Interaction of the endogenous antibody response with activating FcgRs enhance control of Mayaro virus through monocytes

Mayaro virus (MAYV) is an emerging arbovirus. Previous studies have shown antibody Fc effector functions are critical for optimal monoclonal antibody-mediated protection against alphaviruses; however, the requirement of Fc gamma receptors (FcgRs) for protection during natural infection has not been evaluated. Here, we showed mice lacking activating FcgRs (FcRg-/-) developed prolonged clinical disease with more MAYV in joint-associated tissues. Viral clearance was associated with anti-MAYV cell surface binding antibodies rather than neutralizing antibodies. Lack of Fc-FcgR engagement increased the number of monocytes through chronic timepoints. Single cell RNA sequencing showed elevated levels of pro-inflammatory monocytes in joint-associated tissue with increased MAYV RNA present in FcRg-/- monocytes and macrophages. Transfer of FcRg-/- monocytes into wild type animals was sufficient to increase virus in joint-associated tissue. Overall, this study suggests that engagement of antibody Fc with activating FcgRs promotes protective responses during MAYV infection and prevents a pro-viral role for monocytes. Overall design: Mice were infected with 10^3 FFU of MAYV and, at 10 dpi, mice were sacrificed, perfused with PBS, and the ipsilateral feet were dissociated into a single cell suspension, as described above. Cells were stained with anti-CD45 BUV395 (BD Biosciences clone 30-F11; 1:200) and a viability dye. Viable, unfixed, CD45+ or CD45- cells were sorted on a BD FACSAria into RPMI supplemented with 10% FBS. Sorted CD45+ immune cells were centrifuged and resuspended in 1X PBS with BSA 0.04% to analyze using scRNA-seq.