraqi patients with cutaneous leishmaniasis (CL) caused by Leishmania tropica at AL-Karama Hospital in Baghdad were included in this study. Sixty patients were with single sore and the remaining with multiple sores. The study also included 10 atopic patients and 30 healthy individuals as a control group. Cellular and humoral immune response at different stages of the disease activity (early and late) were evaluated by estimation of serum IFN-γ, IL-4 and total IgE antibodies using ELISA kits while, the detection of specific anti leishmanial IgE antibodies was done manually. Specific IgE antibodies were only detected in early CL (<2 months) patients 68 (71.57 %) while, were not detected in late CL, atopic and healthy controls 30 (100 %). The results also showed a positive relationship between this antibody and the number of sores. Th-2 predominates during the early stage of the disease then shifts to Th-1 that proceed in the late stage, but both cytokines increased in CL patients in comparison to control group. The immune response of CL infection is possibly regulated by both Th-1 and Th-2. Multiple sores patients showed an increase of anti leishmanial IgE (0.120 ± 0.014), total IgE (120.7 ± 39.58 IU/ml), IFN-γ (87.4 ± 30.52 pg/ml) and IL-4 (63.70 ± 20.32 pg/ml) levels than single sore patients with mean value of 0.108 ± 0.14, 92.3 ± 35.23 IU/ml, 47.2 ± 27.80 pg/ml and 51.04 ± 15.0 pg/ml respectively. It can be presented also as ratio of INF-γ/IL-4 = 1.37 which is greater than those for single sore 0.9. These results indicated that the immune response of multiple sores patient's is higher than that with single sores.
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Affiliation(s)
- Ban Noori Al-Qadhi
- Biology Department, College of Science, University of Baghdad, Baghdad, Iraq
| | - Israa Salim Musa
- Biology Department, College of Science, University of Baghdad, Baghdad, Iraq
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31
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Novais FO, Scott P. CD8+ T cells in cutaneous leishmaniasis: the good, the bad, and the ugly. Semin Immunopathol 2015; 37:251-9. [PMID: 25800274 DOI: 10.1007/s00281-015-0475-7] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2015] [Accepted: 02/25/2015] [Indexed: 11/30/2022]
Abstract
CD8(+) T lymphocytes are components of the adaptive immune response and play an important role in protection against many viral and bacterial infections. However, their role in parasitic infections is less well understood. In leishmaniasis, a disease caused by intracellular protozoan parasites of the genus Leishmania, CD8(+) T cells have been shown to be protective. However, increasing evidence indicates that CD8(+) T cells may also exacerbate disease. In this review, we will describe the situations where CD8(+) T cells are either good or bad for the outcome of the infection and attempt to reconcile the dual role played by CD8(+) T cells in cutaneous leishmaniasis.
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Affiliation(s)
- Fernanda O Novais
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Room 346 Hill Pavilion, 380 S. University Avenue, Philadelphia, PA, 19104-4539, USA,
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32
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Maekawa Y, Ishifune C, Tsukumo SI, Hozumi K, Yagita H, Yasutomo K. Notch controls the survival of memory CD4+ T cells by regulating glucose uptake. Nat Med 2014; 21:55-61. [PMID: 25501905 DOI: 10.1038/nm.3758] [Citation(s) in RCA: 112] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Accepted: 10/21/2014] [Indexed: 12/14/2022]
Abstract
CD4+ T cells differentiate into memory T cells that protect the host from subsequent infection. In contrast, autoreactive memory CD4+ T cells harm the body by persisting in the tissues. The underlying pathways controlling the maintenance of memory CD4+ T cells remain undefined. We show here that memory CD4+ T cell survival is impaired in the absence of the Notch signaling protein known as recombination signal binding protein for immunoglobulin κ J region (Rbpj). Treatment of mice with a Notch inhibitor reduced memory CD4+ T cell numbers and prevented the recurrent induction of experimental autoimmune encephalomyelitis. Rbpj-deficient CD4+ memory T cells exhibit reduced glucose uptake due to impaired AKT phosphorylation, resulting in low Glut1 expression. Treating mice with pyruvic acid, which bypasses glucose uptake and supplies the metabolite downstream of glucose uptake, inhibited the decrease of autoimmune memory CD4+ T cells in the absence of Notch signaling, suggesting memory CD4+ T cell survival relies on glucose metabolism. Together, these data define a central role for Notch signaling in maintaining memory CD4+ T cells through the regulation of glucose uptake.
