Granulocyte colony-stimulating factor protects against arthritogenic alphavirus pathogenesis in a type I IFN-dependent manner.

Abstract

Arthritogenic alphaviruses cause disease characterized by fever, rash, and incapacitating joint pain. Alphavirus infection stimulates robust inflammatory responses in infected hosts, leading to the upregulation of several cytokines, including granulocyte colony-stimulating factor (G-CSF). G-CSF is secreted by endothelial cells, fibroblasts, macrophages, and monocytes and binds to colony stimulating factor 3 receptor (CSF3R, also known as G-CSFR) on the surface of myeloid cells. G-CSFR signaling initiates proliferation, differentiation, and maturation of myeloid cells, especially neutrophils. Importantly, G-CSF has been found at high levels in both the acute and chronic phases of chikungunya disease; however, the role of G-CSF in arthritogenic alphavirus disease remains unexplored. Here, we sought to test the effect of G-CSF on chikungunya virus (CHIKV) and Mayaro virus (MAYV) infection using G-CSFR-deficient mice (G-CSFR-/-). We observed sustained weight loss in G-CSFR-/- mice following viand MAYV infection compared to wild-type mice. Furthermore, G-CSFR-/- mice had a significantly higher percentage of inflammatory monocytes and reduction in neutrophils throughout infection. The difference in weight loss in G-CSFR-/- mice induced by alphavirus infection was corrected by blocking type I IFN signaling. In summary, these studies show that type I IFN signaling contributes to G-CSFR mediated control of arthritogenic alphavirus disease.