• Apa1
• Bsm1
• PCR-Restriction fragment length polymorphism
• Post Kala Azar Dermal Leishmaniasis
• Taq1
• Visceral leishmaniasis
• Vitamin D receptor

• Humans
• Receptors, Calcitriol/genetics
• Polymorphism, Single Nucleotide
• Male
• Female
• Leishmaniasis, Visceral/genetics
• Leishmaniasis, Visceral/epidemiology
• Risk Factors
• Vitamin D/blood
• Adult
• 25-Hydroxyvitamin D3 1-alpha-Hydroxylase/genetics
• Genotype
• Genetic Predisposition to Disease
• Leishmaniasis, Cutaneous/genetics
• Leishmaniasis, Cutaneous/epidemiology
• Gene Frequency
• Young Adult
• Middle Aged
• Adolescent
• India/epidemiology
• Endemic Diseases
• Child

• Immunomodulation
• Infectious disease
• Leishmaniasis
• Malnutrition
• Nutrients
• Trace elements

• Humans
• Vitamins/pharmacology
• Vitamin A
• Minerals
• Trace Elements/pharmacology
• Micronutrients/therapeutic use
• Zinc/therapeutic use
• Vitamin K
• Leishmaniasis/drug therapy
• Iron
• Malnutrition
• Treatment Outcome

• Cutaneous leishmaniasis
• Leishmaniasis
• Mucocutaneous leishmaniasis
• Vitamin D

The vitamin D receptor as well as its ligand have been localized to various immune tissues and cells. These observations have led researchers to hypothesize a role for vitamin D in the immune system. However, a specific role for vitamin D in immunity has yet to be clearly delineated. The work in this report was undertaken to determine if mounting an antibody response is altered in the face of vitamin D-deficiency or when the signaling pathway is eliminated by removal of the nuclear receptor. This investigation provides direct evidence vitamin D is not necessary for producing antibodies, a process paramount for optimal attack against many foreign organisms. The idea that vitamin D plays a significant role in immunity has been proposed repeatedly for many years. To address this important idea we have carried out studies in mice to determine if vitamin D plays a significant role in antibody production. Two animal models were utilized: mice depleted of vitamin D and mice devoid of the vitamin D receptor. Further, a possible role of hypocalcemia resulting from vitamin D deficiency in antibody production was determined. Neither the absence of vitamin D or the vitamin D receptor nor hypocalcemia affected the ability of mice to mount an antibody response to an antigen challenge. Thus, we found no evidence that vitamin D or normal serum calcium is required for this major form of immunity.

• Mice
• Animals
• Vitamin D
• Receptors, Calcitriol/metabolism
• Antibody Formation
• Hypocalcemia
• Vitamin D Deficiency
• Vitamins

• Wisconsin Alumni Research Foundation

• Tegumentary Leishmaniasis
• chemokines
• cytokines
• immune response
• receptors
• single nucleotide polymorphisms

• immunoregulation
• vitamin D

• COVID-19/complications
• COVID-19/immunology
• COVID-19/virology
• Cytokine Release Syndrome/etiology
• Cytokine Release Syndrome/pathology
• Humans
• Inflammation/etiology
• Inflammation/pathology
• SARS-CoV-2/isolation & purification
• Severity of Illness Index
• Vitamin D Deficiency/immunology
• Vitamin D Deficiency/physiopathology

• R01 AI132819 NIAID NIH HHS
• R03 AI103748 NIAID NIH HHS
• R21 AI131171 NIAID NIH HHS

• Leishmania spp.
• all-trans retinoic acid
• retinol
• vitamin D3
• zinc

• Cytokines
• Immune responses
• Leishmania donovani
• Post-kala-azar dermal leishmaniasis
• T cells

• All-trans retinoic acid
• autoimmune
• calcitriol
• encephalomyelitis
• multiple sclerosis

• Leishmania amazonensis
• NO
• ROS
• Vitamin D
• macrophages

• 25-hydroxyvitamin D
• Cutaneous leishmaniasis
• Iran
• L. tropica
• VDR polymorphism