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Affiliation(s)
- Yoichi Maekawa
- Department of Immunology and Parasitology, Graduate School of Medicine, Tokushima University, Tokushima, Japan
| | - Chieko Ishifune
- Department of Immunology and Parasitology, Graduate School of Medicine, Tokushima University, Tokushima, Japan
| | - Shin-ichi Tsukumo
- Department of Immunology and Parasitology, Graduate School of Medicine, Tokushima University, Tokushima, Japan
| | - Katsuto Hozumi
- Department of Immunology and Research Center for Embryogenesis and Organogenesis, Tokai University School of Medicine, Kanagawa, Japan
| | - Hideo Yagita
- Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan
| | - Koji Yasutomo
- Department of Immunology and Parasitology, Graduate School of Medicine, Tokushima University, Tokushima, Japan
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33
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Lamour SD, Veselkov KA, Posma JM, Giraud E, Rogers ME, Croft S, Marchesi JR, Holmes E, Seifert K, Saric J. Metabolic, Immune, and Gut Microbial Signals Mount a Systems Response to Leishmania major Infection. J Proteome Res 2014; 14:318-29. [DOI: 10.1021/pr5008202] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Sabrina D. Lamour
- Division
of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, Exhibition Road, London SW7 2AZ, United Kingdom
| | - Kirill A. Veselkov
- Division
of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, Exhibition Road, London SW7 2AZ, United Kingdom
| | - Joram M. Posma
- Division
of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, Exhibition Road, London SW7 2AZ, United Kingdom
| | - Emilie Giraud
- Department of Immunology and Infection, London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, United Kingdom
| | - Matthew E. Rogers
- Department of Disease Control, London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, United Kingdom
| | - Simon Croft
- Department of Immunology and Infection, London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, United Kingdom
| | - Julian R. Marchesi
- Cardiff
School of Biosciences, Division of Microbiology, Cardiff University, Museum Avenue, Cardiff, CF10 3AT, United Kingdom
- Centre
for Digestive and Gut Health, Imperial College London, Exhibition Road, London, SW7 2AZ, United Kingdom
| | - Elaine Holmes
- Division
of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, Exhibition Road, London SW7 2AZ, United Kingdom
| | - Karin Seifert
- Department of Immunology and Infection, London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, United Kingdom
| | - Jasmina Saric
- Division
of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, Exhibition Road, London SW7 2AZ, United Kingdom
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34
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Kedzierski L, Evans KJ. Immune responses during cutaneous and visceral leishmaniasis. Parasitology 2014; 141:1544-1562. [PMID: 25075460 DOI: 10.1017/s003118201400095x] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Leishmania are protozoan parasites spread by a sandfly insect vector and causing a spectrum of diseases collectively known as leishmaniasis. The disease is a significant health problem in many parts of the world, resulting in an estimated 1·3 million new cases and 30 000 deaths annually. Current treatment is based on chemotherapy, which is difficult to administer, expensive and becoming ineffective in several endemic regions. To date there is no vaccine against leishmaniasis, although extensive evidence from studies in animal models indicates that solid protection can be achieved upon immunization. This review focuses on immune responses to Leishmania in both cutaneous and visceral forms of the disease, pointing to the complexity of the immune response and to a range of evasive mechanisms utilized by the parasite to bypass those responses. The amalgam of innate and acquired immunity combined with the paucity of data on the human immune response is one of the major problems currently hampering vaccine development and implementation.
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Affiliation(s)
- Lukasz Kedzierski
- Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Pde, Parkville 3052, Victoria, Australia
- Department of Medical Biology, University of Melbourne, Parkville, Melbourne, Victoria 3010, Australia
| | - Krystal J Evans
- Department of Medical Biology, University of Melbourne, Parkville, Melbourne, Victoria 3010, Australia
- Infection and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Pde, Parkville 3052, Victoria, Australia
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35
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Costa DL, Cardoso TM, Queiroz A, Milanezi CM, Bacellar O, Carvalho EM, Silva JS. Tr-1-like CD4+CD25-CD127-/lowFOXP3- cells are the main source of interleukin 10 in patients with cutaneous leishmaniasis due to Leishmania braziliensis. J Infect Dis 2014; 211:708-18. [PMID: 25139022 DOI: 10.1093/infdis/jiu406] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
CD4(+)CD25(+)FOXP3(+) regulatory T cells have long been shown to mediate susceptibility to Leishmania infection, mainly via interleukin 10 production. In this work, we showed that the main sources of interleukin 10 in peripheral blood mononuclear cells (PBMCs) from patients with cutaneous leishmaniasis due to Leishmania braziliensis are CD4(+)CD25(-)CD127(-/low)FOXP3(-) cells. Compared with uninfected controls, patients with CL had increased frequencies of circulating interleukin 10-producing CD4(+)CD25(-)CD127(-/low) cells, which efficiently suppressed tumor necrosis factor α production by the total PBMC population. Also, in CL lesions, interleukin 10 was mainly produced by CD4(+)CD25(-) cells, and interleukin 10 messenger RNA expression was associated with interleukin 27, interleukin 21, and interferon γ expression, rather than with FOXP3 or transforming growth factor β expressions. Active production of both interleukin 27 and interleukin 21, together with production of interferon γ and interleukin 10, was also detected in the lesions. Since these cytokines are associated with the differentiation and activity of Tr-1 cells, our results suggest that this cell population may play an important role in the immunomodulation of CL. Therefore, development of treatments that interfere with this pathway may lead to faster parasite elimination.
