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Modeling host genetic regulation of influenza pathogenesis in the collaborative cross.

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 SK, Katze MG, Pardo-Manuel de Villena F, Baric RS, Heise MT - PLoS Pathog. (2013)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Carolina Vaccine Institute, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, United States of America. mtferris@email.unc.edu

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.

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Diverse disease pathologies present across the pre-CC population.Histopathological examination of lung sections following IAV infection showed a diverse range of phenotypes. Each image is a single 100× magnification image of the lung section of a single pre-CC mouse (strain ID, D4 weight, and log titer (BDL = below detectable limit) are listed over each image). Disease phenotypes were scored for aspects of the damage to, and inflammatory cell infiltration around the airways (A), inflammatory cell infiltration around the vasculature (B), and damage and inflammatory cell infiltration in the alveolar spaces (C). Note that the image of OR219 shows a relatively healthy looking lung, and is useful as a baseline image.
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ppat-1003196-g002: Diverse disease pathologies present across the pre-CC population.Histopathological examination of lung sections following IAV infection showed a diverse range of phenotypes. Each image is a single 100× magnification image of the lung section of a single pre-CC mouse (strain ID, D4 weight, and log titer (BDL = below detectable limit) are listed over each image). Disease phenotypes were scored for aspects of the damage to, and inflammatory cell infiltration around the airways (A), inflammatory cell infiltration around the vasculature (B), and damage and inflammatory cell infiltration in the alveolar spaces (C). Note that the image of OR219 shows a relatively healthy looking lung, and is useful as a baseline image.

Mentions: The infected founder strains varied significantly for all measured phenotypes, including D4 weight, log titer, virus induced inflammation and pathology, except for variation in alveolar debris (p-values ranging from 0.15 to 1.37×10−9, Figure 1, Table S1). Founder strains could be grouped into susceptible (high viral titer, inflammation and weight loss) or resistant (low viral titer, little inflammation and weight loss) groups (Figure 1, Figure S1). As with the founders, many aspects of IAV associated disease were correlated with each other across the pre-CC population (correlation coefficients ranging from −0.78 to 0.78, Figure 1, Table S2), with the exception of alveolar immune cell infiltration as well as gross edema and hemorrhage at time of harvest, which were not strongly correlated with the rest of the host response to infection. Pre-CC mice often showed unique combinations of disease-associated phenotypes (e.g. high levels of viral replication but low inflammation and weight loss, no replication but significant weight loss, Figures 1 and 2). Therefore, though the pre-CC population recapitulated the range of variation within any given phenotype (Table S1), we observed new phenotypic combinations not seen in the parental lines.


Modeling host genetic regulation of influenza pathogenesis in the collaborative cross.

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 SK, Katze MG, Pardo-Manuel de Villena F, Baric RS, Heise MT - PLoS Pathog. (2013)

Diverse disease pathologies present across the pre-CC population.Histopathological examination of lung sections following IAV infection showed a diverse range of phenotypes. Each image is a single 100× magnification image of the lung section of a single pre-CC mouse (strain ID, D4 weight, and log titer (BDL = below detectable limit) are listed over each image). Disease phenotypes were scored for aspects of the damage to, and inflammatory cell infiltration around the airways (A), inflammatory cell infiltration around the vasculature (B), and damage and inflammatory cell infiltration in the alveolar spaces (C). Note that the image of OR219 shows a relatively healthy looking lung, and is useful as a baseline image.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585141&req=5

ppat-1003196-g002: Diverse disease pathologies present across the pre-CC population.Histopathological examination of lung sections following IAV infection showed a diverse range of phenotypes. Each image is a single 100× magnification image of the lung section of a single pre-CC mouse (strain ID, D4 weight, and log titer (BDL = below detectable limit) are listed over each image). Disease phenotypes were scored for aspects of the damage to, and inflammatory cell infiltration around the airways (A), inflammatory cell infiltration around the vasculature (B), and damage and inflammatory cell infiltration in the alveolar spaces (C). Note that the image of OR219 shows a relatively healthy looking lung, and is useful as a baseline image.
Mentions: The infected founder strains varied significantly for all measured phenotypes, including D4 weight, log titer, virus induced inflammation and pathology, except for variation in alveolar debris (p-values ranging from 0.15 to 1.37×10−9, Figure 1, Table S1). Founder strains could be grouped into susceptible (high viral titer, inflammation and weight loss) or resistant (low viral titer, little inflammation and weight loss) groups (Figure 1, Figure S1). As with the founders, many aspects of IAV associated disease were correlated with each other across the pre-CC population (correlation coefficients ranging from −0.78 to 0.78, Figure 1, Table S2), with the exception of alveolar immune cell infiltration as well as gross edema and hemorrhage at time of harvest, which were not strongly correlated with the rest of the host response to infection. Pre-CC mice often showed unique combinations of disease-associated phenotypes (e.g. high levels of viral replication but low inflammation and weight loss, no replication but significant weight loss, Figures 1 and 2). Therefore, though the pre-CC population recapitulated the range of variation within any given phenotype (Table S1), we observed new phenotypic combinations not seen in the parental lines.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Carolina Vaccine Institute, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, United States of America. mtferris@email.unc.edu

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.

Show MeSH
Related in: MedlinePlus