Research ArticleEMERGING INFECTIONS

Fingolimod treatment abrogates chikungunya virus–induced arthralgia

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Science Translational Medicine  01 Feb 2017:
Vol. 9, Issue 375, eaal1333
DOI: 10.1126/scitranslmed.aal1333

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Taming T cells to ameliorate chikungunya arthritis

Mosquito-borne chikungunya virus causes fever and joint pain; some patients suffer from arthritis for years with no treatment options. In this issue, two studies investigated targeting pathogenic CD4+ T cells to prevent arthritis symptoms in a mouse model of chikungunya virus infection. Teo et al. demonstrated that fingolimod, a drug that sequesters immune cells to lymphoid organs, was able to relieve arthritis symptoms without affecting viral replication. Miner et al. used a combination of abatacept, which blocks T cell costimulation, and a human chikungunya neutralizing antibody to reduce both viral replication and disease severity. Repurposing these clinically available therapies could provide treatment options for chikungunya patients.

Abstract

Chikungunya virus (CHIKV) is one of the many rheumatic arthropod-borne alphaviruses responsible for debilitating joint inflammation in humans. Despite the severity in many endemic regions, clinically approved intervention targeting the virus remains unavailable. CD4+ T cells have been shown to mediate CHIKV-induced joint inflammation in mice. We demonstrate here that transfer of splenic CD4+ T cells from virus-infected C57BL/6 mice into virus-infected T cell receptor–deficient (TCR−/−) mice recapitulated severe joint pathology including inflammation, vascular leakages, subcutaneous edema, and skeletal muscle necrosis. Proteome-wide screening identified dominant CD4+ T cell epitopes in nsP1 and E2 viral antigens. Transfer of nsP1- or E2-specific primary CD4+ T cell lines into CHIKV-infected TCR−/− recipients led to severe joint inflammation and vascular leakage. This pathogenic role of virus-specific CD4+ T cells in CHIKV infections led to the assessment of clinically approved T cell–suppressive drugs for disease intervention. Although drugs targeting interleukin-2 pathway were ineffective, treatment with fingolimod, an agonist of sphingosine 1-phosphate receptor, successfully abrogated joint pathology in CHIKV-infected animals by blocking the migration of CD4+ T cells into the joints without any effect on viral replication. These results set the stage for further clinical evaluation of fingolimod in the treatment of CHIKV-induced joint pathologies.

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