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Affiliation(s)
- Diego L Costa
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto
| | - Tiago M Cardoso
- Immunology Service, University Hospital Professor Edgar Santos, Federal University of Bahia National Institute of Science and Technology in Tropical Diseases (INCT-DT), Salvador, Brazil
| | - Adriano Queiroz
- Immunology Service, University Hospital Professor Edgar Santos, Federal University of Bahia National Institute of Science and Technology in Tropical Diseases (INCT-DT), Salvador, Brazil
| | - Cristiane M Milanezi
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto
| | - Olívia Bacellar
- Immunology Service, University Hospital Professor Edgar Santos, Federal University of Bahia National Institute of Science and Technology in Tropical Diseases (INCT-DT), Salvador, Brazil
| | - Edgar M Carvalho
- Immunology Service, University Hospital Professor Edgar Santos, Federal University of Bahia National Institute of Science and Technology in Tropical Diseases (INCT-DT), Salvador, Brazil
| | - João S Silva
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto
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36
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Juhn YJ. Risks for infection in patients with asthma (or other atopic conditions): is asthma more than a chronic airway disease? J Allergy Clin Immunol 2014; 134:247-57; quiz 258-9. [PMID: 25087224 PMCID: PMC4122981 DOI: 10.1016/j.jaci.2014.04.024] [Citation(s) in RCA: 111] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2014] [Revised: 04/22/2014] [Accepted: 04/22/2014] [Indexed: 12/16/2022]
Abstract
Most of the research effort regarding asthma has been devoted to its causes, therapy, and prognosis. There is also evidence that the presence of asthma can influence patients' susceptibility to infections, yet research in this aspect of asthma has been limited. There is additional debate in this field, with current literature tending to view the increased risk of infection among atopic patients as caused by opportunistic infections secondary to airway inflammation, especially in patients with severe atopic diseases. However, other evidence suggests that such risk and its underlying immune dysfunction might be a phenotypic or clinical feature of atopic conditions. This review argues (1) that improved understanding of the effects of asthma or other atopic conditions on the risk of microbial infections will bring important and new perspectives to clinical practice, research, and public health concerning atopic conditions and (2) that research efforts into the causes and effects of asthma must be juxtaposed because they are likely to guide each other.
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MESH Headings
- Asthma/complications
- Asthma/immunology
- Asthma/pathology
- Bacterial Infections/complications
- Bacterial Infections/immunology
- Bacterial Infections/pathology
- Chronic Disease
- Dermatitis, Atopic/complications
- Dermatitis, Atopic/immunology
- Dermatitis, Atopic/pathology
- Disease Susceptibility
- Humans
- Immunity, Innate
- Mycoses/complications
- Mycoses/immunology
- Mycoses/pathology
- Rhinitis, Allergic, Perennial/complications
- Rhinitis, Allergic, Perennial/immunology
- Rhinitis, Allergic, Perennial/pathology
- Rhinitis, Allergic, Seasonal/complications
- Rhinitis, Allergic, Seasonal/immunology
- Rhinitis, Allergic, Seasonal/pathology
- Risk Factors
- Virus Diseases/complications
- Virus Diseases/immunology
- Virus Diseases/pathology
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Affiliation(s)
- Young J Juhn
- Department of Pediatric and Adolescent Medicine/Internal Medicine/Health Sciences Research, Mayo Clinic, Rochester, Minn.
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37
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Bretscher PA. On the mechanism determining the TH1/TH2 phenotype of an immune response, and its pertinence to strategies for the prevention, and treatment, of certain infectious diseases. Scand J Immunol 2014; 79:361-76. [PMID: 24684592 PMCID: PMC4282429 DOI: 10.1111/sji.12175] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2014] [Accepted: 03/27/2014] [Indexed: 12/31/2022]
Abstract
It is well recognized that the physiological/pathological consequences of an immune response, against a foreign or a self-antigen, are often critically dependent on the class of immunity generated. Here we focus on how antigen interacts with the cells of the immune system to determine whether antigen predominantly generates Th1 or Th2 cells. We refer to this mechanism as the 'decision criterion' controlling the Th1/Th2 phenotype of the immune response. A plausible decision criterion should account for the variables of immunization known to affect the Th1/Th2 phenotype of the ensuing immune response. Documented variables include the nature of the antigen, in terms of its degree of foreignness, the dose of antigen and the time after immunization at which the Th1/Th2 phenotype of the immune response is assessed. These are quantitative variables made at the level of the system. In addition, the route of immunization is also critical. I describe a quantitative hypothesis as to the nature of the decision criterion, referred to as the Threshold Hypothesis. This hypothesis accounts for the quantitative variables of immunization known to affect the Th1/Th2 phenotype of the immune response generated. I suggest and illustrate how this is not true of competing, contemporary hypotheses. I outline studies testing predictions of the hypothesis and illustrate its potential utility in designing strategies to prevent or treat medical situations where a predominant Th1 response is required to contain an infection, such as those caused by HIV-1 and by Mycobacterium tuberculosis, or to contain cancers.
