Limits...
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.

Show MeSH

Related in: MedlinePlus

Genetic variation at HrI3 contributes to variation in pulmonary edema in an independent set of Collaborative Cross lines.Following the identification of HrI3, we infected animals from fully inbred Collaborative Cross lines, where each line was homozygous for a single founder allele at HrI3. (A) We found a significant effect of genotype at HrI3 on the extent and severity of pulmonary edema at four days post infection. Mild (B) and Severe (C) pulmonary edema can be seen at 200× magnification in animals from this experiment. Pulmonary edema was scored on the basis of evidence of transudates accumulating in the alveolar spaces (denoted by star marks in panel C).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3585141&req=5

ppat-1003196-g005: Genetic variation at HrI3 contributes to variation in pulmonary edema in an independent set of Collaborative Cross lines.Following the identification of HrI3, we infected animals from fully inbred Collaborative Cross lines, where each line was homozygous for a single founder allele at HrI3. (A) We found a significant effect of genotype at HrI3 on the extent and severity of pulmonary edema at four days post infection. Mild (B) and Severe (C) pulmonary edema can be seen at 200× magnification in animals from this experiment. Pulmonary edema was scored on the basis of evidence of transudates accumulating in the alveolar spaces (denoted by star marks in panel C).

Mentions: In order to confirm the role of HrI3 in contributing to control of pulmonary edema, we challenged a new set of female animals from a small set of completely inbred CC lines with IAV. These animals were homozygous for various founder alleles across the entire candidate region for HrI3 and founder strain alleles were each represented by two CC lines (e.g. two lines that vary across the rest of their genome both share the WSB/EiJ allele at HrI3). We examined the severity of pulmonary edema in these animals at four days post infection. Founder strain alleles at HrI3 significantly affected pulmonary edema (F3,16 = 8.48, p = 0.0013, Figure 5), validating the role of this genome region in the host response to IAV.


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)

Genetic variation at HrI3 contributes to variation in pulmonary edema in an independent set of Collaborative Cross lines.Following the identification of HrI3, we infected animals from fully inbred Collaborative Cross lines, where each line was homozygous for a single founder allele at HrI3. (A) We found a significant effect of genotype at HrI3 on the extent and severity of pulmonary edema at four days post infection. Mild (B) and Severe (C) pulmonary edema can be seen at 200× magnification in animals from this experiment. Pulmonary edema was scored on the basis of evidence of transudates accumulating in the alveolar spaces (denoted by star marks in panel C).
© Copyright Policy
Related In: Results  -  Collection

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

ppat-1003196-g005: Genetic variation at HrI3 contributes to variation in pulmonary edema in an independent set of Collaborative Cross lines.Following the identification of HrI3, we infected animals from fully inbred Collaborative Cross lines, where each line was homozygous for a single founder allele at HrI3. (A) We found a significant effect of genotype at HrI3 on the extent and severity of pulmonary edema at four days post infection. Mild (B) and Severe (C) pulmonary edema can be seen at 200× magnification in animals from this experiment. Pulmonary edema was scored on the basis of evidence of transudates accumulating in the alveolar spaces (denoted by star marks in panel C).
Mentions: In order to confirm the role of HrI3 in contributing to control of pulmonary edema, we challenged a new set of female animals from a small set of completely inbred CC lines with IAV. These animals were homozygous for various founder alleles across the entire candidate region for HrI3 and founder strain alleles were each represented by two CC lines (e.g. two lines that vary across the rest of their genome both share the WSB/EiJ allele at HrI3). We examined the severity of pulmonary edema in these animals at four days post infection. Founder strain alleles at HrI3 significantly affected pulmonary edema (F3,16 = 8.48, p = 0.0013, Figure 5), validating the role of this genome region in the host response to IAV.

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