O papel do eixo CCL2-CCR2 na patogênese da infecção pelo Vírus Mayaro

Abstract

The Mayaro Virus (MAYV) belongs to the Alphavirus genus and the Togaviridae family. MAYV is responsible for sporadic outbreaks of acute febrile illness in South American countries. Clinical signs of Mayaro fever include headache, fever, myalgia and arthralgia, which can be persistent and debilitating. The disease caused by alphaviruses is classified as an immunopathology, and many inflammatory mediators have been described to play a relevant role in the pathogenesis of these viruses, including IL-6, TNF and CCL2. Thus, due to the impact that MAYV disease has on people's quality of life and being poorly understood, the present work aimed to investigate and elucidate the role of the CCR2-CCL2 axis in the pathogenesis of Mayaro Virus infection. For this, mice deficient for the molecules of interest and silencing technique were used. Initially, we first performed the standardization of an immunocompetent model in WT C57BL/6 mice, and then the characterization of the role of the CCR2 receptor in MAYV infection. The results showed that MAYV induced an acute inflammatory disease, characterized by edema, hypernociception and myositis in WT and CCR2-/- mice. The immune response profile in WT was characterized by an increase in the production of inflammatory mediators, such as IL-6, TNF, CCL2 and CCL5. High levels of CCL2 at the local and systemic level were followed by a significant recruitment of CCR2+ macrophages and a cellular response orchestrated by these cells. CCR2-/- mice showed similar levels of edema, hypernociception and myositis when compared to WT mice. However, they showed an increase in CXCL1 levels significantly different from WT mice, followed by a replacement of the inflammatory macrophage infiltrate by neutrophils. On the other hand, although the silencing of ccl2 did not prevent cell migration and reduction of the inflammatory infiltrate, it promoted a significant improvement in hypernociception and reduced expression of important inflammatory molecules, such as ccl5, ccl7 and Tnf. This reveals that CCL2 and TNF have a relevant role in MAYV-induced nociception. In general, it can be concluded that the absence of the CCR2 receptor conferred protection to the animals against MAYV infection, which was observed by the presence of milder signs of disease, lower viral load, less tissue damage and absence of bone loss. Cell culture data show that MAYV infection induces an inflammatory environment that favors osteoclatogenesis, mediated mainly by the cytokines TNF and IL-6. According to this data, infection of IL-6-/- mice resulted in a protective phenotype of bone loss. Therefore, CCR2/CCL2 signaling showed to play an important role in the pathogenesis of the bone loss and pain in MAYV infection, so a promising therapeutic target for developing specific treatment strategies for Mayaro fever.