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Affiliation(s)
- P A Bretscher
- University of SaskatchewanSaskatoon, Saskatchewan, Canada
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38
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Koutsoni O, Barhoumi M, Guizani I, Dotsika E. Leishmania eukaryotic initiation factor (LeIF) inhibits parasite growth in murine macrophages. PLoS One 2014; 9:e97319. [PMID: 24830439 PMCID: PMC4022710 DOI: 10.1371/journal.pone.0097319] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Accepted: 04/16/2014] [Indexed: 01/28/2023] Open
Abstract
The leishmaniases constitute neglected global public health problems that require adequate control measures, prophylactic clinical vaccines and effective and non-toxic drug treatments. In this study, we explored the potential of Leishmania infantum eukaryotic initiation factor (LieIF), an exosomal protein, as a novel anti-infective therapeutic molecule. More specifically, we assessed the efficacy of recombinant LieIF, in combination with recombinant IFN-γ, in eliminating intracellular L. donovani parasites in an in vitro macrophage model. J774A.1 macrophages were initially treated with LieIF/IFN-γ prior to in vitro infection with L. donovani stationary phase promastigotes (pre-infection treatment), and resistance to infection was observed 72 h after infection. J774A.1 macrophages were also treated with LieIF/IFN-γ after L. donovani infection (post-infection treatment), and resistance to infection was also observed at both time points tested (19 h and 72 h) after infection. To elucidate the LieIF/IFN-γ-induced mechanism(s) that mediate the reduction of intracellular parasite growth, we examined the generation of potent microbicidal molecules, such as nitric oxide (NO) and reactive oxygen species (ROS), within infected macrophages. Furthermore, macrophages pre-treated with LieIF/IFN-γ showed a clear up-regulation in macrophage inflammatory protein 1α (MIP-1α) as well as tumor necrosis factor alpha (TNF-α) expression. However, significant different protein levels were not detected. In addition, macrophages pre-treated with LieIF/IFN-γ combined with anti-TNF-α monoclonal antibody produced significantly lower amounts of ROS. These data suggest that during the pre-treatment state, LieIF induces intramacrophage parasite growth inhibition through the production of TNF-α, which induces microbicidal activity by stimulating NO and ROS production. The mechanisms of NO and ROS production when macrophages are treated with LieIF after infection are probably different. Overall, these results indicate that LieIF is a good candidate for use as an anti-leishmanial molecule.
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Affiliation(s)
- Olga Koutsoni
- Laboratory of Cellular Immunology, Department of Microbiology, Hellenic Pasteur Institute, Athens, Greece; Department of Microbiology, Medical School of Athens, National and Kapodistrian University, Athens, Greece
| | - Mourad Barhoumi
- Laboratoire d'Epidémiologie Moléculaire et de Pathologie Expérimentale Appliquée aux Maladies Infectieuses/LR11IPT04, Institut Pasteur de Tunis- Université Tunis El Manar, Tunis-Belvédère, Tunisia
| | - Ikram Guizani
- Laboratoire d'Epidémiologie Moléculaire et de Pathologie Expérimentale Appliquée aux Maladies Infectieuses/LR11IPT04, Institut Pasteur de Tunis- Université Tunis El Manar, Tunis-Belvédère, Tunisia
| | - Eleni Dotsika
- Laboratory of Cellular Immunology, Department of Microbiology, Hellenic Pasteur Institute, Athens, Greece
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Deletion of IL-4 receptor alpha on dendritic cells renders BALB/c mice hypersusceptible to Leishmania major infection. PLoS Pathog 2013; 9:e1003699. [PMID: 24204259 PMCID: PMC3812013 DOI: 10.1371/journal.ppat.1003699] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2012] [Accepted: 08/28/2013] [Indexed: 02/05/2023] Open
Abstract
