Mayaro Virus Replication Restriction and Induction of Muscular Inflammation in Mice Are Dependent on Age, Type-I Interferon Response, and Adaptive Immunity

Abstract

Mayaro virus (MAYV) is an emergent arbovirus first described in forest regions of the American continent, with recent and increasing notification of urban area circulation. Similar to Chikungunya (CHIKV) and other arthritogenic Alphavirus, MAYV-induced disease shows a high prevalence of persistent arthralgia, and myalgia. Despite this, knowledge regarding pathogenesis and characteristics of host immune response of MAYV infections are still limited. Here, using different ages of wild-type (WT), adult Type I Interferon receptor deficient (IFNAR–/–), and adult recombination activation gene-1 deficient (RAG–/–) mice, we have investigated the dependence of age, innate and adaptive immunity for the control of MAYV replication, tissue damage, and inflammation in mice. We have found that MAYV induces clinical signal and replicates in young WT mice, which gain the ability to restrict MAYV replication with aging. In addition, we observed that mice age and type I interferon response are related to restriction of MAYV infection and muscular inflammation in mice. Moreover, MAYV continues to replicate persistently in RAG–/– mice, being detected at blood and tissues 40 days post infection, indicating that adaptive immunity is essential to MAYV clearance. Despite chronic replication, infected adult RAG–/– mice did not develop an apparent signal of muscle damage in early and late infection. On the other hand, MAYV infection in young WT and adult IFNAR-/- mice 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, that were not significantly modulated in adult WT and RAG–/– mice. Taken together, our data demonstrated that age, innate and adaptive immunity are important to restrict MAYV replication and that adaptive immunity is also involved in MAYV-induced tissue damage. These results contribute to the comprehension of MAYV pathogenesis, and describe translational mice models for further studies of MAYV infection, vaccine tests, and therapeutic strategies against this virus.

In-depth characterization of a novel live-attenuated Mayaro virus vaccine candidate using an immunocompetent mouse model of Mayaro disease

“…In the present study, we described a novel model of MAYV infection in adult immunocompetent mice, The age of animals in murine models of alphavirus infections has been considered a determinant factor in the susceptibility and severity of the disease. Neonates and young mice are more susceptible to infection and have been used to emulate alphaviral diseases [37][38][39][40][41] . Of note, Figueiredo and colleagues (2019) 41 have shown that MAYV replication, restriction and induction of muscular inflammation are dependent on age, type-I Interferon response, and adaptive immunity.…”

“…Neonates and young mice are more susceptible to infection and have been used to emulate alphaviral diseases [37][38][39][40][41] . Of note, Figueiredo and colleagues (2019) 41 have shown that MAYV replication, restriction and induction of muscular inflammation are dependent on age, type-I Interferon response, and adaptive immunity. Indeed, MAYV infection of young (25-21-day-old) SV129 and BALB/c mice successfully caused arthritis and myositis, common hallmarks of MF 40,41 .…”

“…Of note, Figueiredo and colleagues (2019) 41 have shown that MAYV replication, restriction and induction of muscular inflammation are dependent on age, type-I Interferon response, and adaptive immunity. Indeed, MAYV infection of young (25-21-day-old) SV129 and BALB/c mice successfully caused arthritis and myositis, common hallmarks of MF 40,41 . As for other arboviruses, such as Zika and Dengue 42,43 , resistance of adult mice to alphavirus infection is especially due to innate immune components such as type I interferons, which quickly provide an antiviral state of non-infected cells 28,29,41 .…”

“…Indeed, MAYV infection of young (25-21-day-old) SV129 and BALB/c mice successfully caused arthritis and myositis, common hallmarks of MF 40,41 . As for other arboviruses, such as Zika and Dengue 42,43 , resistance of adult mice to alphavirus infection is especially due to innate immune components such as type I interferons, which quickly provide an antiviral state of non-infected cells 28,29,41 . Accordingly, infection of type I interferon receptor-deficient mice (A129 −/− ) with CHIKV 29 , as well as infection of adult A129 −/− or recombination activation gene-1 deficient mice (RAG −/− ) with MAYV 26,41 provides a model that reproduces many of the clinical manifestations of human MF disease.…”

“…As for other arboviruses, such as Zika and Dengue 42,43 , resistance of adult mice to alphavirus infection is especially due to innate immune components such as type I interferons, which quickly provide an antiviral state of non-infected cells 28,29,41 . Accordingly, infection of type I interferon receptor-deficient mice (A129 −/− ) with CHIKV 29 , as well as infection of adult A129 −/− or recombination activation gene-1 deficient mice (RAG −/− ) with MAYV 26,41 provides a model that reproduces many of the clinical manifestations of human MF disease. Recently, MAYV infection of 3-4-week-old mice resulted in non-lethal models that emulated several clinical signs of MF in immunocompetent young-adult mice, such as footpad swelling, viremia and hepatic injury, although the arthritogenic effects of the virus were not investigated 26,44 .…”