GM-CSF and M-CSF Driven Differentiation Differentially Regulates Chikungunya Virus Infection and Antiviral Responses in Human Monocyte-Derived Macrophages

Authors

Veloz, J., Zyulina, V., Thannickal, S., Chebishev, E., Bernal-Rubio, D., Villanueva Guzman, M. D. M., Wu, C., Valencia, E., Novillo, D., Dhamapurkar, V., Espinar Barranco, L., Webb, L. G., Fenutria, R., Noval, M. G., Fernandez-Sesma, A.

Abstract

Chikungunya virus is an arthritogenic alphavirus causing debilitating joint pain in infected individuals. The mechanisms driving CHIKV-associated arthralgia are poorly understood, however, macrophages have been implicated as potential reservoirs of persistent viral material and mediators of immunopathology. Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) and Macrophage-Colony Stimulating Factor (M-CSF) are cytokines that serve as myeloid growth factors that bias macrophages toward pro-inflammatory and anti-inflammatory phenotypes, respectively. In this study, we examined how cytokine-driven macrophage differentiation via GM-CSF and M-CSF influences susceptibility to and responses against CHIKV infection in vitro. Using parallel donor-matched cultures of primary macrophages, we show that GM-CSF-differentiated macrophages are highly permissive to CHIKV and Mayaro virus (MAYV) infection and support robust viral replication, whereas M-CSF-differentiated macrophages are resistant to CHIKV replication and lack detectable levels of viral protein expression. Despite these differences, we observed pro-inflammatory, M1-skewing of CHIKV-infected macrophages, regardless of differentiation state. Interestingly, we observe higher production of IFN-alpha and IP10/CXCL10 in M-CSF differentiated macrophages, suggesting that M-CSF promotes an antiviral state that restricts CHIKV infection. Stimulation of macrophages with double-stranded RNA (polyinosinic:polycytidylic acid; poly(I:C)), but not with single-stranded RNA (resiquimod, R848), recapitulated the antiviral cytokine and chemokine response induced by CHIKV infection. These findings suggest that dsRNA sensing plays a more prominent role than ssRNA sensing in driving the macrophage antiviral response to CHIKV. Together, these findings highlight macrophage differentiation as a critical determinant of CHIKV susceptibility and antiviral immunity in humans, with implications for understanding inflammatory pathogenesis during infection.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 13 Mar 2026.

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