Persistent viral infections are associated with long-term health issues and prolonged transmission. How external perturbations after initial exposure affect the duration of infection is unclear. Here we discovered that murine astrovirus, an enteric RNA virus, persists indefinitely when mice remain unperturbed but is cleared rapidly after cage change. In addition to eliminating the external viral reservoir, cage change also induced interferon-stimulated genes in the intestinal epithelium that are necessary for viral clearance. We further identified that displacing infected animals initially caused a temporary period of immune suppression through the stress hormone corticosterone, which was followed by an immune rebound characterized by activation of CD8 T cells responsible for downstream epithelial antiviral responses. Our findings show how viral persistence can be disrupted by preventing re-exposure and activating immunity upon stress recovery, indicating that external factors can be manipulated to shorten the duration of a viral infection.

Cytokines and chemokines play a crucial role in orchestrating the immune response to chikungunya virus (CHIKV) infection, influencing disease course and outcome. Although significant efforts have been made to understand the cytokine signatures associated with CHIKV infection, the identification of specific cytokine biomarkers across different disease stages remains incomplete.

We have assessed CHIKV-specific cytokine, chemokine profiles of 17 analytes in 50 acute chikungunya patients, 31 chronic chikungunya arthritis patients, 30 recovered individuals, and 23 healthy controls. The cytokine and chemokines were measured in the supernatant of PBMCs stimulated in vitro with inactivated chikungunya virus.

It was observed that chronic chikungunya arthritis patients exhibited significantly higher levels of IL-1β, IL-6, and GM-CSF compared to all other groups. MCP-1 levels were elevated in patient groups compared to recovered and control individuals. IL-1β emerged as a potential biomarker for chronic chikungunya arthritis based on ROC analysis. A negative correlation between IFN-γ levels and CHIKV load was observed in acute patients, suggesting its antiviral role. IL-12 levels were higher in recovered individuals compared to all other groups, while IFN-γ levels were elevated in recovered individuals compared to acute patients.

Our findings highlight IL-1β as a potential biomarker for chronic chikungunya arthritis and suggest that GM-CSF inhibition could serve as a therapeutic intervention for disease-associated chronic inflammation. The observed co-regulation of IL-12 and IFN-γ in recovered individuals needs further investigation into their role in disease resolution. These insights provide a deeper understanding of the immunopathogenesis of CHIKV infection and may contribute in future diagnostic and therapeutic strategies.

Post-acute infection syndromes (PAIS), i.e., long-lasting pathologies subsequent to infections that do not properly resolve, have both a common core and a broad diversity of manifestations. PAIS include a group of core symptoms (pathological fatigue, cognitive problems, sleep disorders and pain) accompanied by a large set of diverse symptoms. Core and diverse additional symptoms, which can persist for years, exhibiting periods of relapses and remissions, usually start suddenly after an apparently common infection. PAIS display highly variable clinical features depending on the nature of the initial pathogen, and to an even larger extent, on the diversity of preexisting individual terrains in which PAIS are rooted. In a first part, I discuss biological issues related to the persistence of microbial antigens, dysregulated immune responses, reactivation of latent viruses, different potential self-sustained inflammatory loops, mitochondrial dysfunction, metabolic disorders in the tryptophan- kynurenin pathway (TKP) with impact on serotonin, and consequences of a dysfunctional bidirectional microbiota-gut-brain axis. The second part deals with the nervous system dependence of PAIS. I rely on the concept of interoception, the process by which the brain senses, integrates and interprets signals originating from within the body, and sends feebacks aimed at maintaining homeostasis. Interoception is central for understanding the origin of fatigue, dysautonomia, dysfunctioning of the hypothalamus-pituitary-adrenal (HPA) axis, and its relation with stress, inflammation or depression. I propose that all individual predispositions leading to self-sustained vicious circles constitute building blocks that can self-assemble in many possible ways, to give rise to both core and diverse features of PAIS. A useful discrimination between different PAIS subtypes should be obtained with a composite profiling including biomarkers, questionnaires and functional tests so as to take into account PAIS multidimensionality.

Several viruses cause acute and chronic arthritis. Millions of people suffered from Chikungunya(CHIK) during the recent epidemics/outbreaks in Asia, Africa and the Americas. Almost 20-40 % failed to recover completely and suffered from chronic pain and arthritis sequel. A wide spectrum of clinical phenotypic arthritis was described. Non-specific arthralgias(NSA) and soft tissue pains were predominant although inflammatory arthritis (mostly undifferentiated)(IA-U) was substantial. Specifically, rheumatoid arthritis(RA) and spondyloarthritis(SpA) like disorders were described. The frequency of biomarkers such as rheumatoid factor(RF) was low. Arthritis was mostly non-erosive in population studies. Abnormal immune mechanisms and persistent specific CHIK virus (CHIKV) IgM and IgG antibodies were shown. The etiopathogenetic evidence was divided between intense joint tissue inflammation due to prolonged virus persistence and abnormal autoimmune mechanisms. There was no specific therapy. The symptomatic management was often combined with an empirical use of disease modifying anti rheumatoid drugs and steroids. Substantial research is required to address knowledge gaps and unravel evidence-based medicine.