In BALB/c mice, susceptibility to infection with the intracellular parasite Leishmania major is driven largely by the development of T helper 2 (Th2) responses and the production of interleukin (IL)-4 and IL-13, which share a common receptor subunit, the IL-4 receptor alpha chain (IL-4Rα). While IL-4 is the main inducer of Th2 responses, paradoxically, it has been shown that exogenously administered IL-4 can promote dendritic cell (DC) IL-12 production and enhance Th1 development if given early during infection. To further investigate the relevance of biological quantities of IL-4 acting on DCs during in vivo infection, DC specific IL-4Rα deficient (CD11c(cre)IL-4Rα(-/lox)) BALB/c mice were generated by gene targeting and site-specific recombination using the cre/loxP system under control of the cd11c locus. DNA, protein, and functional characterization showed abrogated IL-4Rα expression on dendritic cells and alveolar macrophages in CD11c(cre)IL-4Rα(-/lox) mice. Following infection with L. major, CD11c(cre)IL-4Rα(-/lox) mice became hypersusceptible to disease, presenting earlier and increased footpad swelling, necrosis and parasite burdens, upregulated Th2 cytokine responses and increased type 2 antibody production as well as impaired classical activation of macrophages. Hypersusceptibility in CD11c(cre)IL-4Rα(-/lox) mice was accompanied by a striking increase in parasite burdens in peripheral organs such as the spleen, liver, and even the brain. DCs showed increased parasite loads in CD11c(cre)IL-4Rα(-/lox) mice and reduced iNOS production. IL-4Rα-deficient DCs produced reduced IL-12 but increased IL-10 due to impaired DC instruction, with increased mRNA expression of IL-23p19 and activin A, cytokines previously implicated in promoting Th2 responses. Together, these data demonstrate that abrogation of IL-4Rα signaling on DCs is severely detrimental to the host, leading to rapid disease progression, and increased survival of parasites in infected DCs due to reduced killing effector functions.
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Lazarski CA, Ford J, Katzman SD, Rosenberg AF, Fowell DJ. IL-4 attenuates Th1-associated chemokine expression and Th1 trafficking to inflamed tissues and limits pathogen clearance. PLoS One 2013; 8:e71949. [PMID: 23991011 PMCID: PMC3753298 DOI: 10.1371/journal.pone.0071949] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2013] [Accepted: 07/09/2013] [Indexed: 12/21/2022] Open
Abstract
Interleukin 4 (IL-4) plays a central role in the orchestration of Type 2 immunity. During T cell activation in the lymph node, IL-4 promotes Th2 differentiation and inhibits Th1 generation. In the inflamed tissue, IL-4 signals promote innate and adaptive Type-2 immune recruitment and effector function, positively amplifying the local Th2 response. In this study, we identify an additional negative regulatory role for IL-4 in limiting the recruitment of Th1 cells to inflamed tissues. To test IL-4 effects on inflammation subsequent to Th2 differentiation, we transiently blocked IL-4 during ongoing dermal inflammation (using anti-IL-4 mAb) and analyzed changes in gene expression. Neutralization of IL-4 led to the upregulation of a number of genes linked to Th1 trafficking, including CXCR3 chemokines, CCL5 and CCR5 and an associated increase in IFNγ, Tbet and TNFα genes. These gene expression changes correlated with increased numbers of IFNγ-producing CD4+ T cells in the inflamed dermis. Moreover, using an adoptive transfer approach to directly test the role of IL-4 in T cell trafficking to the inflamed tissues, we found IL-4 neutralization led to an early increase in Th1 cell recruitment to the inflamed dermis. These data support a model whereby IL-4 dampens Th1-chemokines at the site of inflammation limiting Th1 recruitment. To determine biological significance, we infected mice with Leishmania major, as pathogen clearance is highly dependent on IFNγ-producing CD4+ T cells at the infection site. Short-term IL-4 blockade in established L. major infection led to a significant increase in the number of IFNγ-producing CD4+ T cells in the infected ear dermis, with no change in the draining LN. Increased lymphocyte influx into the infected tissue correlated with a significant decrease in parasite number. Thus, independent of IL-4's role in the generation of immune effectors, IL-4 attenuates lymphocyte recruitment to the inflamed/infected dermis and limits pathogen clearance.
