RNA-Seq analysis of chikungunya virus infection and identification of granzyme A as a major promoter of arthritic inflammation

Chikungunya virus (chikv) is an arthritogenic alphavirus causing epidemics of acute and chronic arthritic disease. herein we describe a comprehensive rna-seq analysis of feet and lymph nodes at peak viraemia (day 2 post infection),acute arthritis (day 7) and chronic disease (day 30) in the chikv adult wild-type mouse model. genes previously shown to be up-regulated in chikv patients were also up-regulated in the mouse model. chikv sequence information was also obtained with up to ≈8% of the reads mapping to the viral genome; however,no adaptive viral genome changes were apparent. although day 2,7 and 30 represent distinct stages of infection and disease,there was a pronounced overlap in up-regulated host genes and pathways. type i interferon response genes (irgs) represented up to ≈50% of up-regulated genes,even after loss of type i interferon induction on days 7 and 30. bioinformatic analyses suggested a number of interferon response factors were primarily responsible for maintaining type i irg induction. a group of genes prominent in the rna-seq analysis and hitherto unexplored in viral arthropathies were granzymes a,b and k. granzyme a-/-and to a lesser extent granzyme k-/-,but not granzyme b-/-,mice showed a pronounced reduction in foot swelling and arthritis,with analysis of granzyme a-/-mice showing no reductions in viral loads but reduced nk and t cell infiltrates post chikv infection. treatment with serpinb6b,a granzyme a inhibitor,also reduced arthritic inflammation in wild-type mice. in non-human primates circulating granzyme a levels were elevated after chikv infection,with the increase correlating with viral load. elevated granzyme a levels were also seen in a small cohort of human chikv patients. taken together these results suggest granzyme a is an important driver of arthritic inflammation and a potential target for therapy. trial registration: clinicaltrials.gov nct00281294 © 2017 wilson et al.