Arthritogenic alphaviruses are arboviruses (arthropod-borne viruses) that are genetically and serologically related positive-strand RNA viruses and cause epidemics on a global scale. They are transmitted by mosquitoes and cause diseases in humans that are mainly characterized by fever and often debilitating, sometimes chronic polyarthralgia. At present, approved treatments or vaccines are not available for most arthritogenic alphaviruses, and recently licensed vaccines against chikungunya virus are awaiting implementation in endemic areas. Most arthritogenic alphaviruses are currently limited to specific geographic areas due to vector distributions and availability of amplifying hosts, but they pose a substantial risk of emergence in other regions. The exception is chikungunya virus, which has emerged repeatedly from Africa, established sustained and efficient transmission in urban areas (including in temperate climates) and has caused major epidemics across the world. In this Review, we highlight recent advances in our understanding of the transmission cycles of arthritogenic alphaviruses, their vectors, epidemiology, transmission dynamics, evolution, pathophysiology and immune responses. We also outline strategies and countermeasures to anticipate and mitigate the impact of arthritogenic alphaviruses on human health.

Pain is an important symptom associated with the arboviral disease caused by the Chikungunya virus (CHIKV). For a significant number of patients, this symptom can persist for months or even years, negatively affecting their quality of life. Unfortunately, pharmacological options for this condition are limited and only partially effective, as the underlying mechanisms associated with CHIKV-induced pain are still poorly understood. The re-emergence of CHIKV has led to new outbreaks, and the expected high prevalence of pain in these global events requires new scientific advances to find more effective solutions. Here we review the main aspects of pain caused by CHIKV infection, such as the anatomy of the affected sites, the prevalence and management of this symptom, the diversity of possible cellular and molecular mechanisms, and finally highlight a promising meningeal pathway to elucidate the mechanisms involved in the unsolved problem of CHIKV-associated pain.

Chikungunya virus (CHIKV), an arthritogenic alphavirus, is a significant public health threat in endemic and newly affected regions. This study investigates viral kinetics, immune responses, and the potential of monoclonal antibody (mAb) therapies to mitigate viraemia and transmission during acute CHIKV infection, providing novel insights into early intervention strategies. Using data from 29 patients in Cambodia, serial sampling and viral load quantification revealed that the population-average peak viral load occurred ~1.87 days prior to symptom onset. Children demonstrated higher peak viral loads and faster replication rates compared to adults, although symptom severity and burden were similar across age groups. IgM antibodies appeared earlier in adults (median: 4.1 days) than in children (median: 5.1 days; p = 0.036). C-reactive protein (CRP) levels were transiently elevated in about 50% of patients but showed no correlation with disease severity. Mathematical modeling highlighted that prophylactic mAb therapies, when administered 3 days before symptoms onset, could substantially reduce viral load and potentially prevent detectable viraemia. While these findings underscore the potential of mAbs as an early therapeutic strategy, further studies are necessary to evaluate the robustness of these results and assess their practical implications to curb CHIKV outbreaks by minimizing viraemia and presymptomatic transmission.

In 2005-2006, a chikungunya epidemic of unprecedented magnitude hit Reunion Island, which raised a public health concern through the substantial proportions of long-lasting manifestations. To understand the pathophysiology underlying chronic chikungunya (CC), we designed the CHIKGene cohort study and collected blood samples from 133 subjects diagnosed with CC and from 86 control individuals that had recovered within 3 months, 12-to-15 years after exposure.

We conducted bulk RNAseq analysis on peripheral blood mononuclear cells to find differentially expressed genes (DEGs), gene set enrichment analysis (GSEA) and gene ontologies to uncover top-level enriched terms associated with DEGs, and weighted gene correlation network analysis (WGCNA) to elucidate underlying cellular processes.

Among 1549 DEGs, gene expression analysis identified 10 top genes including NR4A2 and TRIM58 (upregulated in CC), IGHG3 and IGHV3-49 (downregulated in CC) linked to immune regulation, OSBP2 (upregulated in CC) and SEMA6B (downregulated in CC) linked to neuronal homeostasis and axon guidance, respectively. GSEA and WGCNA unveiled cellular processes such as "Metabolism of RNA" and "Cell Cycle".

This study uncovers a shift in gene expression of CC subjects. IGHG3 and IGHV3-49 gene shut-offs spotlight the importance of neutralizing antibodies against chikungunya virus in the progression to chronic disease. Human diseases associations highlight connections to rheumatoid arthritis, nervous and cardiac systems. GSEA and WGCNA bounce the hypotheses of a persistent viral reservoir or an increased susceptibility to RNA viral pathogens with new onset infections. Together, our findings might offer potential targets for therapeutic options aimed at alleviating chronic chikungunya.

Arboviral arthritides are a group of viral infections affecting the musculoskeletal system. Mosquitoes are vectors for some of the arboviral febrile diseases such as due to chikungunya, dengue and Zika viruses, which constitute a major proportion of arboviral arthritide syndromes in humans. They have gained epidemiological importance as the natural habitats of these mosquitoes are in the vicinity of human dwellings. Chikungunya virus infection frequently leads to post-infectious chronic musculoskeletal syndromes including erosive inflammatory arthritis, which resembles RA. Clinical features of the chronic phase result from the chronic persistence of the virus in certain tissues after the acute infection has resolved. In addition, the triggering of autoimmunity has also been implicated in musculoskeletal syndromes. Due to the diversity of clinical presentations and overlapping features with other viral illnesses and inflammatory arthritides, diagnosis and management are challenging. Poor prognostic factors for predicting evolution to chronic arthritides are not well delineated. There is no universal agreement regarding when to start immunomodulatory agents and the duration of such therapy. The lack of specific antiviral agents adds to the complexity of the situation. A live-attenuated vaccine has been recently approved by the US Food and Drug Administration for the prevention of chikungunya virus infection. This review discusses the musculoskeletal syndromes related to arboviral infections, with a major focus on chikungunya virus-related arthritis to provide practical guidance to clinicians involved in managing patients with chikungunya and its sequelae.

