Modeling host genetic regulation of influenza pathogenesis in the collaborative cross.
Document Type
Article
Publication Date
2-2013
JAX Source
PLoS Pathog 2013 Feb; 9(2):e1003196
Volume
9
Issue
2
First Page
1003196
Last Page
1003196
ISSN
1553-7374
PMID
23468633
Abstract
Genetic variation contributes to host responses and outcomes following infection by influenza A virus or other viral infections. Yet narrow windows of disease symptoms and confounding environmental factors have made it difficult to identify polymorphic genes that contribute to differential disease outcomes in human populations. Therefore, to control for these confounding environmental variables in a system that models the levels of genetic diversity found in outbred populations such as humans, we used incipient lines of the highly genetically diverse Collaborative Cross (CC) recombinant inbred (RI) panel (the pre-CC population) to study how genetic variation impacts influenza associated disease across a genetically diverse population. A wide range of variation in influenza disease related phenotypes including virus replication, virus-induced inflammation, and weight loss was observed. Many of the disease associated phenotypes were correlated, with viral replication and virus-induced inflammation being predictors of virus-induced weight loss. Despite these correlations, pre-CC mice with unique and novel disease phenotype combinations were observed. We also identified sets of transcripts (modules) that were correlated with aspects of disease. In order to identify how host genetic polymorphisms contribute to the observed variation in disease, we conducted quantitative trait loci (QTL) mapping. We identified several QTL contributing to specific aspects of the host response including virus-induced weight loss, titer, pulmonary edema, neutrophil recruitment to the airways, and transcriptional expression. Existing whole-genome sequence data was applied to identify high priority candidate genes within QTL regions. A key host response QTL was located at the site of the known anti-influenza gene. We sequenced the coding regions of in the eight CC founder strains, and identified a novel allele that showed reduced ability to inhibit viral replication, while maintaining protection from weight loss.
Recommended Citation
Ferris M,
Aylor D,
Bottomly D,
Whitmore A,
Aicher L,
Bell T,
Bradel-Tretheway B,
Bryan J,
Buus R,
Gralinski L,
Haagmans B,
McMillan L,
Miller D,
Rosenzweig E,
Valdar W,
Wang J,
Churchill G,
Threadgill D,
McWeeney S,
Katze M,
Pardo-Manuel de Villena F,
Baric R,
Heise M.
Modeling host genetic regulation of influenza pathogenesis in the collaborative cross. PLoS Pathog 2013 Feb; 9(2):e1003196