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Affiliation(s)
- Christopher A. Lazarski
- David H. Smith Center for Vaccine Biology and Immunology, Aab Institute of Biomedical Sciences, Department of Microbiology and Immunology, University of Rochester, Rochester, New York, United States of America
| | - Jill Ford
- David H. Smith Center for Vaccine Biology and Immunology, Aab Institute of Biomedical Sciences, Department of Microbiology and Immunology, University of Rochester, Rochester, New York, United States of America
| | - Shoshana D. Katzman
- David H. Smith Center for Vaccine Biology and Immunology, Aab Institute of Biomedical Sciences, Department of Microbiology and Immunology, University of Rochester, Rochester, New York, United States of America
| | - Alexander F. Rosenberg
- Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, New York, United States of America
| | - Deborah J. Fowell
- David H. Smith Center for Vaccine Biology and Immunology, Aab Institute of Biomedical Sciences, Department of Microbiology and Immunology, University of Rochester, Rochester, New York, United States of America
- * E-mail:
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Schwarz T, Remer KA, Nahrendorf W, Masic A, Siewe L, Müller W, Roers A, Moll H. T cell-derived IL-10 determines leishmaniasis disease outcome and is suppressed by a dendritic cell based vaccine. PLoS Pathog 2013; 9:e1003476. [PMID: 23825956 PMCID: PMC3694851 DOI: 10.1371/journal.ppat.1003476] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2012] [Accepted: 05/20/2013] [Indexed: 12/17/2022] Open
Abstract
In the murine model of Leishmania major infection, resistance or susceptibility to the parasite has been associated with the development of a Th1 or Th2 type of immune response. Recently, however, the immunosuppressive effects of IL-10 have been ascribed a crucial role in the development of the different clinical correlates of Leishmania infection in humans. Since T cells and professional APC are important cellular sources of IL-10, we compared leishmaniasis disease progression in T cell-specific, macrophage/neutrophil-specific and complete IL-10-deficient C57BL/6 as well as T cell-specific and complete IL-10-deficient BALB/c mice. As early as two weeks after infection of these mice with L. major, T cell-specific and complete IL-10-deficient animals showed significantly increased lesion development accompanied by a markedly elevated secretion of IFN-γ or IFN-γ and IL-4 in the lymph nodes draining the lesions of the C57BL/6 or BALB/c mutants, respectively. In contrast, macrophage/neutrophil-specific IL-10-deficient C57BL/6 mice did not show any altered phenotype. During the further course of disease, the T cell-specific as well as the complete IL-10-deficient BALB/c mice were able to control the infection. Furthermore, a dendritic cell-based vaccination against leishmaniasis efficiently suppresses the early secretion of IL-10, thus contributing to the control of parasite spread. Taken together, IL-10 secretion by T cells has an influence on immune activation early after infection and is sufficient to render BALB/c mice susceptible to an uncontrolled Leishmania major infection. The clinical symptoms caused by infections with Leishmania parasites range from self-healing cutaneous to uncontrolled visceral disease and depend not only on the parasite species but also on the type of the host's immune response. It is estimated that 350 million people worldwide are at risk, with a global incidence of 1–1.5 million cases of cutaneous and 500,000 cases of visceral leishmaniasis. Murine leishmaniasis is the best-characterized model to elucidate the mechanisms underlying resistance or susceptibility to Leishmania major parasites in vivo. Using T cell-specific and macrophage-specific mutant mice, we demonstrate that abrogating the secretion of the immunosuppressive cytokine IL-10 by T cells is sufficient to render otherwise susceptible mice resistant to an infection with the pathogen. The healing phenotype is accompanied by an elevated specific inflammatory immune response very early after infection. We further show that dendritic cell-based vaccination against leishmaniasis suppresses the early secretion of IL-10 following challenge infection. Thus, our study unravels a molecular mechanism critical for host immune defense, aiding in the development of an effective vaccine against leishmaniasis.
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Affiliation(s)
- Tobias Schwarz
- Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany
| | - Katharina A. Remer
- Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany
| | - Wiebke Nahrendorf
- Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany
| | - Anita Masic
- Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany
| | - Lisa Siewe
- Department of Dermatology, University of Cologne, Cologne, Germany
| | - Werner Müller
- Department of Experimental Immunology, The Helmholtz Centre for Infection Research, Braunschweig, Germany
- Bill Ford Chair of Cellular Immunology, Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom
| | - Axel Roers
- Department of Dermatology, University of Cologne, Cologne, Germany
- Institute for Immunology, University of Dresden, Dresden, Germany
| | - Heidrun Moll
- Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany
- * E-mail:
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Abstract
Allograft rejection is a complex process, which requires
interactions between different cell types and a variety of soluble
factors, such as cytokines. In this review we discuss the role of
cytokines in the induction and effector phases of the rejection
process and in the induction and maintenance of allospecific graft
tolerance. Furthermore, we discuss the feasibility of clinical graft
function monitoring by measuring cytokines and the possibilities for
intervention in the cytokine network in order to inhibit graft
rejection and eventually obtain graft acceptance.
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The three dimensions of functional T-cell tolerance: from research to practice. J Invest Dermatol 2012; 132:508-11. [PMID: 22327262 DOI: 10.1038/jid.2011.465] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
In this issue, Paek et al. describe two phenomena. First, they show that intermediate concentrations of a "transgenic" autoantigen may cause a lichen planus-like autoimmune disease. Second, and more importantly, they show that high doses of peptide antigen suppress the expression of the T-cell receptor and coreceptors, particularly CD8, and that this suppression improves this T-cell-mediated, destructive inflammatory skin disease that is similar to erosive lichen planus.