• Human macrophages
• IL-15
• IL-32
• Leishmania braziliensis
• Vitamin D

The early inflammatory skin micromilieu affects resistance in experimental infection with Leishmania major. We pursue the concept that macrophages, which take up parasites during early infection, exert decisive influence on the inflammatory micromilieu after infection. In order to analyze their distinctive potential, we identified differentially regulated genes of murine granuloma macrophages (GMΦ) from resistant and susceptible mice after their infection with metacyclic Leishmania major. We found induction of several cytokines in GMΦ from both strains and a stronger upregulation of the transcription factor aryl hydrocarbon receptor (AhR) in GMΦ from resistant mice. Using both an AhR agonist and antagonist we demonstrated that AhR is involved in Leishmania-induced production of TNF in macrophages. In vivo, single local injection of an AhR agonist in early lesions of susceptible mice caused an increased induction of Tnf and other cytokines in the skin. Importantly, local agonist treatment led to a reduction of disease severity, reduced parasite loads and a weaker Th2 response. Our results demonstrate that local activation of AhR has a beneficial effect in experimental leishmaniasis.

• AhR
• epidermis
• leishmaniasis
• macrophages
• skin infection

In cutaneous Leishmaniasis the parasitic control in human host macrophages is still poorly understood. We found an increased expression of the human cathelicidin CAMP in skin lesions of Ethiopian patients with cutaneous leishmaniasis. Vitamin D driven, Cathelicidin-type antimicrobial peptides (CAMP) play an important role in the elimination of invading microorganisms. Recombinant cathelicidin was able to induce cell-death characteristics in Leishmania in a dose dependent manner. Using human primary macrophages, we demonstrated pro-inflammatory macrophages (hMDM1) to express a higher level of human cathelicidin, both on gene and protein level, compared to anti-inflammatory macrophages (hMDM2). Activating the CAMP pathway using Vitamin D in hMDM1 resulted in a cathelicidin-mediated-Leishmania restriction. Finally, a reduction of cathelicidin in hMDM1, using a RNA interference (RNAi) approach, increased Leishmania parasite survival. In all, these data show the human cathelicidin to contribute to the innate immune response against Leishmaniasis in a human primary cell model.

• Leishmania
• antimicrobial activity
• cathelicidin (LL-37)
• human macrophages
• human primary immune cells
• vitamin D

• Vitamin D

• Adaptive Immunity/immunology
• Animals
• Female
• Listeriosis/immunology
• Mice
• Mice, Inbred C57BL
• Vitamin D/immunology
• Vitamin D Deficiency/immunology

Investigation of immune modulatory anti-leishmanial molecules is now being strongly encouraged to overcome the immunosuppression manifested during visceral leishmaniasis (VL), resistance, toxicity and high cost associated with conventional therapeutics. In the present study, we explored the protective efficacy of vitamin D₃, retinoic acid and isoprenoid chenodeoxycholic acid (CDCA) combinations against L. donovani infected BALB/c mice. We also probed the immune modulatory response (Th1 & Th2 cytokines) and infection dynamics following experimental infections with drug treated animals. Our results indicate that Vit.D₃/RA and CDCA/RA combination treatment led to significant inhibition of parasite load on days 21 and 28 post treatment. Furthermore, there was a marked inhibition of Th2 type immune responses in IL-4, IL-5 and polarization of Th1 biased immunity along with upregulation of IL-1, IFN-γ, and TNF-α levels on day 28 post treatment. In addition, mice treated with Vit.D₃/RA and CDCA/RA demonstrates here that splenic histological recovery against the virulent challenge of L. donovani by day 28 was comparable to control group. The conclusions derived from this study suggests that a combination of vitamin A, D₃ and isoprenoids may have a potential immunomodulatory therapeutic role against leishmaniasis.