Post-chikungunya viral arthritis may persist for months to years after infection and is characterized by relapsing and remitting symptoms. This study investigates the relationship between autoantibodies and chikungunya arthritis severity, providing insights into arthritis pathogenesis. We assessed arthritis measures in a cohort of serologically confirmed chikungunya cases from Colombia between 2019 and 2021 (n = 144). We measured arthritis disease severity, flare intensity, pain, and disability, then plasma antibody levels of rheumatoid factor IgM, anti-cyclic citrullinated peptide (CCP), anti-citrullinated α-enolase peptide 1 (CEP-1), anti-nuclear antibody (ANA), anti-citrullinated vimentin (Sa), and immunoglobulins produced in response to chikungunya, Zika and Mayaro. Finally, we examined the correlation between the arthritis measures with the titers of antibodies hypothesized to play a potential role in arthritis pathogenesis. Cases were characterized by moderate disease severity (Disease Activity Score-28 mean, 3.66 ± 1.23) in current arthritis flare with moderate intensity (Flare Score, 25.42 ± 12.38), moderate pain (61.47 ± 27.23 on visual analog scale 0-100), and some disability (Health Assessment Questionnaire 0.77 ± 0.58). After Bonferroni adjustment, there were no statistically significant correlations between the levels of antibodies and arthritis measures. Weak correlations between rheumatoid factor IgM with arthritis severity and pain (P < 0.01) and anti-CEP1 with disability (P < 0.05) were observed when unadjusted for multiple comparisons. The data suggest that autoantibodies, such as RF, anti-CCP, and anti-CEP-1, do not correlate with post-chikungunya arthritis disease severity, thus unlikely to significantly contribute to pathogenesis. Exposure to other arboviral infections was not related to worse post-chikungunya arthritis. This suggests that other pathways for arthritis disease pathogenesis should be examined.IMPORTANCEThis cohort study describes the correlation between levels of autoantibodies, viral antibodies, and arthritis outcomes, suggesting that autoantibodies known to play an important role in other autoimmune diseases do not correlate with chikungunya arthritis relapse disease severity and are unlikely to contribute significantly to arthritis pathogenesis. This suggests that other pathways for arthritis disease pathogenesis should be examined to identify diagnostic and prognostic markers of alphaviral arthritis.

Arboviral diseases are viral infections transmitted to humans through the bites of arthropods, such as mosquitoes, often causing a variety of pathologies associated with high levels of morbidity and mortality. Over the past decades, these infections have proven to be a significant challenge to health systems worldwide, particularly following the considerable geographic expansion of the dengue virus (DENV) and its most recent outbreak in Latin America as well as the difficult-to-control outbreaks of yellow fever virus (YFV), chikungunya virus (CHIKV), and Zika virus (ZIKV), leaving behind a substantial portion of the population with complications related to these infections. Currently, the world is experiencing a period of intense globalization, which, combined with global warming, directly contributes to wider dissemination of arbovirus vectors across the globe. Consequently, all continents remain on high alert for potential new outbreaks. Thus, this review aims to provide a comprehensive understanding of the pathogenesis of the four main arboviruses today (DENV, ZIKV, YFV, and CHIKV) discussing their viral characteristics, immune responses, and mechanisms of viral evasion, as well as important clinical aspects for patient management. This includes associated symptoms, laboratory tests, treatments, existing or developing vaccines and the main associated complications, thus integrating a broad historical, scientific and clinical approach.

Alphaviruses are re-emerging vector-born pathogens that cause arthralgia or encephalitic diseases on a global scale. While a vaccine against chikungunya virus was recently approved, no vaccines currently exist for other alphaviruses, nor are there antiviral drugs for the treatment of alphavirus infections. Alphaviruses have positive-strand RNA genomes, and their RNA replication is coordinated by activities of the multifunctional nonstructural protein 2 (nsP2), a helicase-protease and a subunit of viral RNA replicase. We provide a comprehensive overview of nsP2 functions and inhibitors of its activities for their potential as effective antivirals. Furthermore, analysis of nsP2 activities suggests that it could be targeted to develop advanced live attenuated vaccines and strategies for controlling alphavirus transmission by mosquito vectors.

Mayaro virus (MAYV) is an arthritogenic arbovirus that causes a debilitating illness that can progress to a chronic rheumatic disease characterized by persistent viral replication in macrophages within joint tissues. Here, we report that MAYV-infected macrophages release decondensed DNA traps (DNA extracellular traps, DETs) through a mechanism driven by the production of reactive oxygen species and peptidyl arginine deiminase activation, resembling the classical mechanism of pathogen clearance by activated neutrophils. Unlike traditional pathogen clearance observed for NETs released by neutrophils, MAYV-induced DETs did not inactivate the virus. Instead, DET-ensnared viruses are internalized by neighboring uninfected macrophages, increasing the number of infected cells. Collectively, these findings suggest that MAYV-containing DETs act as a "Trojan horse" that facilitates viral dissemination within inflamed tissues, connecting macrophage-mediated inflammatory response to viral persistence in the articular tissue in chronic MAYV disease.

