Modeling Host Genetic Regulation of Influenza Pathogenesis in the Collaborative Cross

Martin T. Ferris, David L. Aylor, Daniel Bottomly, Alan C. Whitmore, Lauri D. Aicher, Timothy A. Bell, Birgit Bradel-Tretheway, Janine T. Bryan, Ryan J. Buus, Lisa E. Gralinski, Bart L. Haagmans, Leonard McMillan, Darla R. Miller, Elizabeth Rosenzweig, William Valdar, Jeremy Wang, Gary A. Churchill, David W. Threadgill, Shannon McWeeney, Michael G. Katze & 3 others Fernando Pardo-Manuel de Villena, Ralph S. Baric, Mark T. Heise

Research output: Contribution to journalArticle

104 Citations (Scopus)

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 Mx1 gene. We sequenced the coding regions of Mx1 in the eight CC founder strains, and identified a novel Mx1 allele that showed reduced ability to inhibit viral replication, while maintaining protection from weight loss.

Original languageEnglish (US)
Article numbere1003196
JournalPLoS Pathogens
Volume9
Issue number2
DOIs
StatePublished - Feb 2013

Fingerprint

Human Influenza
Quantitative Trait Loci
Weight Loss
Virus Replication
Viruses
Phenotype
Population
Inflammation
Confounding Factors (Epidemiology)
Neutrophil Infiltration
Influenza A virus
Genetic Polymorphisms
Virus Diseases
Pulmonary Edema
Genes
Alleles
Genome
Infection

ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

Ferris, M. T., Aylor, D. L., Bottomly, D., Whitmore, A. C., Aicher, L. D., Bell, T. A., ... Heise, M. T. (2013). Modeling Host Genetic Regulation of Influenza Pathogenesis in the Collaborative Cross. PLoS Pathogens, 9(2), [e1003196]. https://doi.org/10.1371/journal.ppat.1003196

Modeling Host Genetic Regulation of Influenza Pathogenesis in the Collaborative Cross. / Ferris, Martin T.; Aylor, David L.; Bottomly, Daniel; Whitmore, Alan C.; Aicher, Lauri D.; Bell, Timothy A.; Bradel-Tretheway, Birgit; Bryan, Janine T.; Buus, Ryan J.; Gralinski, Lisa E.; Haagmans, Bart L.; McMillan, Leonard; Miller, Darla R.; Rosenzweig, Elizabeth; Valdar, William; Wang, Jeremy; Churchill, Gary A.; Threadgill, David W.; McWeeney, Shannon; Katze, Michael G.; Pardo-Manuel de Villena, Fernando; Baric, Ralph S.; Heise, Mark T.

In: PLoS Pathogens, Vol. 9, No. 2, e1003196, 02.2013.

Research output: Contribution to journalArticle

Ferris, MT, Aylor, DL, Bottomly, D, Whitmore, AC, Aicher, LD, Bell, TA, Bradel-Tretheway, B, Bryan, JT, Buus, RJ, Gralinski, LE, Haagmans, BL, McMillan, L, Miller, DR, Rosenzweig, E, Valdar, W, Wang, J, Churchill, GA, Threadgill, DW, McWeeney, S, Katze, MG, Pardo-Manuel de Villena, F, Baric, RS & Heise, MT 2013, 'Modeling Host Genetic Regulation of Influenza Pathogenesis in the Collaborative Cross', PLoS Pathogens, vol. 9, no. 2, e1003196. https://doi.org/10.1371/journal.ppat.1003196
Ferris MT, Aylor DL, Bottomly D, Whitmore AC, Aicher LD, Bell TA et al. Modeling Host Genetic Regulation of Influenza Pathogenesis in the Collaborative Cross. PLoS Pathogens. 2013 Feb;9(2). e1003196. https://doi.org/10.1371/journal.ppat.1003196
Ferris, Martin T. ; Aylor, David L. ; Bottomly, Daniel ; Whitmore, Alan C. ; Aicher, Lauri D. ; Bell, Timothy A. ; Bradel-Tretheway, Birgit ; Bryan, Janine T. ; Buus, Ryan J. ; Gralinski, Lisa E. ; Haagmans, Bart L. ; McMillan, Leonard ; Miller, Darla R. ; Rosenzweig, Elizabeth ; Valdar, William ; Wang, Jeremy ; Churchill, Gary A. ; Threadgill, David W. ; McWeeney, Shannon ; Katze, Michael G. ; Pardo-Manuel de Villena, Fernando ; Baric, Ralph S. ; Heise, Mark T. / Modeling Host Genetic Regulation of Influenza Pathogenesis in the Collaborative Cross. In: PLoS Pathogens. 2013 ; Vol. 9, No. 2.
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