• IL-10
• Leishmania amazonensis
• Th1
• immunonutrition
• leishmaniasis
• vitamin D

Vitamin D generates many extraskeletal effects due to the vitamin D receptor (VDR) which is present in most tissues throughout the body. The possible role of vitamin D in infections is implied from its impact on the innate and adaptive immune responses. A significant effect is also the suppression of inflammatory processes. Because vitamin D could be acknowledged as a “seasonal stimulus”, as defined by R. Edgar Hope-Simpson, it would be crucial to prove it from a potential easy and cheap prophylaxis or therapy support perspective as far as influenza infections are concerned. The survey of the literature data generates some controversies and doubts about the possible role of vitamin D in the prevention of influenza virus. The most important point is to realise that the broad spectrum of this vitamin’s activity does not exclude such a possibility. According to most of the authors, more randomized controlled trials with effective, large populations are needed to explore the preventive effect of vitamin D supplementation on viral influenza infections.

• influenza
• respiratory tract infections
• vitamin D

• CYP27B1
• cancer
• cardiovascular
• immune system
• skin
• vitamin D

• Antimicrobials
• Cathelicidin
• PKDL
• TLR
• Visceral leishmaniasis
• Vitamin D3

The relationship between vitamin D deficiency and the risk of suffering from a plethora of health disorders, ranging from autoimmune processes to infectious diseases has been widely described. Nonetheless, the potential role of vitamin D in visceral leishmaniasis remains uncharacterized. In the Mediterranean basin, where the dog is leishmania’s main peri-domestic reservoir, control measures against the canine disease have shown beneficial effects on the incidence of human leishmaniasis. In this study, we measured the vitamin D levels in serum samples from a cohort of 68 healthy and disease dogs from a highly endemic area and we have also studied the relationship of these levels with parasitological and immunological parameters. The sick dogs presented significantly lower (P < 0.001) vitamin D levels (19.6 ng/mL) than their non-infected (31.8 ng/mL) and the asymptomatic counterparts (29.6 ng/mL). In addition, vitamin D deficiency correlated with several parameters linked to leishmaniasis progression. However, there was no correlation between vitamin D levels and the Leishmania-specific cellular immune response. Moreover, both the leishmanin skin test and the IFN-γ levels displayed negative correlations with serological, parasitological and clinical signs. Further studies to determine the functional role of vitamin D on the progression and control of canine leishmaniasis are needed.

This study aims to explore effects of 1,25(OH)₂D₃ and vitamin D receptor (VDR) on peripheral CD4⁺/CD8⁺ double‐positive (DP) T lymphocytes in systemic lupus erythematosus (SLE). MRL‐LPr/LPr mice with SLE (n = 20) and normal MRL mice (n = 20) were assigned into the control group (normal mice, without feeding with 1,25(OH)₂D₃), the 1,25(OH)₂D₃ group (SLE mice, feeding with 1,25(OH)₂D₃), the VDR‐knock‐in + 1,25(OH)₂D₃ group (SLE mice, VDR‐knock‐in, feeding with 1,25(OH)₂D₃) and the VDR‐knockout group (normal mice, VDR‐knockout, without feeding with 1,25(OH)₂D₃) (n = 10 per group). Levels of T lymphocytes were measured by flow cytometry. The mRNA and proteins expressions of inflammatory factors were measured by qRT‐PCR and ELISA. Extracellular signal‐regulated kinase‐1/2 (ERK1/2) expression was measured by Western blotting. Compared with normal mice, SLE mice showed reduced levels of CD4⁺, CD4⁺/CD8⁺ ratio, and DP lymphocytes. The levels of SLE‐related indicators all increased significantly, followed with severe skin ulcers and urinary system infection. With the increase in time, skin ulcers and urinary system infection were significantly improved, levels of CD4⁺, CD4⁺/CD8⁺ ratio, and DP lymphocytes increased, and levels of SLE‐related indicators all decreased in the 1,25(OH)₂D₃ group. There were no significant changes in bioindicators in the control and the VDR‐knock‐in + 1,25(OH)₂D₃ groups. The symptoms of SLE gradually occurred in the VDR‐knockout group. This study demonstrates that VDR and 1,25(OH)₂D₃ could elevate CD4⁺/CD8⁺ DP T lymphocytes and reduce expressions of inflammatory factors, thus inhibiting the development and progression of SLE.

