title: Modeling host genetic regulation of influenza pathogenesis in the collaborative cross.
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.
authors.affiliation: Carolina Vaccine Institute, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, United States of America. mtferris@email.unc.edu
authors.forename: Martin T
authors.initials: MT
authors.lastname: Ferris
authors.forename: David L
authors.initials: DL
authors.lastname: Aylor
authors.forename: Daniel
authors.initials: D
authors.lastname: Bottomly
authors.forename: Alan C
authors.initials: AC
authors.lastname: Whitmore
authors.forename: Lauri D
authors.initials: LD
authors.lastname: Aicher
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Bell
authors.forename: Birgit
authors.initials: B
authors.lastname: Bradel-Tretheway
authors.forename: Janine T
authors.initials: JT
authors.lastname: Bryan
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Buus
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Gralinski
authors.forename: Bart L
authors.initials: BL
authors.lastname: Haagmans
authors.forename: Leonard
authors.initials: L
authors.lastname: McMillan
authors.forename: Darla R
authors.initials: DR
authors.lastname: Miller
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Rosenzweig
authors.forename: William
authors.initials: W
authors.lastname: Valdar
authors.forename: Jeremy
authors.initials: J
authors.lastname: Wang
authors.forename: Gary A
authors.initials: GA
authors.lastname: Churchill
authors.forename: David W
authors.initials: DW
authors.lastname: Threadgill
authors.forename: Shannon K
authors.initials: SK
authors.lastname: McWeeney
authors.forename: Michael G
authors.initials: MG
authors.lastname: Katze
authors.forename: Fernando
authors.initials: F
authors.lastname: Pardo-Manuel de Villena
authors.forename: Ralph S
authors.initials: RS
authors.lastname: Baric
authors.forename: Mark T
authors.initials: MT
authors.lastname: Heise
mesh_terms: D000818:Animals; D003433:Crosses, Genetic; D005260:Female; D014644:Genetic Variation; D054884:Host-Pathogen Interactions / Q000235:genetics*; D006801:Humans; D009980:Influenza A virus; D007251:Influenza, Human / Q000235:genetics / Q000473:pathology / Q000821:virology*; D008168:Lung / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D008957:Models, Genetic; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000473:pathology / Q000821:virology*; D010641:Phenotype; D016865:Reassortant Viruses / Q000235:genetics / Q000472:pathogenicity; D011995:Recombination, Genetic; D012376:Rodent Diseases / Q000235:genetics / Q000473:pathology / Q000821:virology*; D013045:Species Specificity; D014779:Virus Replication