Differential restriction of chikungunya virus in primary human cardiac endothelial cells occurs at multiple steps in the viral life cycle

Abstract

Arthropod-borne viruses (arboviruses) constitute a significant ongoing public health threat, as the mechanisms of pathogenesis remain incompletely understood. Cardiovascular symptomatology is emerging as an important manifestation of arboviral infection. We have recently studied the cardiac tropism and mechanisms implicated in cardiac damage in mice for the alphavirus chikungunya virus (CHIKV), and we therefore sought to evaluate the cardiac tropism of other emerging alphaviruses and arboviruses. Using human primary cardiac cells, we found that arboviruses from diverse viral families were able to replicate within these cells. Interestingly, we noted that while the closely related alphavirus Mayaro virus (MAYV) could replicate to high titers in primary human cardiac microvascular endothelial cells, pulmonary, and brain endothelial cells, the Indian Ocean Lineage of CHIKV (CHIKV-IOL) was completely restricted in all endothelial cells tested. Upon further investigation, we discovered that this restriction occurs at both entry and egress stages. Additionally, we observed that compared to CHIKV, MAYV may antagonize or evade the innate immune response more efficiently in human cardiac endothelial cells to increase infection. Overall, this study explores the tropism of arboviruses in human primary cardiac cells and characterizes the strain-specific restriction of CHIKV-IOL in human endothelial cells. Further work is needed to understand how the differential restriction of alphaviruses in human endothelial cells impacts pathogenesis in a living model, as well as the specific host factors responsible. Author SummaryMosquito-borne viruses, such as those within the alphavirus genus, are an ongoing concern to human health globally. While we have recently begun to explore the mechanisms of CHIKV-induced pathology in the heart, little is known about other arboviruses and alphaviruses related to CHIKV. Here, we identified that multiple cardiac cell types are susceptible to infection by several arboviruses important to public health. Specifically, we noted differences in how two related viruses, CHIKV and MAYV, infect endothelial cells from multiple origins. This work highlights the potential for other emerging arboviruses, in addition to CHIKV, to directly infect cardiac tissue. Moreover, it emphasizes the ability for MAYV, an emerging virus that is less studied, to infect various endothelial cell types to high titers, suggesting the need for further research on MAYV pathogenesis. Finally, this research identifies differences in infection between individual strains of CHIKV, suggesting a finely tuned mechanism of restriction in endothelial cells that can be further explored, as well as the need to study use different viral strains for future alphavirus research.