• 1,25(OH)2D3
• CD4+
• CD8+
• T lymphocytes
• mouse model
• systemic lupus erythematosus
• vitamin D receptor

• Adult
• Aged
• Alleles
• Cardiomyopathies/complications
• Cardiomyopathies/genetics
• Cardiomyopathies/parasitology
• Chagas Disease/complications
• Chagas Disease/genetics
• Cohort Studies
• Colombia
• Female
• Gene Frequency
• Genetic Predisposition to Disease
• Genotype
• Homeostasis
• Humans
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Receptors, Calcitriol/genetics
• Regression Analysis
• Risk
• Trypanosoma cruzi

Effective adaptive immune responses rely upon appropriate activation of T cells by antigenic peptide-major histocompatibility complex on the surface of antigen presenting cells (APCs). Activation relies on additional signals including co-stimulatory molecules on the surface of the APCs that promote T cell expansion. The immune response is further sculpted by the cytokine environment. However, T cells also respond to other environmental signals including hormones, neurotransmitters, and vitamins. In this review, we summarize the mechanisms through which vitamins A and D impact immune responses, particularly in the context of T cell responses.

• Vitamin D
• Retinoic acid
• T helper cells
• Cytokines
• Transcription factors
• Allergy
• Autoimmune diseases

• IL-5
• TH1
• TH17
• TH2
• Treg
• cytokines
• evolution
• fish
• i1-i2 axis
• immunology

The high level of functional diversity and plasticity in monocytes/macrophages has been defined within in vitro systems as M1 (classically activated), M2 (alternatively activated) and deactivated macrophages, of which the latter two subtypes are associated with suppression of cell mediated immunity, that confers susceptibility to intracellular infection. Although the Leishmania parasite modulates macrophage functions to ensure its survival, what remains an unanswered yet pertinent question is whether these macrophages are deactivated or alternatively activated. This study aimed to characterize the functional plasticity and polarization of monocytes/macrophages and delineate their importance in the immunopathogenesis of Post kala-azar dermal leishmaniasis (PKDL), a chronic dermatosis of human leishmaniasis. Monocytes from PKDL patients showed a decreased expression of TLR-2/4, along with an attenuated generation of reactive oxidative/nitrosative species. At disease presentation, an increased mRNA expression of classical M2 markers CD206, ARG1 and PPARG in monocytes and lesional macrophages indicated M2 polarization of macrophages which was corroborated by increased expression of CD206 and arginase-1. Furthermore, altered vitamin D signaling was a key feature in PKDL, as disease presentation was associated with raised plasma levels of monohydroxylated vitamin D₃ and vitamin D3- associated genes, features of M2 polarization. Taken together, in PKDL, monocyte/macrophage subsets appear to be alternatively activated, a phenotype that might sustain disease chronicity. Importantly, repolarization of these monocytes to M1 by antileishmanial drugs suggests that switching from M2 to M1 phenotype might represent a therapeutic opportunity, worthy of future pharmacological consideration.

Monocyte/macrophage subsets following their polarization by the microenvironement serve as important immune sentinels that play a vital role in host defense and homeostasis. The polarization of macrophage function has been broadly classified as M1 (classical) and M2 (alternate) activation, wherein M1 polarised cells display a strong pro-inflammatory microbicidal response, while M2 polarization is linked to production of an anti-inflammatory milieu leading to tissue regeneration and wound healing. Data pertaining to macrophage polarization are primarily derived from murine models, but increasing evidence is highlighting the inadequacy of direct inter-species translation. In leishmaniasis, a protozoan infection caused by the genus Leishmania, manipulation of host macrophage function is central to pathogenesis. In this study we report that monocyte/macrophage subsets in Post kala-azar dermal leishmaniasis are polarized to an M2 phenotype. This study provides insights into systemic and local regulation of macrophage/ monocyte functions in this important human disease and highlights the influence of immunomodulatory anti-leishmanial chemotherapy on macrophage/monocyte polarization.

