Ly6Chi monocytes mediate control of acute alphavirus infection by MAVS-dependent production of type I IFN

Abstract

Abstract Chikungunya virus (CHIKV) and Ross River virus (RRV) are mosquito-borne alphaviruses that cause epidemics of debilitating musculoskeletal disease. Monocytes have been implicated in the pathogenesis of these infections, but their specific roles are less clear. To assess the role of monocytes in alphavirus pathogenesis, we used CCR2-DTR transgenic mice to deplete CCR2+ cells by administering diphtheria toxin (DT). DT-treated CCR2-DTR+ mice showed reduced weight gain and more severe disease following infection and had fewer Ly6Chi monocytes and NK cells in circulation compared to DT-treated WT mice. Also, depletion of CCR2+ cells, but not NK cells alone, restored virulence and increased viral loads in the muscle tissue of mice infected with RRV encoding attenuating mutations in nsP1 to levels seen in monocyte-depleted mice infected with fully virulent RRV. A similar increase in disease severity and viral loads was observed in DT-treated CCR2-DTR+;Rag1−/− mice infected with the nsP1 mutant virus, confirming that these effects are independent of adaptive immunity. In vitro, culture of Ly6Chi monocytes with RRV-infected cells resulted in induction of IFNα gene expression in monocytes that was MAVS-dependent. IFNα expression in monocytes also required new virus particle production from infected cells. Furthermore, monocytes sorted from the circulation and muscle of infected mice had elevated expression of Irf7. Finally, viral loads of the attenuated nsP1 mutant virus were equivalent to those of WT RRV in the muscle tissue of MAVS−/− mice. Collectively, these data suggest that MAVS-dependent production of type I IFN by monocytes is critical for control of acute alphavirus infection and that determinants in nsP1 counteract this response.