Chikungunya virus (CHIKV) infection often results in a chronic joint condition known as Post-Chikungunya Chronic Inflammatory Joint Disease (pCHIKV-CIJD). This condition disrupts individuals' daily lives and contributes to increased healthcare expenditure. This study investigated the molecular mechanisms underlying pCHIKV-CIJD development by analyzing RNA transcripts, including small RNAs, of whole blood from CHIKV-infected patients. By comparing patients who evolved to pCHIKV-CIJD with those who did not, we identified molecular signatures associated with chronification in acute and post-acute disease phases. These molecules were primarily associated with an altered immune response regulation. Notably, LIFR, an immune receptor that enhanced IL-6 transcription, was down-regulated in the acute phase of pCHIKV-CIJD patients, while its inhibitor, hsa-miR-98-5p, was up-regulated in these individuals. Other downregulated genes include members of immune mechanisms whose impairment can lead to a reduction in the first line of antiviral response, thereby promoting virus persistence for a longer period in these patients. Additionally, pCHIKV-CIJD patients exhibited reduced transcript levels of MMP8, LFT, and DDIT4, genes already implicated in the pathological process of other types of inflammatory arthritis and seemingly relevant for pCHIKV-CIJD development. Overall, our findings provide insights into the early molecular mechanisms involved in the chronification and highlight potential targets for further investigation.

The aim of this systematic review of prevalence is to observe and discuss the clinical manifestations of Chikungunya Virus disease in its chronic phase.

To be eligible, the observational studies should accompany the individuals for at least six months. The research was conducted using electronic databases MEDLINE and EMBASE. The methodological quality was evaluated using the "Joanna Briggs Institute's critical appraisal checklist for studies reporting prevalence data" tool.

The search has found 175 articles. The application of the inclusion criteria defined a total of 29 selected studies. From the included studies, only one did not present arthralgia as a prevalent symptom in the chronic phase. Other signs and symptoms observed were: fatigue; sleep disorders; myalgia; skin lesions; depression; digestive disorders.

Because it is an often incapacitating symptom, arthralgia can affect the individuals' quality of life, with implications in their social and work life. Since the chronic phase is common in infected individuals, all levels of health care should be prepared to monitor, in the medium to long term, the patients affected by this condition.

Humans contract the Chikungunya virus (CHIKV), an alphavirus transmitted by mosquitoes that induces acute and chronic musculoskeletal discomfort and fever. Millions of cases of the disease have been attributed to CHIKV in the Indian Ocean region since 2004, and the virus has since spread to Europe, the Middle East, and the Pacific. The exponential proliferation of CHIKV in recent times underscores the critical nature of implementing preventative measures and exploring potential control strategies. The principal laboratory test employed to diagnose infection in serum samples collected over six days after the onset of symptoms is the detection of CHIKV or viral RNA. Although two commercially available real-time reverse transcription-polymerase chain reaction products exist, data on their validity are limited. A diagnostic instrument that is rapid, sensitive, specific, and cost-effective is, therefore an absolute necessity, particularly in developing nations. Biosensors have demonstrated considerable potential in the realm of pathogen detection. The rapid and sensitive detection of viruses has been facilitated by the development of numerous types of biosensors, including affinity-based nano-biosensors, graphene affinity-based biosensors, optical nano-biosensors, surface Plasmon Resonance-based optical nano-biosensors, and electrochemical nano-biosensors. Furthermore, the utilization of nanomaterials for signal extension, including but not limited to gold and silver nanoparticles, quantum dots, and iron oxide NPs, has enhanced the precision and sensitivity of biosensors. The developed innovative diagnostic method is time-efficient, precise, and economical; it can be implemented as a point-of-care device. The technique may be implemented in diagnostic laboratories and hospitals to identify patients infected with CHIKV. Throughout this article, we have examined a multitude of CHIKV nano-biosensors and their respective properties. Following a discussion of representative nanotechnologies for biosensors, numerous NPs-assisted CHIKV nano-biosensors are summarized in this article. As a result, we anticipate that this review will furnish a significant foundation for advancing innovative CHIKV nano-biosensors.

Chikungunya fever, caused by Chikungunya virus (CHIKV) exhibits clinical features that mimic that of other arbovirus infections such as dengue. CHIKV Envelope 2 (E2) protein, an antigenic epitope of CHIKV, has been identified as an ideal marker for diagnostics. The current CHIKV antigen detection tests are largely based on antibodies but are beleaguered by issues such as sensitivity to high temperature, expensive and prone to batch-to-batch variations. Aptamers are suitable alternatives to antibodies as they are cheaper and have no batch-to-batch variations compared to antibodies. In this study, DNA aptamer selection against CHIKV E2 proteins was performed using two different randomized ssDNA libraries. Chik-2 (96-mer) and Chik-3 (76-mer) were isolated from these two libraries and were identified as the potential aptamers against CHIKV E2 protein. The binding affinity of Chik-2 and Chik-3 against CHIKV E2 protein was estimated at 177.5 ± 32.69 nM and 30.01 ± 3.60 nM, respectively. A sandwich ELASA was developed, and this assay showed a detection limit of 2.17 x 103 PFU/mL. The sensitivity and specificity of the assay were 80 % and 100 %, respectively. The assay showed no cross-reactivity with dengue-positive samples, demonstrating the enormous diagnostic potential of these aptamers for the detection of CHIKV.

