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

Autor:	Wilson JA; QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.; Australian Infectious Disease Research Centre, The University of Queensland, Brisbane, Queensland, Australia., Prow NA; QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia., Schroder WA; QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia., Ellis JJ; QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia., Cumming HE; Hudson Institute of Medical Research, Clayton, Victoria, Australia., Gearing LJ; Hudson Institute of Medical Research, Clayton, Victoria, Australia., Poo YS; QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.; Australian Infectious Disease Research Centre, The University of Queensland, Brisbane, Queensland, Australia., Taylor A; Institute for Glycomics, Griffith University, Gold Coast, Queensland, Australia., Hertzog PJ; Hudson Institute of Medical Research, Clayton, Victoria, Australia., Di Giallonardo F; Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia., Hueston L; Centre for Infectious Diseases and Microbiology Laboratory Services, Westmead Hospital, Sydney, NSW, Australia., Le Grand R; CEA, Inserm, Université Paris Sud; iMETI; UMR 1184 Immunology of Viral infections and Autoimmune diseases, Fontenay-aux-Roses, France., Tang B; QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia., Le TT; QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia., Gardner J; QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia., Mahalingam S; Institute for Glycomics, Griffith University, Gold Coast, Queensland, Australia., Roques P; CEA, Inserm, Université Paris Sud; iMETI; UMR 1184 Immunology of Viral infections and Autoimmune diseases, Fontenay-aux-Roses, France., Bird PI; Biomedicine Discovery Institute, Monash University, Victoria 3800, Australia., Suhrbier A; QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.; Australian Infectious Disease Research Centre, The University of Queensland, Brisbane, Queensland, Australia.
Jazyk:	angličtina
Zdroj:	PLoS pathogens [PLoS Pathog] 2017 Feb 16; Vol. 13 (2), pp. e1006155. Date of Electronic Publication: 2017 Feb 16 (Print Publication: 2017).
DOI:	10.1371/journal.ppat.1006155
Abstrakt:	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.
Databáze:	MEDLINE
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