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

PLoS Pathogens

Suresh Mahalingam¹  Joy Gardner²  Paul J. Hertzog³  Natalie A. Prow³  Thuy T. Le⁴  Bing Tang⁵  Roger Le Grand⁶  Yee Suan Poo⁷  Linden J. Gearing⁷  Linda Hueston⁷  Francesca Di Giallonardo⁸  Pierre Roques⁹  Wayne A. Schroder⁹  Adam Taylor⁹  Jane A. C. Wilson⁹  Jonathan J. Ellis⁹  Andreas Suhrbier⁹  Helen E. Cumming⁹  Phillip I. Bird⁹ 

[1] UMR 1184 Immunology of Viral infections and Autoimmune diseases, Fontenay-aux-Roses, France;iMETI;Australian Infectious Disease Research Centre, The University of Queensland, Brisbane, Queensland, Australia;CEA, Inserm, Université Paris Sud;Centre for Infectious Diseases and Microbiology Laboratory Services, Westmead Hospital, Sydney, NSW, Australia;Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia;Hudson Institute of Medical Research, Clayton, Victoria, Australia;Institute for Glycomics, Griffith University, Gold Coast, Queensland, Australia;QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

关键词: Chikungunya virus;    Chikungunya infection;    Mammalian genomics;    Lymph nodes;    Mouse models;    Transcription factors;    Interferons;    Viremia;   

DOI  :  10.1371/journal.ppat.1006155

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY