Fingolimod treatment abrogates chikungunya virus-induced arthralgia.
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.
Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore, Singapore.
Teck-Hui
TH
Teo
Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore, Singapore.|NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore.
Yi-Hao
YH
Chan
Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore, Singapore.|NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore.
Wendy W L
WW
Lee
Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore, Singapore.
Fok-Moon
FM
Lum
Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore, Singapore.
Siti Naqiah
SN
Amrun
Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore, Singapore.
Zhisheng
Z
Her
Advanced Molecular Pathology Laboratory, A*STAR, Singapore, Singapore.
Ravisankar
R
Rajarethinam
Institute of Technology, University of Tartu, 50411 Tartu, Estonia.
Andres
A
Merits
Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore, Singapore.
Olaf
O
Rötzschke
Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore, Singapore. lisa_ng@immunol.a-star.edu.sg renia_laurent@immunol.a-star.edu.sg.
Laurent
L
Rénia
Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore, Singapore. lisa_ng@immunol.a-star.edu.sg renia_laurent@immunol.a-star.edu.sg.|Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.|Institute of Infection and Global Health, University of Liverpool, Liverpool, U.K.
Lisa F P
LF
Ng
D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D018771:Arthralgia / Q000188:drug therapy* / Q000821:virology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000821:virology; D065632:Chikungunya Fever / Q000188:drug therapy*; D002646:Chikungunya virus; D000939:Epitopes / Q000737:chemistry; D000068876:Fingolimod Hydrochloride / Q000627:therapeutic use*; D007249:Inflammation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009336:Necrosis
D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000939:Epitopes; D000068876:Fingolimod Hydrochloride