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

Citation

Andoniou, CE and Sutton, VR and Wikstrom, ME and Fleming, P and Thia, KY and Matthews, AY and Kaiserman, D and Schuster, IS and Coudert, JD and Eldi, P and Chaudri, G and Karupiah, G and Bird, PI and Trapani, JA and Degli-Esposti, MA, A Natural Genetic Variant of Granzyme B Confers Lethality to a Common Viral Infection, PLoS pathogens, 10, (12) pp. 1-13. ISSN 1553-7366 (2014) [Refereed Article]


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Copyright 2014 Andoniou et al. Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0) http://creativecommons.org/licenses/by/4.0/

DOI: doi:10.1371/journal.ppat.1004526

Abstract

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.

Item Details

Item Type:Refereed Article
Keywords:Murine cytomegalovirus, granzyme B mediated CD8 T cell control of infection
Research Division:Medical and Health Sciences
Research Group:Immunology
Research Field:Cellular Immunology
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Infectious Diseases
Author:Karupiah, G (Associate Professor Guna Karupiah)
ID Code:107782
Year Published:2014
Web of Science® Times Cited:6
Deposited By:Medicine (Discipline)
Deposited On:2016-03-23
Last Modified:2017-11-07
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