Chikungunya virus (CHIKV) is a mosquito-transmitted arbovirus that has re-emerged and spread globally since 2006, affecting 112 countries worldwide, including the US. Cases of myocarditis, dilated cardiomyopathy, and heart failure were found associated with CHIKV infections during the past outbreaks, and were linked with 22% of CHIKV-related mortality cases during the La Runion Island outbreak. Despite the association between CHIKV and cardiomyopathies, there has been little research in this area, and we still do not understand the nature of CHIKV-induced cardiovascular disease. I have found that CHIKV infects and replicates in the heart of wild-type C57BL/6 mice, inducing an early cardiac infiltration of neutrophils. In addition, I identified cardiac fibroblasts as the potential target cell type for CHIKV infection. Based on these studies, my hypothesis is that cardiac fibroblasts are the main target of CHIKV during heart infection and that both viral replication and immune-mediated responses lead to CHIKV-induced cardiac tissue damage. To test this hypothesis, in Aim 1 I will determine the dynamics of CHIKV infection in the heart and the specific cardiac cell types infected by CHIKV. I will infect wild-type C57BL/6 mice with a CHIKV fluorescent reporter virus developed by our group, and I will quantify infectious particles and viral RNA in heart tissue at different time-points. In addition, I will identify CHIKV-infected cardiac cells by confocal microscopy and will validate these observations by flow cytometry. In Aim 2 I will elucidate how CHIKV is inducing cardiac damage through apoptosis, mononuclear cell infiltration, and/or fibrosis at different infection time-points by histopathologic and multiparametric imaging analyses. In addition, I will use knockout mice to determine the role of CD4+ T cells, CD8+ T cells and B cells in CHIKV-induced cardiac damage. The completion of this proposal will address the fundamental aspects of how CHIKV can induce cardiac disease, through identifying and characterizing CHIKV-infected cells in the heart and determining how the virus and the host immune response influence CHIKV-induced cardiac damage. Understanding these basic aspects of CHIKV-induced cardiopathies is fundamental in the development of future preventive strategies. Finally, the knowledge acquired for CHIKV-induced cardiopathies will be applied to future studies underscoring the role of the host immune system in other viral-induced cardiac diseases.
|Program type||Postdoctoral Fellowship|
|Effective start/end date||01/01/2020 → 12/31/2021|