M-CSF Differentiation Restricts Chikungunya Virus Replication in Human Macrophages In Vitro

In parallel donor-matched cultures of primary human monocyte-derived macrophages, granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) differentially regulate susceptibility to Chikungunya virus (CHIKV) infection and host antiviral responses in vitro. Researchers Jeury Veloz, Victoria Zyulina, Sara Thannickal, Eva Chebishev, Dabeiba Bernal-Rubio, Maria del Mar Villanueva Guzman, Chenyang Wu, Estefania Valencia, Danielle Novillo, Vrushali Dhamapurkar, Laura Espinar-Barranco, Laurence Gabriel Webb, Rafael Fenutria, Maria G. Noval, and Ana Fernandez-Sesma demonstrated that GM-CSF-differentiated primary macrophages are highly permissive to CHIKV infection and support robust viral replication. In contrast, donor-matched primary macrophages differentiated with M-CSF are resistant to CHIKV replication and lack detectable levels of viral protein expression.

Chikungunya virus is classified as an arthritogenic alphavirus that causes debilitating joint pain in infected individuals.

To investigate the cellular basis of infection, the authors examined how cytokine-driven differentiation programs influence viral vulnerability and immune defense. Granulocyte-macrophage colony-stimulating factor and macrophage colony-stimulating factor serve as essential myeloid growth factors that steer macrophage maturation in opposite directions, biasing cells toward pro-inflammatory and anti-inflammatory phenotypes, respectively. Despite these stark baseline differences and the profound divergence in viral replication rates, the authors observed pro-inflammatory, M1-skewing of CHIKV-infected macrophages regardless of their differentiation state.

The experiments revealed higher production of interferon-alpha (IFNα) and the chemokine IP10/CXCL10 in M-CSF-differentiated macrophages than in GM-CSF-differentiated cells. This selective upregulation suggests that M-CSF-driven differentiation establishes an active antiviral state capable of restricting CHIKV infection and suppressing viral protein synthesis in human macrophages.

Stimulation of primary macrophages with double-stranded RNA, using polyinosinic:polycytidylic acid (poly(I:C)), successfully recapitulated the specific antiviral cytokine and chemokine response induced by Chikungunya virus infection. In contrast, stimulation with single-stranded RNA, using resiquimod (R848), failed to reproduce this cytokine and chemokine profile. These findings suggest that double-stranded RNA sensing plays a substantially more prominent role than single-stranded RNA sensing in driving the human macrophage antiviral response to CHIKV.

Subject of Research: Cytokine-driven macrophage differentiation and Chikungunya virus susceptibility

Article Title: GM-CSF and M-CSF driven differentiation differentially regulates Chikungunya virus infection and antiviral responses in human monocyte-derived macrophages

Article References: 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. (2026). GM-CSF and M-CSF driven differentiation differentially regulates Chikungunya virus infection and antiviral responses in human monocyte-derived macrophages. PLOS Pathogens, 22(11), e1014773. https://doi.org/10.1371/journal.ppat.1014773

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DOI: 10.1371/journal.ppat.1014773

Keywords: Chikungunya virus, CHIKV, Mayaro virus, macrophage differentiation, monocyte-derived macrophages, GM-CSF, M-CSF, viral replication, antiviral immunity, interferon-alpha, IP10/CXCL10, dsRNA sensing, poly(I:C), resiquimod, M1-skewing, arthritogenic alphavirus