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Genetics of gene expression in immunity to infection.

ABSTRACT: Mapping gene expression as a quantitative trait (eQTL mapping) can reveal local and distant associations with functionally important genetic variation informative for disease. Recent studies are reviewed which have demonstrated that this approach is particularly informative when applied to diverse immune cell populations and situations relevant to infection and immunity. Context-specific eQTL have now been characterised following endotoxin activation, induction with interferons, mycobacteria, and influenza, together with genetic determinants of response to vaccination. The application of genetical genomic approaches offers new opportunities to advance our understanding of gene-environment interactions and fundamental processes in innate and adaptive immunity.

SUBMITTER: Fairfax BP

PROVIDER: S-EPMC4426291 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Genetics of gene expression in immunity to infection.

Fairfax Benjamin P BP Knight Julian C JC

Current opinion in immunology 20140731

Mapping gene expression as a quantitative trait (eQTL mapping) can reveal local and distant associations with functionally important genetic variation informative for disease. Recent studies are reviewed which have demonstrated that this approach is particularly informative when applied to diverse immune cell populations and situations relevant to infection and immunity. Context-specific eQTL have now been characterised following endotoxin activation, induction with interferons, mycobacteria, an ...[more]

PMID: 25078545

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Project description:The pathogenesis of Plasmodium falciparum malaria is linked to the variant surface antigen PfEMP1, which mediates tethering of infected erythrocytes to the host endothelium and is encoded by approximately 60 var genes per parasite genome. Repeated episodes of malaria infection result in the gradual acquisition of protective antibodies against PfEMP1 variants. The antibody repertoire is believed to provide a selective pressure driving the clonal expansion of parasites expressing unrecognized PfEMP1 variants, however, due to the lack of experimental in vivo models there is only limited experimental evidence in support of this concept. To get insight into the impact of naturally acquired immunity on the expressed var gene repertoire early during infection we performed controlled human malaria infections of 20 adult African volunteers with life-long malaria exposure using aseptic, purified, cryopreserved P. falciparum sporozoites (Sanaria PfSPZ Challenge) and correlated serological data with var gene expression patterns from ex vivo parasites. Among the 10 African volunteers who developed patent infections, individuals with low antibody levels showed a steep rise in parasitemia accompanied by broad activation of multiple, predominantly subtelomeric var genes, similar to what we previously observed in naïve volunteers. In contrast, individuals with intermediate antibody levels developed asymptomatic infections and the ex vivo parasite populations expressed only few var gene variants, indicative of clonal selection. Importantly, in contrast to parasites from naïve volunteers, expression of var genes coding for endothelial protein C receptor (EPCR)-binding PfEMP1 that are associated with severe childhood malaria was rarely detected in semi-immune adult African volunteers. Moreover, we followed var gene expression for up to six parasite replication cycles and demonstrated for the first time in vivo a shift in the dominant var gene variant. In conclusion, our data suggest that P. falciparum activates multiple subtelomeric var genes at the onset of blood stage infection facilitating rapid expansion of parasite clones which express PfEMP1 variants unrecognized by the host's immune system, thus promoting overall parasite survival in the face of host immunity.

Dataset Information

Genetics of gene expression in immunity to infection.

Publications

Genetics of gene expression in immunity to infection.

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