O'nyong-nyong virus (ONNV) is a neglected mosquito-borne alphavirus belonging to the Togaviridae family. ONNV is known to be responsible for sporadic outbreaks of acute febrile disease and polyarthralgia in Africa. As climate change increases the geographical range of known and potential new vectors, recent data indicate a possibility for ONNV to spread outside of the African continent and grow into a greater public health concern. In this review, we summarise the current knowledge on ONNV epidemiology, host-pathogen interactions, vector-virus responses, and insights into possible avenues to control risk of further epidemics. In this review, the limited ONNV literature is compared and correlated to other findings on mainly Old World alphaviruses. We highlight and discuss studies that investigate viral and host factors that determine viral-vector specificity, along with important mechanisms that determine severity and disease outcome of ONNV infection.

Chikungunya virus (CHIKV) is a mosquito-transmitted, RNA virus that causes an often-severe musculoskeletal illness characterized by fever, joint pain, and a range of debilitating symptoms. The virus has re-emerged as a global health threat in recent decades, spreading from its origin in Africa across Asia and the Americas, leading to widespread outbreaks impacting millions of people. Despite more than 50 years of research into the pathogenesis of CHIKV, there is still no curative treatment available. Current management of CHIKV infections primarily involves providing supportive care to alleviate symptoms and improve the patient's quality of life. Given the ongoing threat of CHIKV, there is an urgent need to better understand its pathogenesis. This understanding is crucial for deciphering the mechanisms underlying the disease and for developing effective strategies for both prevention and management. This review aims to provide a comprehensive overview of CHIKV and its pathogenesis, shedding light on the complex interactions of viral genetics, host factors, immune responses, and vector-related factors. By exploring these intricate connections, the review seeks to contribute to the knowledge base surrounding CHIKV, offering insights that may ultimately lead to more effective prevention and management strategies for this re-emerging global health threat.

Chikungunya virus (CHIKV) is responsible for the most endemic alphavirus infections called Chikungunya. The endemicity of Chikungunya has increased over the past two decades, and it is a pathogen with pandemic potential. There is currently no approved direct-acting antiviral to treat the disease. As part of our antiviral drug discovery program focused on alphaviruses and the non-structural protein 2 protease, we discovered that J12 and J13 can inhibit CHIKV nsP2 protease and block the replication of CHIKV in cell cultures. Both compounds are metabolically stable to human liver microsomal and S9 enzymes. J13 has excellent oral bioavailability in pharmacokinetics studies in mice and ameliorated Chikungunya symptoms in preliminary efficacy studies in mice. J13 exhibited an excellent safety profile in in vitro safety pharmacology and off-target screening assays, making J13 and its analogs good candidates for drug development against Chikungunya.

Persistent viral infections are associated with long-term health issues and prolonged transmission. How external perturbations after initial exposure affect the duration of infection is unclear. We discovered that murine astrovirus, an enteric RNA virus, persists indefinitely when mice remain unperturbed but is cleared rapidly after cage change. Besides eliminating the external viral reservoir, cage change also induced a transcriptional defense response in the intestinal epithelium. We further identified that displacing infected animals initially caused a temporary period of immune suppression through the stress hormone corticosterone, which was followed by an immune rebound characterized by an increase in CD8 T cells responsible for the epithelial antiviral responses. Our findings show how viral persistence can be disrupted by preventing re-exposure and activating immunity upon stress recovery, indicating that external factors can be manipulated to shorten the duration of a viral infection.

Common respiratory viruses, including the human parainfluenza viruses, threaten human health seasonally and associate with the development of chronic lung diseases. Evidence suggests that these viruses can persist, but the sources of viral products in vivo and their impact on chronic respiratory diseases remain unknown. Using the murine parainfluenza virus Sendai, we demonstrate that viral protein and RNA persist in lung macrophages, type 2 innate lymphoid cells (ILC2s) and dendritic cells long after the infectious virus is cleared. Cells containing persistent viral protein expressed Th2 inflammation-related transcriptomic signatures associated with the development of chronic lung diseases, including asthma. Lineage tracing demonstrated that distinct functional groups of cells contribute to the chronic pathology. Importantly, targeted ablation of infected cells significantly ameliorated chronic lung disease. Overall, we identified persistent infection of innate immune cells as a key factor in the progression from acute to chronic lung disease after infection with parainfluenza virus.

Background: The chikungunya virus (CHIKV), transmitted by infected Aedes mosquitoes, has caused a significant number of infections worldwide. In Brazil, the emergence of the CHIKV-ECSA genotype in 2014 posed a major public health challenge due to its association with more severe symptoms. Objectives/Methods: This study aimed to shed new light on the host immune response by examining the whole-blood transcriptomic profile of both CHIKV-acute and chronically infected individuals from Feira de Santana, Bahia, Brazil, a region heavily affected by CHIKV, Dengue, and Zika virus epidemics. Results: Our data reveal complex symptomatology characterized by arthralgia and post-chikungunya neuropathy in individuals with chronic sequelae, particularly affecting women living in socially vulnerable situations. Analysis of gene modules suggests heightened metabolic processes, represented by an increase in NADH, COX5A, COA3, CYC1, and cap methylation in patients with acute disease. In contrast, individuals with chronic manifestations exhibit a distinct pattern of histone methylation, probably mediated by NCOA3 in the coactivation of different nuclear receptors, KMT2 genes, KDM3B and TET2, and with alterations in the immunological response, majorly led by IL-17RA, IL-6R, and STAT3 Th17 genes. Conclusion: Our results emphasize the complexity of CHIKV disease progression, demonstrating the heterogeneous gene expression and symptomatologic scenario across both acute and chronic phases. Moreover, the identification of specific gene modules associated with viral pathogenesis provides critical insights into the molecular mechanisms underlying these distinct clinical manifestations.

