A natural genetic variant of granzyme B confers lethality to a common viral infection.
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 susce...
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doaj-fab4ea6805264d57a3bb478bdec9e2f42021-04-21T17:39:39ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742014-12-011012e100452610.1371/journal.ppat.1004526A natural genetic variant of granzyme B confers lethality to a common viral infection.Christopher E AndoniouVivien R SuttonMatthew E WikstromPeter FlemingKevin Y T ThiaAntony Y MatthewsDion KaisermanIona S SchusterJerome D CoudertPreethi EldiGeeta ChaudhriGunasegaran KarupiahPhillip I BirdJoseph A TrapaniMariapia A Degli-EspostiMany 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.https://doi.org/10.1371/journal.ppat.1004526 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Christopher E Andoniou Vivien R Sutton Matthew E Wikstrom Peter Fleming Kevin Y T Thia Antony Y Matthews Dion Kaiserman Iona S Schuster Jerome D Coudert Preethi Eldi Geeta Chaudhri Gunasegaran Karupiah Phillip I Bird Joseph A Trapani Mariapia A Degli-Esposti |
spellingShingle |
Christopher E Andoniou Vivien R Sutton Matthew E Wikstrom Peter Fleming Kevin Y T Thia Antony Y Matthews Dion Kaiserman Iona S Schuster Jerome D Coudert Preethi Eldi Geeta Chaudhri Gunasegaran Karupiah Phillip I Bird Joseph A Trapani Mariapia A Degli-Esposti A natural genetic variant of granzyme B confers lethality to a common viral infection. PLoS Pathogens |
author_facet |
Christopher E Andoniou Vivien R Sutton Matthew E Wikstrom Peter Fleming Kevin Y T Thia Antony Y Matthews Dion Kaiserman Iona S Schuster Jerome D Coudert Preethi Eldi Geeta Chaudhri Gunasegaran Karupiah Phillip I Bird Joseph A Trapani Mariapia A Degli-Esposti |
author_sort |
Christopher E Andoniou |
title |
A natural genetic variant of granzyme B confers lethality to a common viral infection. |
title_short |
A natural genetic variant of granzyme B confers lethality to a common viral infection. |
title_full |
A natural genetic variant of granzyme B confers lethality to a common viral infection. |
title_fullStr |
A natural genetic variant of granzyme B confers lethality to a common viral infection. |
title_full_unstemmed |
A natural genetic variant of granzyme B confers lethality to a common viral infection. |
title_sort |
natural genetic variant of granzyme b confers lethality to a common viral infection. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Pathogens |
issn |
1553-7366 1553-7374 |
publishDate |
2014-12-01 |
description |
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. |
url |
https://doi.org/10.1371/journal.ppat.1004526 |
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