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Tacchini-Cottier F, Weinkopff T, Launois P. Does T Helper Differentiation Correlate with Resistance or Susceptibility to Infection with L. major? Some Insights From the Murine Model. Front Immunol 2012; 3:32. [PMID: 22566916 PMCID: PMC3342012 DOI: 10.3389/fimmu.2012.00032] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2011] [Accepted: 02/13/2012] [Indexed: 11/13/2022] Open
Abstract
The murine model of Leishmania major infection has been an invaluable tool in understanding T helper differentiation in vivo. The initial evidence for a role of distinct CD4+ T helper subsets in the outcome of infection was first obtained with this experimental model. The development of CD4+ Th1 cells was associated with resolution of the lesion, control of parasite replication, and resistance to re-infection in most of the mouse strains investigated (i.e., C57BL/6). In contrast, differentiation of CD4+ Th2 cells correlated with the development of unhealing lesions, and failure to control parasite load in a few strains (i.e., BALB/c). Since these first reports, an incredible amount of effort has been devoted to understanding the various parameters involved in the differentiation of these, and more recently discovered T helper subsets such as Th17 and T regulatory cells. The discovery of cross-talk between T helper subsets, as well as their plasticity force us to reevaluate the events driving a protective/deleterious T helper immune response following infection with L. major in mice. In this review, we describe the individual contributions of each of these CD4+ T helper subsets following L. major inoculation, emphasizing recent advances in the field, such as the impact of different substrains of L. major on the pathogenesis of disease.
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Affiliation(s)
- Fabienne Tacchini-Cottier
- Department of Biochemistry, WHO Immunology Research and Training Center, University of Lausanne Epalinges, Switzerland
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Debock I, Delbauve S, Dubois A, Pétein M, Leo O, Goldman M, Flamand V. Th17 alloimmunity prevents neonatal establishment of lymphoid chimerism in IL-4-deprived mice. Am J Transplant 2012; 12:81-9. [PMID: 21992234 DOI: 10.1111/j.1600-6143.2011.03778.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Immune responses in newborn mice are known to be biased toward the helper type 2 phenotype. This may account for their propensity to develop tolerance. Herein, we evaluated the effects of IL-4 deprivation on CD4(+) T-cell activities elicited by neonatal exposure to allogeneic spleen cells. We showed that chimerism, Th2-type polarization and pathology, as well as skin allograft acceptance were inhibited in BALB/c mice immunized at birth with (A/J x BALB/c) F(1) spleen cells upon in vivo IL-4 neutralization. While IL-4 neutralization inhibited the development of Th2 cells in this model, it led to the accumulation of IL-17A, IL-17F, IL-22, IL-6 and RORγt mRNA in the spleen or graft tissues. Moreover, IL-4 deprivation led to the differentiation of donor-specific Th17 cells with a concomitant Th1 response characterized by IFN-γ production. The Th17-type response emerging in IL-4-deprived mice was found to mediate both intragraft neutrophil infiltration and the abrogation of B-cell chimerism. Neutralization of this Th17 response failed however to restore functional skin graft acceptance. Collectively, our observations indicate that the neonatal Th2 response opposes the development of Th17 cells, and that Th17 cells are responsible for controlling lymphoid chimerism in mice neonatally injected with semiallogeneic cells.