This study aimed to determine the incidence of post-chikungunya chronic rheumatism (pCHIK-CR) and its impact on quality of life (QoL) and chronic fatigue in adults seven years after the 2014-2015 CHIKV outbreak in Piedecuesta, Colombia. We evaluated 78 adults (median age: 30 years, IQR: 21.0; women 60.3%) with confirmed CHIKV infection. In 2022, participants underwent a GALS examination and completed surveys on disability, stiffness, health status, and fatigue. A rheumatologist evaluated patients who reported arthralgia, morning stiffness, and abnormal GALS examination. Chronic fatigue was defined as fatigue persisting for over six months. Seven years after infection, 14.1% of participants were classified as pCHIK-CR cases, 41.0% as having non-inflammatory pain, likely degenerative (NIP-LD), and 44.9% without rheumatic disease (Wo-RM). Patients with pCHIK-CR and NIP-LD exhibited significantly worse QoL compared to Wo-RM cases. Chronic fatigue prevalence increased from 8.6% in Wo-RM patients to 25.0% in NIP-LD and 54.6% in pCHIK-CR cases. This study implemented a comprehensive clinical assessment to objectively estimate and characterize the incidence of chronic rheumatological disease attributed to CHIKV infection. One in seven cases with CHIKV infection develops pCHIK-CR, which impacts both QoL and chronic fatigue. This study contributes to understanding the burden of these arboviruses in the medium term.

Obesity induces diverse changes in host immunity, resulting in worse disease outcomes following infection with various pathogens, including arthritogenic alphaviruses. However, the impact of obesity on the functional landscape of immune cells during arthritogenic alphavirus infection remains unexplored. Here, we used single-cell RNA sequencing (scRNA-seq) to dissect the blood and tissue immune responses to Mayaro virus (MAYV) infection in lean and obese mice. Footpad injection of MAYV caused significant shifts in immune cell populations and induced robust expression of interferon response and proinflammatory cytokine genes and related pathways in both blood and tissue. In MAYV-infected lean mice, analysis of the local tissue response revealed a unique macrophage subset with high expression of IFN response genes that was not found in obese mice. This was associated with less severe inflammation in lean mice. These results provide evidence for a unique macrophage population that may contribute to the superior capacity of lean mice to control arthritogenic alphavirus infection.

Chikungunya is a re-emerging viral infection across the globe. The purpose of this article is to review the systemic and ophthalmic manifestations associated with chikungunya fever.

A review of literature was conducted using online databases.

In this report, we have reviewed the presently available literature on uveitis caused by chikungunya and highlighted the current knowledge of its clinical manifestations, imaging features, laboratory diagnostics, and the available therapeutic modalities from the systemic and ophthalmic standpoint.

Ocular involvement in chikungunya infection may occur at the time of systemic manifestations or it may occur as a delayed presentation many weeks after the fever. Treatment relies on a supportive therapy for systemic illness. Treatment of ocular manifestation depends on the type of manifestations and usually includes a combination of topical and oral steroids.

Despite their role as innate sentinels, macrophages can serve as cellular reservoirs of chikungunya virus (CHIKV), a highly-pathogenic arthropod-borne alphavirus that has caused large outbreaks among human populations. Here, with the use of viral chimeras and evolutionary selection analysis, we define CHIKV glycoproteins E1 and E2 as critical for virion production in THP-1 derived human macrophages. Through proteomic analysis and functional validation, we further identify signal peptidase complex subunit 3 (SPCS3) and eukaryotic translation initiation factor 3 subunit K (eIF3k) as E1-binding host proteins with anti-CHIKV activities. We find that E1 residue V220, which has undergone positive selection, is indispensable for CHIKV production in macrophages, as its mutation attenuates E1 interaction with the host restriction factors SPCS3 and eIF3k. Finally, we show that the antiviral activity of eIF3k is translation-independent, and that CHIKV infection promotes eIF3k translocation from the nucleus to the cytoplasm, where it associates with SPCS3. These functions of CHIKV glycoproteins late in the viral life cycle provide a new example of an intracellular evolutionary arms race with host restriction factors, as well as potential targets for therapeutic intervention.

Chikungunya fever (CHIKF), caused by the Chikungunya virus (CHIKV), manifests as acute febrile illness often associated with polyarthritis and polyarthralgia. Although the acute symptoms resolve within two weeks, many patients experience prolonged joint pain and inflammation, resembling rheumatoid arthritis (RA). This study aimed to identify molecular markers related to joint pain and chronicity in CHIKV-infected individuals by analyzing blood transcriptomes using bulk RNA sequencing. B- and T-cell receptor (BCR and TCR) diversity was assessed through computational analysis of RNA-seq data, revealing a significant reduction in CDR3 diversity in CHIKV-infected individuals compared to healthy controls. This reduced diversity was associated with the upregulation of genes involved in osteoclast differentiation and activation, particularly through the RANK/RANKL signaling pathway. These findings suggest a potential link between immune dysregulation and enhanced osteoclast activity, which may contribute to the persistence of joint pain in chronic CHIKF. Targeting osteoclast-related pathways could offer therapeutic strategies for managing chronic symptoms in CHIKF patients.

