Activating FcγRs on monocytes are necessary for optimal Mayaro virus clearance

Area of Science:

• Virology
• Immunology
• Infectious Diseases

Background:

• Mayaro virus (MAYV) is an emerging arbovirus with significant public health implications.
• Antibody Fc effector functions are known to be critical for protection against alphaviruses, but their role in natural MAYV infection is unclear.
• Fc gamma receptors (FcγRs) mediate antibody effector functions.

Purpose of the Study:

• To investigate the role of activating Fc gamma receptors (FcγRs) in protection against Mayaro virus (MAYV) during natural infection.
• To determine the impact of FcγR deficiency on disease progression, viral clearance, and immune cell responses in MAYV-infected mice.

Main Methods:

• Utilized FcRγ knockout mice (FcRγ-/-) lacking activating FcγRs and wild-type controls.
• Assessed clinical disease, viral load in joint-associated tissues, and antibody functions (neutralizing vs. cell surface binding).
• Employed single-cell RNA sequencing to analyze immune cell populations, particularly monocytes and macrophages, in affected tissues.

Main Results:

• Mice lacking activating FcγRs (FcRγ-/-) exhibited prolonged clinical disease and increased viral burden in joint-associated tissues.
• Viral clearance correlated with anti-MAYV cell surface binding antibodies, not neutralizing antibodies.
• FcRγ-/- mice showed an increased number of monocytes, with elevated pro-inflammatory monocytes and increased MAYV RNA in monocytes and macrophages.
• Transfer of FcRγ-/- monocytes into wild-type animals exacerbated viral load in joint tissues.

Conclusions:

• Engagement of antibody Fc with activating FcγRs is essential for protective immune responses during Mayaro virus infection.
• FcγR signaling prevents monocytes from becoming targets for MAYV replication, thereby controlling viral spread.
• This study underscores the importance of FcγR-mediated effector functions in combating arboviral infections like MAYV.