Abstract
Arthritogenic alphaviruses, including Ross River virus (RRV) and chikungunya virus (CHIKV), are responsible for explosive epidemics involving millions of cases. These mosquito-transmitted viruses cause inflammation and injury in skeletal muscle and joint tissues that results in debilitating pain. We previously showed that arginase 1 (Arg1) was highly expressed in myeloid cells in the infected and inflamed musculoskeletal tissues of RRV- and CHIKV-infected mice, and specific deletion of Arg1 from myeloid cells resulted in enhanced viral control. Here, we show that Arg1, along with other genes associated with suppressive myeloid cells, is induced in PBMCs isolated from CHIKV-infected patients during the acute phase as well as the chronic phase, and that high Arg1 expression levels were associated with high viral loads and disease severity. Depletion of both CD4 and CD8 T cells from RRV-infected Arg1-deficient mice restored viral loads to levels detected in T cell-depleted wild-type mice. Moreover, Arg1-expressing myeloid cells inhibited virus-specific T cells in the inflamed and infected musculoskeletal tissues, but not lymphoid tissues, following RRV infection in mice, including suppression of interferon-γ and CD69 expression. Collectively, these data enhance our understanding of the immune response following arthritogenic alphavirus infection and suggest that immunosuppressive myeloid cells may contribute to the duration or severity of these debilitating infections.
Highlights
Arthritogenic alphaviruses, including chikungunya virus (CHIKV) and Ross River virus (RRV), are re-emerging, mosquito-transmitted alphaviruses that cause both endemic and explosive epidemics of debilitating musculoskeletal inflammatory disease [1]
We further showed that mice deleted for arginase 1 (Arg1) in myeloid cells had reduced viral loads, as well as improved tissue pathology, at late, but not early, times post-RRV infection, indicating that Arg1+ macrophages prevent efficient host control of RRV infection in musculoskeletal tissues [44]
Arg1 is induced in peripheral blood mononuclear cells (PBMCs) from CHIKV-infected patients and Arg1 expression levels are associated with viral load and disease severity
Summary
Arthritogenic alphaviruses, including chikungunya virus (CHIKV) and Ross River virus (RRV), are re-emerging, mosquito-transmitted alphaviruses that cause both endemic and explosive epidemics of debilitating musculoskeletal inflammatory disease [1]. CHIKV has caused outbreaks of unprecedented scale involving millions of persons in the Indian Ocean Islands [2], India [3], Southeast Asia [4,5,6] and Europe [7]. CHIKV has emerged in the Western Hemisphere where ongoing epidemics on multiple islands in the Caribbean as well as in Central and South America have resulted far in more than one million suspected cases [8,9,10]. RRV, which causes ~4,000–7,000 cases in Australia and Papua New Guinea annually, has caused explosive outbreaks [11]. There are no specific therapies for the treatment of alphavirus-induced rheumatological disease and no licensed vaccines
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