Chikungunya virus (CHIKV) is an arbovirus causing acute febrile illness with severe joint pain, often leading to chronic arthralgia. This study investigated the adaptive immune responses during the early stages of symptomatic acute CHIKV infection, focusing on the transcription factors and cytokines linked to Th1, Th2, Th17, and Treg cells. Thirty-six individuals were enrolled: nine healthy controls and 27 CHIKV-positive patients confirmed by qRT-PCR. Blood samples were analyzed for the mRNA expression of transcription factors (Tbet, GATA3, FoxP3, STAT3, RORγt) and cytokines (IFN-γ, IL-4, IL-17, IL-22, TGF-β, IL-10). The results showed the significant upregulation of Tbet, GATA3, FoxP3, STAT3, and RORγt in CHIKV-positive patients, with RORγt displaying the highest increase. Correspondingly, cytokines IFN-γ, IL-4, IL-17, and IL-22 were upregulated, while TGF-β was downregulated. Principal component analysis (PCA) confirmed the distinct immune profiles between CHIKV-positive and healthy individuals. A correlation analysis indicated that higher Tbet expression correlated with a lower viral load, whereas FoxP3 and TGF-β were associated with higher viral loads. Our study sheds light on the intricate immune responses during acute CHIKV infection, characterized by a mixed Th1, Th2, Th17, and Treg response profile. These results emphasize the complex interplay between different adaptive immune responses and how they may contribute to the pathogenesis of Chikungunya fever.

Diseases transmitted by arthropod-borne viruses such as West Nile virus (WNV) and chikungunya virus (CHIKV) pose threat to global public health. Unfortunately, to date, there is no available approved drug for severe symptoms caused by both viruses. It has been reported that reverse transcriptase inhibitors can effectively inhibit RNA polymerase activity of RNA viruses. We screened the anti-WNV activity of the FDA-approved reverse transcriptase inhibitor library and found that 4 out of 27 compounds showed significant antiviral activity. Among the candidates, etravirine markedly inhibited WNV infection in both Huh 7 and SH-SY5Y cells. Further assays revealed that etravirine inhibited the infection of multiple arboviruses, including yellow fever virus (YFV), tick-borne encephalitis virus (TBEV), and CHIKV. A deeper study at the phase of action showed that the drug works primarily during the viral replication process. This was supported by the strong interaction potential between etravirine and the RNA-dependent RNA polymerase (RdRp) of WNV and alphaviruses, as evaluated using molecular docking. In vivo, etravirine significantly rescued mice from WNV infection-induced weight loss, severe neurological symptoms, and death, as well as reduced the viral load and inflammatory cytokines in target tissues. Etravirine showed antiviral effects in both arthrophlogosis and lethal mouse models of CHIKV infection. This study revealed that etravirine is an effective anti-WNV and CHIKV arbovirus agent both in vitro and in vivo due to the inhibition of viral replication, providing promising candidates for clinical application.

Chikungunya (CHIKV) and Mayaro (MAYV) viruses are arthritogenic alphaviruses that promote an incapacitating and long-lasting inflammatory muscle-articular disease. Despite studies pointing out the importance of skeletal muscle (SkM) in viral pathogenesis, the long-term consequences on its physiology and the mechanism of persistence of symptoms are still poorly understood. Combining molecular, morphological, nuclear magnetic resonance imaging, and histological analysis, we conduct a temporal investigation of CHIKV and MAYV replication in a wild-type mice model, focusing on the impact on SkM composition, structure, and repair in the acute and late phases of infection. We found that viral replication and induced inflammation promote a rapid loss of muscle mass and reduction in fiber cross-sectional area by upregulation of muscle-specific E3 ubiquitin ligases MuRF1 and Atrogin-1 expression, both key regulators of SkM fibers atrophy. Despite a reduction in inflammation and clearance of infectious viral particles, SkM atrophy persists until 30 days post-infection. The genomic CHIKV and MAYV RNAs were still detected in SkM in the late phase, along with the upregulation of chemokines and anti-inflammatory cytokine expression. In agreement with the involvement of inflammatory mediators on induced atrophy, the neutralization of TNF and a reduction in oxidative stress using monomethyl fumarate, an agonist of Nrf2, decreases atrogen expression and atrophic fibers while increasing weight gain in treated mice. These data indicate that arthritogenic alphavirus infection could chronically impact body SkM composition and also harm repair machinery, contributing to a better understanding of mechanisms of arthritogenic alphavirus pathogenesis and with a description of potentially new targets of therapeutic intervention.