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Cell Differentiation
• Child
• Female
• Gene Expression Profiling
• Humans
• Immunosuppression Therapy
• India
• Leishmaniasis, Cutaneous/immunology
• Leishmaniasis, Visceral/complications
• Macrophages/immunology
• Male
• Middle Aged
• Monocytes/immunology
• Young Adult

• G1000230 Medical Research Council

• CD8 T cells
• Calcitriol
• Cyp27B1
• differentiation
• effector cells
• immunological memory
• protective immunity
• vitamin D receptor

Within the last decade, vitamin D has emerged as a central regulator of host defense against infections. In this regard, vitamin D triggers effective antimicrobial pathways against bacterial, fungal and viral pathogens in cells of the human innate immune system. However, vitamin D also mediates potent tolerogenic effects: it is generally believed that vitamin D attenuates inflammation and acquired immunity, and thus potentially limits collateral tissue damage. Nevertheless, several studies indicate that vitamin D promotes aspects of acquired host defense. Clinically, vitamin D deficiency has been associated with an increased risk for various infectious diseases in epidemiological studies; yet, robust data from controlled trials investigating the use of vitamin D as a preventive or therapeutic agent are missing. In this review, we summarize the current knowledge regarding the effect of vitamin D on innate and acquired host defense, and speculate on the difficulties to translate the available molecular medicine data into practical therapeutic or preventive recommendations.

• T cell
• Vitamin D
• dendritic cell
• infection and immunity
• macrophage

• vitamin d receptor
• microbiota
• innate lymphoid cells

• Animals
• Anti-Bacterial Agents/adverse effects
• Bone Marrow Transplantation
• Citrobacter rodentium/immunology
• Colony Count, Microbial
• Disease Susceptibility
• Dysbiosis/chemically induced
• Dysbiosis/genetics
• Dysbiosis/immunology
• Dysbiosis/microbiology
• Enterobacteriaceae Infections/genetics
• Enterobacteriaceae Infections/immunology
• Enterobacteriaceae Infections/microbiology
• Enterobacteriaceae Infections/pathology
• Fecal Microbiota Transplantation
• Gene Expression
• Germ-Free Life/immunology
• Interleukins/biosynthesis
• Interleukins/immunology
• Lymphocytes/drug effects
• Lymphocytes/immunology
• Lymphocytes/microbiology
• Mice
• Mice, Knockout
• Microbiota/drug effects
• Microbiota/immunology
• Receptors, Calcitriol/deficiency
• Receptors, Calcitriol/genetics
• Receptors, Calcitriol/immunology
• Interleukin-22

• R01 AT005378 NCCIH NIH HHS
• R01 NS067563 NINDS NIH HHS
• NS067563 NINDS NIH HHS
• AT005378 NCCIH NIH HHS

Beyond its critical function in calcium homeostasis, vitamin D has recently been found to play an important role in the modulation of the immune/inflammation system via regulating the production of inflammatory cytokines and inhibiting the proliferation of proinflammatory cells, both of which are crucial for the pathogenesis of inflammatory diseases. Several studies have associated lower vitamin D status with increased risk and unfavorable outcome of acute infections. Vitamin D supplementation bolsters clinical responses to acute infection. Moreover, chronic inflammatory diseases, such as atherosclerosis-related cardiovascular disease, asthma, inflammatory bowel disease, chronic kidney disease, nonalcoholic fatty liver disease, and others, tend to have lower vitamin D status, which may play a pleiotropic role in the pathogenesis of the diseases. In this article, we review recent epidemiological and interventional studies of vitamin D in various inflammatory diseases. The potential mechanisms of vitamin D in regulating immune/inflammatory responses in inflammatory diseases are also discussed.