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Affiliation(s)
- I Debock
- Institut d'Immunologie Médicale, Université Libre de Bruxelles, Belgium
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Divanovic S, Trompette A, Ashworth JI, Rao MB, Karp CL. Therapeutic enhancement of protective immunity during experimental leishmaniasis. PLoS Negl Trop Dis 2011; 5:e1316. [PMID: 21909452 PMCID: PMC3167777 DOI: 10.1371/journal.pntd.0001316] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2010] [Accepted: 08/01/2011] [Indexed: 12/15/2022] Open
Abstract
Background Leishmaniasis remains a significant cause of morbidity and mortality in the tropics. Available therapies are problematic due to toxicity, treatment duration and emerging drug resistance. Mouse models of leishmaniasis have demonstrated that disease outcome depends critically on the balance between effector and regulatory CD4+ T cell responses, something mirrored in descriptive studies of human disease. Recombinant IL-2/diphtheria toxin fusion protein (rIL-2/DTx), a drug that is FDA-approved for the treatment of cutaneous T cell lymphoma, has been reported to deplete regulatory CD4+ T cells. Methodology/Principal Findings We investigated the potential efficacy of rIL-2/DTx as adjunctive therapy for experimental infection with Leishmania major. Treatment with rIL-2/DTx suppressed lesional regulatory T cell numbers and was associated with significantly increased antigen-specific IFN-γ production, enhanced lesion resolution and decreased parasite burden. Combined administration of rIL-2/DTx and sodium stibogluconate had additive biological and therapeutic effects, allowing for reduced duration or dose of sodium stibogluconate therapy. Conclusions/Significance These data suggest that pharmacological suppression of immune counterregulation using a commercially available drug originally developed for cancer therapy may have practical therapeutic utility in leishmaniasis. Rational reinvestigation of the efficacy of drugs approved for other indications in experimental models of neglected tropical diseases has promise in providing new candidates to the drug discovery pipeline. Leishmaniasis is an infectious disease that causes a large burden of morbidity and mortality in the tropics. Caused by protozoan parasites of the genus Leishmania that are transmitted by sandflies, leishmaniasis causes a wide spectrum of human disease. The severe end of the spectrum, visceral leishmaniasis, causes an annual mortality of approximately 50,000, largely in India and Sudan. Available therapies for leishmaniasis are problematic due to emerging drug resistance, toxicity and/or the need for lengthy courses of treatment. There is thus an urgent need for novel therapeutic approaches to this neglected tropical disease. To address this problem, the authors examined whether a commercially available drug developed for cancer therapy (Ontak), reported to have immunological activity of relevance to the immunobiology of Leishmania infection, exhibited efficacy in mouse models of leishmaniasis. The study found therapeutic efficacy for the drug alone in these models, as well as additive therapeutic efficacy in combination with standard antimicrobial therapy. Rational reinvestigation of the efficacy of already approved drugs in experimental models of neglected tropical diseases has promise in providing needed new candidates to the drug discovery pipeline.
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Affiliation(s)
- Senad Divanovic
- Division of Molecular Immunology, Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America
| | - Aurelien Trompette
- Division of Molecular Immunology, Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America
| | - Jamie I. Ashworth
- Division of Molecular Immunology, Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America
| | - Marepalli B. Rao
- Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America
| | - Christopher L. Karp
- Division of Molecular Immunology, Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America
- * E-mail:
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KSAC, the first defined polyprotein vaccine candidate for visceral leishmaniasis. CLINICAL AND VACCINE IMMUNOLOGY : CVI 2011; 18:1118-24. [PMID: 21632891 DOI: 10.1128/cvi.05024-11] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
A subunit vaccine using a defined antigen(s) may be one effective solution for controlling leishmaniasis. Because of genetic diversity in target populations, including both dogs and humans, a multiple-antigen vaccine will likely be essential. However, the cost of a vaccine to be used in developing countries must be considered. We describe herein a multiantigen vaccine candidate comprised of antigens known to be protective in animal models, including dogs, and to be recognized by humans immune to visceral leishmaniasis. The polyprotein (KSAC) formulated with monophosphoryl lipid A, a widely used adjuvant in human vaccines, was found to be immunogenic and capable of inducing protection against Leishmania infantum, responsible for human and canine visceral leishmaniasis, and against L. major, responsible for cutaneous leishmaniasis. The results demonstrate the feasibility of producing a practical, cost-effective leishmaniasis vaccine capable of protecting both humans and dogs against multiple Leishmania species.
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Barthelmann J, Nietsch J, Blessenohl M, Laskay T, van Zandbergen G, Westermann J, Kalies K. The protective Th1 response in mice is induced in the T-cell zone only three weeks after infection with Leishmania major and not during early T-cell activation. Med Microbiol Immunol 2011; 201:25-35. [PMID: 21547563 DOI: 10.1007/s00430-011-0201-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2011] [Indexed: 10/18/2022]
Abstract
The protozoan parasite Leishmania spp. causes clinical pictures ranging in severity from spontaneously healing skin ulcers to systemic disease. The immune response associated with healing involves the differentiation of IFNγ-producing Th1 cells, whereas the non-healing phenotype is associated with IL4-producing Th2 cells. The widespread assumption has been that the T-cell differentiation that leads to a healing or non-healing phenotype is established at the time of T-cell activation early after infection. By selectively analyzing the expression of cytokine genes in the T-cell zones of lymph nodes of resistant (Th1) C57BL/6 mice and susceptible (Th2) BALB/c mice during an infection with Leishmania major in vivo, we show that the early T-cell response does not differ between C57BL/6 mice and BALB/c mice. Instead, Th1/Th2 polarization appears suddenly 3 weeks after infection. At the same time point, the number of parasites increases in lymph nodes of both mouse strains, but about 100-fold more in susceptible BALB/c mice. We conclude that the protective Th1 response in C57BL/6 mice is facilitated by the capacity of their innate effector cells to keep parasite numbers at low levels.
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Affiliation(s)
- Julia Barthelmann
- Center for Structural and Cell Biology in Medicine, Institute of Anatomy, University of Lübeck, Lübeck, Germany
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