Arthritogenic alphaviruses pose a significant public health concern due to their ability to cause joint inflammation, with emerging evidence of potential neurological consequences. In this review, we examine the immunopathology and immune evasion strategies employed by these viruses, highlighting their complex mechanisms of pathogenesis and neurological implications. We delve into how these viruses manipulate host immune responses, modulate inflammatory pathways, and potentially establish persistent infections. Further, we explore their ability to breach the blood-brain barrier, triggering neurological complications, and how co-infections exacerbate neurological outcomes. This review synthesizes current research to provide a comprehensive overview of the immunopathological mechanisms driving arthritogenic alphavirus infections and their impact on neurological health. By highlighting knowledge gaps, it underscores the need for research to unravel the complexities of virus-host interactions. This deeper understanding is crucial for developing targeted therapies to address both joint and neurological manifestations of these infections.

Chikungunya virus, an arthropod-borne pathogen is recognized by the World Health Organization as a top priority Emerging Infectious Disease and is ranked fourth in public health needs according to the Coalition for Epidemic Preparedness Innovations. Despite its substantial impact, as evidenced by an annual estimate of 120 274 disability-adjusted life years, our understanding of the chronic aspects of chikungunya disease remains limited. This review focuses on chronic chikungunya disease, emphasizing its clinical manifestations, immunopathogenesis, therapeutic options and disease burden.

Chikungunya fever (CF) is caused by an arbovirus whose manifestations are extremely diverse, and it has evolved with significant severity in recent years. The clinical signs triggered by the Chikungunya virus are similar to those of other arboviruses. Generally, fever starts abruptly and reaches high levels, followed by severe polyarthralgia and myalgia, as well as an erythematous or petechial maculopapular rash, varying in severity and extent. Around 40% to 60% of affected individuals report persistent arthralgia, which can last from months to years. The symptoms of CF mainly represent the tissue tropism of the virus rather than the immunopathogenesis triggered by the host's immune system. The main mechanisms associated with arthralgia have been linked to an increase in T helper type 17 cells and a consequent increase in receptor activator of nuclear factor kappa-Β ligand and bone resorption. This review suggests that persistent arthralgia results from the presence of viral antigens post-infection and the constant activation of signaling lymphocytic activation molecule family member 7 in synovial macrophages, leading to local infiltration of CD4+ T cells, which sustains the inflammatory process in the joints through the secretion of pro-inflammatory cytokines. The term "long chikungunya" was used in this review to refer to persistent arthralgia since, due to its manifestation over long periods after the end of the viral infection, this clinical condition seems to be characterized more as a sequel than as a symptom, given that there is no active infection involved.

Zika (ZIKV) and Chikungunya (CHIKV) viruses are mosquito-transmitted infections, or vector-borne pathogens, that emerged a few years ago. Reliable diagnostic tools for ZIKV and CHIKV-inexpensive, multiplexed, rapid, highly sensitive, and specific point-of-care (POC) systems-are vital for appropriate risk management and therapy. We recently studied a detection system with great success in Mexico (Villahermosa, state of Tabasco), working with human sera from patients infected with those viruses. The research conducted in Mexico validated the efficacy of a novel two-step rapid isothermal amplification technique (RAMP). This approach, which encompasses recombinase polymerase amplification (RPA) followed by loop-mediated isothermal amplification (LAMP), had been previously established in the lab using lab-derived Zika (ZIKV) and Chikungunya (CHIKV) viruses. Crucially, our findings confirmed that this technique is also effective when applied to human sera samples collected from locally infected individuals in Mexico.

Mayaro fever is an emerging viral disease that manifests as an acute febrile illness. The disease is self-limiting, however joint pain can persist for months leading to chronic arthralgia. There is no specific treatment available, which ultimately leads to socioeconomic losses in populations at risk as well as strains to the public health systems.

We reviewed the candidate treatments proposed for Mayaro virus (MAYV) infection and disease, including antiviral compounds targeting viral or host mechanisms, and pathways involved in disease development and pathogenicity. We assessed compound screening technologies and experimental infection models used in these studies and indicated the advantages and limitations of available technologies and intended therapeutic strategies.

Although several compounds have been suggested as candidate treatments against MAYV infection, notably those with antiviral activity, most compounds were assessed only in vitro. Compounds rarely progress toin vivo or preclinical studies, and such difficulty may be associated with limited experimental models. MAYV biology is largely inferred from related alphaviruses and reflected by few studies focusing on target proteins or mechanisms of action for MAYV. Therapeutic strategies targeting pathogenic inflammatory responses have shown potential against MAYV-induced disease in vivo, which might reduce long-term sequelae.

Communications between immune cells are essential to ensure appropriate coordination of their activities. Here, we observed the infiltration of activated macrophages into the joint-footpads of chikungunya virus (CHIKV)-infected animals. Large numbers of CD64+MHCII+ and CD64+MHCII- macrophages were present in the joint-footpad, preceded by the recruitment of their CD11b+Ly6C+ inflammatory monocyte precursors. Recruitment and differentiation of these myeloid subsets were dependent on CD4+ T cells and GM-CSF. Transcriptomic and gene ontology analyses of CD64+MHCII+ and CD64+MHCII- macrophages revealed 89 differentially expressed genes, including genes involved in T cell proliferation and differentiation pathways. Depletion of phagocytes, including CD64+MHCII+ macrophages, from CHIKV-infected mice reduced disease pathology, demonstrating that these cells play a pro-inflammatory role in CHIKV infection. Together, these results highlight the synergistic dynamics of immune cell crosstalk in driving CHIKV immunopathogenesis. This study provides new insights in the disease mechanism and offers opportunities for development of novel anti-CHIKV therapeutics.