Dysregulated TGF-β Production Underlies the Age-Related Vulnerability to Chikungunya Virus

Uhrlaub, Jennifer L.; Pulko, Vesna; DeFilippis, Victor R.; Broeckel, Rebecca; Streblow, Daniel N.; Coleman, Gary D.; Park, Byung; Lindo, John; Vickers, Ivan; Anzinger, Joshua J.; Nikolich‐Žugich, Janko

doi:10.1371/journal.ppat.1005891

Cited by 50 publications

(52 citation statements)

References 45 publications

(57 reference statements)

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“…In experimentally infected macaques, joints, muscles, lymphoid organs, and liver harbor infectious CHIKV or CHIKV RNA for months (18,19). Wild-type (WT) C57BL/6 mice infected with CHIKV develop chronic synovitis (20), and CHIKV RNA and infectious virus can be detected in joint-associated tissue for months (20)(21)(22)(23). The severity of chronic joint disease is increased in aged WT mice with persistent CHIKV infection, and is associated with defects in adaptive immunity (22).…”

Section: Introductionmentioning

confidence: 99%

Chikungunya virus impairs draining lymph node function by inhibiting HEV-mediated lymphocyte recruitment

McCarthy¹,

Davenport²,

Reynoso³

et al. 2018

JCI Insight

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Chikungunya virus (CHIKV) causes acute and chronic rheumatologic disease. Pathogenic CHIKV strains persist in joints of immunocompetent mice, while the attenuated CHIKV strain 181/25 is cleared by adaptive immunity. We analyzed the draining lymph node (dLN) to define events in lymphoid tissue that may contribute to CHIKV persistence or clearance. Acute 181/25 infection resulted in dLN enlargement and germinal center (GC) formation, while the dLN of mice infected with pathogenic CHIKV became highly disorganized and depleted of lymphocytes. Using CHIKV strains encoding ovalbumin-specific TCR epitopes, we found that lymphocyte depletion was not due to impaired lymphocyte proliferation. Instead, the accumulation of naive lymphocytes transferred from the vasculature to the dLN was reduced, which was associated with fewer high endothelial venule cells and decreased CCL21 production. Following NP-OVA immunization, NP-specific GC B cells in the dLN were decreased during pathogenic, but not attenuated, CHIKV infection. Our data suggest that pathogenic, persistent strains of CHIKV disable the development of adaptive immune responses within the dLN.

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Section: Introductionmentioning

confidence: 99%

Chikungunya virus impairs draining lymph node function by inhibiting HEV-mediated lymphocyte recruitment

McCarthy¹,

Davenport²,

Reynoso³

et al. 2018

JCI Insight

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“…Interestingly, we observed that levels of TGF-β expression were reduced in young WT mice infected with MAYV. High levels of TGF-β were associated with a reduced immune response, persistent viremia, and with joint pathology in CHIKV infection in old mice (46). Therefore, the lower levels of TGF-β in MAYV infection could be important to sustain an immune response that restricts muscle damage.…”

Section: Discussionmentioning

confidence: 99%

Mayaro virus replication restriction and induction of muscular inflammation in mice are dependent on age and type-I interferon response

Figueiredo

Leopoldino

et al. 2019

Preprint

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These authors contributed equally to this work. AbstractMayaro virus (MAYV) is an emergent Arbovirus belonging to the Alphavirus genus from the Togaviridae family which has been circulated in forest regions of American continent through small outbreaks. Recent studies warned for the risk of MAYV dispersion to new areas and for the potential establishment of an urban epidemic cycle.Similar to Chikungunya and other arthritogenic Alphavirus, MAYV-induced disease shows a high prevalence of arthralgia and myalgia that can persist for months. Despite this, knowledge regarding pathogenesis, characteristics of host immune response, and resolution of MAYV infections are still limited. Here we investigated the dependence of age, innate and adaptive immunity for the control of MAYV replication and induction of inflammation in mice. We observed that age and type I interferon response are related to restriction of MAYV infection and tissue inflammation in mice. Moreover, we showed that MAYV continues to replicate persistently in adult recombination activation gene-1 efficient mice (RAG1 -/-), indicating that adaptive immunity is essential to MAYV clearance. Despite chronic replication, infected adult RAG1 -/mice did not develop an apparent signal of muscle damage at late infection. On the other hand, MAYV infection induces muscular and paw inflammation in young WT and adult Type I Interferon receptor deficient mice (IFNAR -/-). In addition, MAYV infection triggers an increase in the expression of pro-inflammatory mediators, such as TNF, IL-6, KC, IL-1β, MCP-1, and RANTES, in muscle tissue, and decreases TGF-β expression.Taken together, our study contributes to the comprehension of MAYV pathogenesis, and describes a translational mouse model for further studies of MAYV infection, as well for testing vaccine and therapeutic strategies against this virus. Author SummaryMAYV-induced disease presents a high prevalence of arthralgia and myalgia that potentially persist for months, which is characteristic of the arthritogenic Alphavirus group. However, information regarding MAYV infection and the molecular mechanism of pathogenesis is still scarce. Here we investigated the dependence of age, innate and adaptive immunity for the control of MAYV replication and induction of inflammation in mice. We observed that tissue inflammation and the restriction of MAYV replication in mice are affected by aging and type I interferon response. Besides, we also showed that adaptive immunity was important for MAYV clearance in adult mice. Histological analyses demonstrated that MAYV replication triggered muscular and paw inflammation in young WT and adult type-I interferon receptor deficient mice. In addition, the level of expression of several pro-inflammatory cytokines was increased in the muscle MAYV-infected mice. Our data provide an advance for understanding the molecular mechanism involved in MAYV pathogenesis, as well as describes an in vivo model for further investigations on MAYV infection and for antiviral compounds and vaccine testing.

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“…The sufficiency of dsRNA to induce arthritis in mice suggests that suppressing immune responses could alleviate post-CHIKV chronic arthralgia and synovitis, which is associated with the presence of vRNA [51,52,54–56,58] and persistently elevated type I IFN production [51,55]. Immunosuppressive therapy using methotrexate, corticosteroids, or TNF blockers has shown some efficacy, although not universal, at improving symptoms and limiting progressive joint damage in patients with chronic CHIKV disease [70,71].…”

Section: Viral Pamps - Does Vrna Drive Chronic Disease?mentioning

confidence: 99%

Persistent RNA virus infections: do PAMPS drive chronic disease?

McCarthy

Morrison

2017

Current Opinion in Virology

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Chronic disease associated with persistent RNA virus infections represents a key public health concern. While human immunodeficiency virus-1 and hepatitis C virus are perhaps the most well-known examples of persistent RNA viruses that cause chronic disease, evidence suggests that many other RNA viruses, including re-emerging viruses such as chikungunya virus, Ebola virus and Zika virus, establish persistent infections. The mechanisms by which RNA viruses drive chronic disease are poorly understood. Here, we discuss how the persistence of viral RNA may drive chronic disease manifestations via the activation of RNA sensing pathways.

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Dysregulated TGF-β Production Underlies the Age-Related Vulnerability to Chikungunya Virus

Cited by 50 publications

References 45 publications

Chikungunya virus impairs draining lymph node function by inhibiting HEV-mediated lymphocyte recruitment

Chikungunya virus impairs draining lymph node function by inhibiting HEV-mediated lymphocyte recruitment

Mayaro virus replication restriction and induction of muscular inflammation in mice are dependent on age and type-I interferon response

Persistent RNA virus infections: do PAMPS drive chronic disease?

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