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

TL;DR

This study shows that antibody interactions with activating FcγRs help control Mayaro virus infection by preventing monocytes from prolonging the disease.

Contribution

The study reveals that FcγR engagement during natural alphavirus infection is crucial for protection and prevents monocytes from supporting viral persistence.

Findings

Mice lacking activating FcγRs showed prolonged disease and higher virus levels in joint tissues.

Monocytes from FcγR-deficient mice harbored more virus RNA and contributed to increased viral burden when transferred to wild-type mice.

Antibody Fc effector functions, not neutralizing antibodies, were critical for viral clearance.

Abstract

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 (FcγRs) for protection during natural infection has not been evaluated. Here, we showed mice lacking activating FcγRs (FcRγ−/−) developed prolonged clinical disease with increased MAYV in joint-associated tissues. Viral reduction was associated with anti-MAYV cell surface binding antibodies rather than neutralizing antibodies. Lack of Fc-FcγR engagement increased the number of monocytes present in the joint-associated tissue through chronic timepoints. Single-cell RNA sequencing showed elevated levels of pro-inflammatory monocytes in joint-associated tissue with increased MAYV RNA present in FcRγ−/− monocytes and macrophages. Transfer of FcRγ−/− 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 FcγRs promotes protective responses during MAYV infection and prevents a pro-viral role for monocytes.

Arthritogenic alphaviruses, including Mayaro virus (MAYV), are mosquito-transmitted viruses of global concern. Antibodies are important for clearance of infectious virus; however, the specific antibody activities (neutralization versus Fc effector functions) required for optimal protection during alphavirus infection have not been evaluated. Fc effector functions can enhance viral clearance and alter the immune response through engagement of the antibody Fc domain with host receptors, such as Fc gamma receptors (FcγRs). Here, we infected mice that lack activating FcγRs (FcRγ−/−) with MAYV to determine the importance of Fc-FcγR interactions during natural alphavirus infection. In our study, FcRγ−/− mice showed prolonged disease and infection in the joint-associated tissue. Reduction of MAYV in the joint-associated tissue was more dependent on Fc-FcγR engagement rather than neutralizing antibodies. FcRγ−/− mice had more monocytes present during disease resolution time points and these cells harbored more MAYV RNA as compared to wild type (WT) mice. The FcRγ−/− monocytes failed to produce appreciable levels of infectious MAYV; however, transfer of these cells into WT mice increased MAYV burden within the joint-associated tissue. This study suggests that engagement of antibody Fc with activating FcγRs promotes a protective response during MAYV infection and prevents monocytes from driving a prolonged infection.

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