Myeloid cell Arg1 and iNOS inhibit control of arthritogenic alphavirus infection by suppressing anti-viral T cells (VIR1P.965)

Abstract

Abstract Mosquito-borne alphaviruses, including chikungunya virus (CHIKV) and Ross River virus (RRV), cause a debilitating, and often chronic, rheumatologic disease in humans. Utilizing mouse models that recapitulate many aspects of the human disease we found that arginase 1 (Arg1) and nitric oxide synthase 2 (iNOS) are highly induced in inflamed musculoskeletal tissues and infiltrating macrophages in RRV- and CHIKV-infected mice. Similar to myeloid-derived suppressor cells (MDSCs), these Arg1/iNOS-expressing macrophages suppress T cell proliferation ex vivo. Depletion of T cells restored RRV loads in musculoskeletal tissues of Arg1-deficient mice to similar levels as T cell-depleted WT mice, suggesting that Arg1+ suppressor cells inhibit T cell-mediated control of alphavirus infection. Moreover, myeloid cell Arg1 reduced T cell production of anti-viral cytokines and altered the activation phenotype of virus-specific T cells in inflamed muscle tissue, but not lymphoid tissue, of RRV-infected mice. Furthermore, the expression of Arg1 and several other MDSC-associated genes were significantly higher in PBMCs collected from CHIKV-infected patients compared to PBMCs from healthy controls. Expression of Arg1 remained elevated months after illness onset, and increased expression levels of Arg1 correlated with higher viremia. These studies suggest that CHIKV/RRV infection activates immunosuppressive monocytes/macrophages that antagonize virus control and may contribute to chronic disease.