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A Natural Genetic Variant of Granzyme B Confers Lethality to a Common Viral Infection.
- Source :
- PLoS Pathogens; Dec2014, Vol. 10 Issue 12, p1-13, 13p
- Publication Year :
- 2014
-
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 (GzmB<superscript>W</superscript>) common in wild mouse. While retaining ‘Asp-ase’ activity, GzmB<superscript>W</superscript> has substrate preferences that differ considerably from GzmB<superscript>P</superscript>, which is common to all inbred strains. In vitro, GzmB<superscript>W</superscript> preferentially cleaves recombinant Bid, whereas GzmB<superscript>P</superscript> activates pro-caspases directly. Recombinant GzmB<superscript>W</superscript> and GzmB<superscript>P</superscript> induced equivalent apoptosis of uninfected targets cells when delivered with perforin in vitro. Nonetheless, mice homozygous for GzmB<superscript>W</superscript> 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, GzmB<superscript>W</superscript>-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 GzmB<superscript>W</superscript> 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. [ABSTRACT FROM AUTHOR]
- Subjects :
- GENES
IMMUNE response
GRANZYMES
VIRUS diseases
MICROORGANISMS
Subjects
Details
- Language :
- English
- ISSN :
- 15537366
- Volume :
- 10
- Issue :
- 12
- Database :
- Complementary Index
- Journal :
- PLoS Pathogens
- Publication Type :
- Academic Journal
- Accession number :
- 100185651
- Full Text :
- https://doi.org/10.1371/journal.ppat.1004526