title: Myeloid Cell Arg1 Inhibits Control of Arthritogenic Alphavirus Infection by Suppressing Antiviral T Cells.
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.
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, United States of America.
authors.forename: Kristina S
authors.initials: KS
authors.lastname: Burrack
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology, and Research, Singapore.
authors.forename: Jeslin J L
authors.initials: JJ
authors.lastname: Tan
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, United States of America.
authors.forename: Mary K
authors.initials: MK
authors.lastname: McCarthy
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology, and Research, Singapore.
authors.forename: Zhisheng
authors.initials: Z
authors.lastname: Her
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, United States of America.
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Berger
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology, and Research, Singapore.
authors.forename: Lisa F P
authors.initials: LF
authors.lastname: Ng
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, United States of America.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Morrison
mesh_terms: D019264:Adoptive Transfer; D018354:Alphavirus Infections / Q000276:immunology*; D000818:Animals; D001119:Arginase / Q000276:immunology*; D015153:Blotting, Western; D065632:Chikungunya Fever / Q000276:immunology; D002646:Chikungunya virus; D005434:Flow Cytometry; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000276:immunology*; D016133:Polymerase Chain Reaction; D012398:Ross River virus / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D019562:Viral Load / Q000276:immunology*
chemical_list: C574619:ARG1 protein, human; C544448:Arg1 protein, mouse; D001119:Arginase