A Natural Genetic Variant of Granzyme B Confers Lethality to a Common Viral Infection

PLoS Pathogens

Matthew E. Wikstrom¹  Jerome D. Coudert¹  Vivien R. Sutton²  Iona S. Schuster²  Joseph A. Trapani²  Antony Y. Matthews²  Geeta Chaudhri³  Gunasegaran Karupiah³  Christopher E. Andoniou⁴  Mariapia A. Degli-Esposti⁴  Kevin Y. T. Thia⁴  Dion Kaiserman⁴  Phillip I. Bird⁴  Peter Fleming⁵  Preethi Eldi⁵ 

[1] Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia;Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Western Australia, Australia;Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia;Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, Western Australia, Australia;Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia

关键词: T cells;    Cytotoxic T cells;    Apoptosis;    Inbreeding;    Spleen;    Infectious disease control;    Viral load;    Inbred strains;   

DOI  :  10.1371/journal.ppat.1004526

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Many immune response genes are highly polymorphic, consistent with the selective pressure imposed by pathogens over evolutionary time, and the need to balance infection control with the risk of auto-immunity. Epidemiological and genomic studies have identified many genetic variants that confer susceptibility or resistance to pathogenic micro-organisms. While extensive polymorphism has been reported for the granzyme B (GzmB) gene, its relevance to pathogen immunity is unexplored. Here, we describe the biochemical and cytotoxic functions of a common allele of GzmB (GzmBW) common in wild mouse. While retaining ‘Asp-ase’ activity, GzmBW has substrate preferences that differ considerably from GzmBP, which is common to all inbred strains. In vitro, GzmBW preferentially cleaves recombinant Bid, whereas GzmBP activates pro-caspases directly. Recombinant GzmBW and GzmBP induced equivalent apoptosis of uninfected targets cells when delivered with perforin in vitro. Nonetheless, mice homozygous for GzmBW were unable to control murine cytomegalovirus (MCMV) infection, and succumbed as a result of excessive liver damage. Although similar numbers of anti-viral CD8 T cells were generated in both mouse strains, GzmBW-expressing CD8 T cells isolated from infected mice were unable to kill MCMV-infected targets in vitro. Our results suggest that known virally-encoded inhibitors of the intrinsic (mitochondrial) apoptotic pathway account for the increased susceptibility of GzmBW mice to MCMV. We conclude that different natural variants of GzmB have a profound impact on the immune response to a common and authentic viral pathogen.

【 授权许可】

CC BY