• asthma
• atherosclerosis
• chronic kidney disease
• inflammatory bowel disease

Intracellular pathogens modulate host cell function to promote their survival. However, in vitro infection studies do not account for the impact of host-derived inflammatory signals. Examining the response of liver-resident macrophages (Kupffer cells) in mice infected with the parasite Leishmania donovani, we identified a transcriptomic network operating in uninfected Kupffer cells exposed to inflammation but absent from Kupffer cells from the same animal that contained intracellular Leishmania. To test the hypothesis that regulated expression of genes within this transcriptomic network might impact parasite survival, we pharmacologically perturbed the activity of retinoid X receptor alpha (RXRα), a key hub within this network, and showed that this intervention enhanced the innate resistance of Kupffer cells to Leishmania infection. Our results illustrate a broadly applicable strategy for understanding the host response to infection in vivo and identify Rxra as the hub of a gene network controlling antileishmanial resistance.

•

Leishmania infection rapidly activates infected and uninfected Kupffer cells in mice

•

Sodium antimony gluconate contributes towards the pathogenesis of PKDL.

Post kala-azar dermal leishmaniasis (PKDL), a cutaneous sequela of visceral leishmaniasis (VL), develops in some patients alongside but more commonly after apparent cure from VL. In view of the pivotal role of PKDL patients in the transmission of VL, here we review clinical, epidemiological, parasitological, and immunological perspectives of this disease, focusing on five hypotheses to explain the development of PKDL: (i) the role of antimonial drugs; (ii) UV-induced skin damage; (iii) reinfection; (iv) organ specific failure of memory T cell responses; and (v) genetic susceptibility of the host. This review will enable researchers and clinicians to explore the unresolved mystery of PKDL and provide a framework for future application of ‘omic’ approaches for the control and eventual elimination of VL.

• UV light
• antimony
• post kala-azar dermal leishmaniasis (PKDL)
• regulatory T cells
• vitamin D

• Gene polymorphism
• Mycobacterium tuberculosis
• Tuberculosis development
• Tuberculosis infection
• Tuberculosis protection
• Tuberculosis susceptibility

Different non-invasive real-time imaging techniques have been developed over the last decades to study bacterial pathogenic mechanisms in mouse models by following infections over a time course. In vivo investigations of bacterial infections previously relied mostly on bioluminescence imaging (BLI), which is able to localize metabolically active bacteria, but provides no data on the status of the involved organs in the infected host organism. In this study we established an in vivo imaging platform by magnetic resonance imaging (MRI) for tracking bacteria in mouse models of infection to study infection biology of clinically relevant bacteria.

We have developed a method to label Gram-positive and Gram-negative bacteria with iron oxide nano particles and detected and pursued these with MRI. The key step for successful labeling was to manipulate the bacterial surface charge by producing electro-competent cells enabling charge interactions between the iron particles and the cell wall. Different particle sizes and coatings were tested for their ability to attach to the cell wall and possible labeling mechanisms were elaborated by comparing Gram-positive and -negative bacterial characteristics. With 5-nm citrate-coated particles an iron load of 0.015 ± 0.002 pg Fe/bacterial cell was achieved for Staphylococcus aureus. In both a subcutaneous and a systemic infection model induced by iron-labeled S. aureus bacteria, high resolution MR images allowed for bacterial tracking and provided information on the morphology of organs and the inflammatory response.

Labeled with iron oxide particles, in vivo detection of small S. aureus colonies in infection models is feasible by MRI and provides a versatile tool to follow bacterial infections in vivo. The established cell labeling strategy can easily be transferred to other bacterial species and thus provides a conceptual advance in the field of molecular MRI.

• 1,25(OH)2D3
• BALB/c mice
• Cutaneous leishmaniasis
• Leishmania mexicana

• Adaptive Immunity
• Animals
• Bacterial Infections/immunology
• Bacterial Infections/prevention & control
• Communicable Diseases/immunology
• Dietary Supplements
• Disease Susceptibility
• Humans
• Immunity, Innate
• Immunologic Factors/immunology
• Immunologic Factors/therapeutic use
• Parasitic Diseases/immunology
• Parasitic Diseases/prevention & control
• Virus Diseases/immunology
• Virus Diseases/prevention & control
• Vitamin D/blood
• Vitamin D/immunology
• Vitamin D/therapeutic use