Modeling host genetic regulation of influenza pathogenesis in the collaborative cross.
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 o...
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2013
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oai:doaj.org-article:7b65541d5dda41df84e78d9a797b012a2021-11-18T06:05:58ZModeling host genetic regulation of influenza pathogenesis in the collaborative cross.1553-73661553-737410.1371/journal.ppat.1003196https://doaj.org/article/7b65541d5dda41df84e78d9a797b012a2013-02-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23468633/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Genetic 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.Martin T FerrisDavid L AylorDaniel BottomlyAlan C WhitmoreLauri D AicherTimothy A BellBirgit Bradel-TrethewayJanine T BryanRyan J BuusLisa E GralinskiBart L HaagmansLeonard McMillanDarla R MillerElizabeth RosenzweigWilliam ValdarJeremy WangGary A ChurchillDavid W ThreadgillShannon K McWeeneyMichael G KatzeFernando Pardo-Manuel de VillenaRalph S BaricMark T HeisePublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 9, Iss 2, p e1003196 (2013) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 |
| spellingShingle |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 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 K McWeeney Michael G Katze Fernando Pardo-Manuel de Villena Ralph S Baric Mark T Heise Modeling host genetic regulation of influenza pathogenesis in the collaborative cross. |
| description |
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. |
| format |
article |
| author |
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 K McWeeney Michael G Katze Fernando Pardo-Manuel de Villena Ralph S Baric Mark T Heise |
| author_facet |
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 K McWeeney Michael G Katze Fernando Pardo-Manuel de Villena Ralph S Baric Mark T Heise |
| author_sort |
Martin T Ferris |
| title |
Modeling host genetic regulation of influenza pathogenesis in the collaborative cross. |
| title_short |
Modeling host genetic regulation of influenza pathogenesis in the collaborative cross. |
| title_full |
Modeling host genetic regulation of influenza pathogenesis in the collaborative cross. |
| title_fullStr |
Modeling host genetic regulation of influenza pathogenesis in the collaborative cross. |
| title_full_unstemmed |
Modeling host genetic regulation of influenza pathogenesis in the collaborative cross. |
| title_sort |
modeling host genetic regulation of influenza pathogenesis in the collaborative cross. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/7b65541d5dda41df84e78d9a797b012a |
| work_keys_str_mv |
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| _version_ |
1718424612271816704 |