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      Modeling Host Genetic Regulation of Influenza Pathogenesis in the Collaborative Cross

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          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.

          Author Summary

          Host responses to an infectious agent are highly variable across the human population, however, it is not entirely clear how various factors such as pathogen dose, demography, environment and host genetic polymorphisms contribute to variable host responses and infectious outcomes. In this study, a new in vivo experimental model was used that recapitulates many of the genetic characteristics of an outbred population, such as humans. By controlling viral dose, environment and demographic variables, we were able to focus on the role that host genetic variation plays in influenza virus infection. Both the range of disease phenotypes and the combinations of sets of disease phenotypes at 4 days post infection across this population exhibited a large amount of diversity, reminiscent of the variation seen across the human population. Multiple host genome regions were identified that contributed to different aspects of the host response to influenza infection. Taken together, these results emphasize the critical role of host genetics in the response to infectious diseases. Given the breadth of host responses seen within this population, several new models for unique host responses to infection were identified.

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          Most cited references69

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          Avian influenza A (H5N1) infection in humans.

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            Systems Biology of Seasonal Influenza Vaccination in Humans

            We used a systems biological approach to study innate and adaptive responses to influenza vaccination in humans, during 3 consecutive influenza seasons. Healthy adults were vaccinated with inactivated (TIV) or live attenuated (LAIV) influenza vaccines. TIV induced greater antibody titers and enhanced numbers of plasmablasts than LAIV. In TIV vaccinees, early molecular signatures correlated with, and accurately predicted, later antibody titers in two independent trials. Interestingly, the expression of Calcium/calmodulin-dependent kinase IV (CamkIV) at day 3 was inversely correlated with later antibody titers. Vaccination of CamkIV −/− mice with TIV induced enhanced antigen-specific antibody titers, demonstrating an unappreciated role for CaMKIV in the regulation of antibody responses. Thus systems approaches can predict immunogenicity, and reveal new mechanistic insights about vaccines.
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              Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study.

              Hepatitis C virus (HCV) induces chronic infection in 50% to 80% of infected persons; approximately 50% of these do not respond to therapy. We performed a genome-wide association study to screen for host genetic determinants of HCV persistence and response to therapy. The analysis included 1362 individuals: 1015 with chronic hepatitis C and 347 who spontaneously cleared the virus (448 were coinfected with human immunodeficiency virus [HIV]). Responses to pegylated interferon alfa and ribavirin were assessed in 465 individuals. Associations between more than 500,000 single nucleotide polymorphisms (SNPs) and outcomes were assessed by multivariate logistic regression. Chronic hepatitis C was associated with SNPs in the IL28B locus, which encodes the antiviral cytokine interferon lambda. The rs8099917 minor allele was associated with progression to chronic HCV infection (odds ratio [OR], 2.31; 95% confidence interval [CI], 1.74-3.06; P = 6.07 x 10(-9)). The association was observed in HCV mono-infected (OR, 2.49; 95% CI, 1.64-3.79; P = 1.96 x 10(-5)) and HCV/HIV coinfected individuals (OR, 2.16; 95% CI, 1.47-3.18; P = 8.24 x 10(-5)). rs8099917 was also associated with failure to respond to therapy (OR, 5.19; 95% CI, 2.90-9.30; P = 3.11 x 10(-8)), with the strongest effects in patients with HCV genotype 1 or 4. This risk allele was identified in 24% of individuals with spontaneous HCV clearance, 32% of chronically infected patients who responded to therapy, and 58% who did not respond (P = 3.2 x 10(-10)). Resequencing of IL28B identified distinct haplotypes that were associated with the clinical phenotype. The association of the IL28B locus with natural and treatment-associated control of HCV indicates the importance of innate immunity and interferon lambda in the pathogenesis of HCV infection. 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                February 2013
                February 2013
                28 February 2013
                : 9
                : 2
                : e1003196
                Affiliations
                [1 ]Carolina Vaccine Institute, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, United States of America
                [2 ]Department of Genetics, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, United States of America
                [3 ]Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon, United States of America
                [4 ]Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Portland, Oregon, United States of America
                [5 ]Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, United States of America
                [6 ]Department of Epidemiology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, United States of America
                [7 ]Erasmus Medical Center, Rotterdam, the Netherlands
                [8 ]Department of Computer Science, University of North Carolina–Chapel Hill, Chapel Hill, North Carolina, United States of America
                [9 ]The Jackson Laboratory, Bar Harbor, Maine, United States of America
                [10 ]Department of Genetics, North Carolina State University, Raleigh, North Carolina, United States of America
                [11 ]Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, United States of America
                Fox Chase Cancer Center, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: MTF DLA LEG GAC DWT MGK FPMdV RSB MTH. Performed the experiments: MTF DLA DB ACW LDA TAB RJB BLH ER. Analyzed the data: MTF DLA DB WV SKM FPMdV MTH. Contributed reagents/materials/analysis tools: MTF DLA DB BBT JTB BLH LM DRM WV JW SKM MGK FPMdV. Wrote the paper: MTF DLA DB SKM FPMdV MTH.

                Article
                PPATHOGENS-D-12-00894
                10.1371/journal.ppat.1003196
                3585141
                23468633
                459a5862-c00e-45b2-9c36-e9aafe052a48
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 16 April 2012
                : 2 January 2013
                Page count
                Pages: 15
                Funding
                This work was funded by U54AI081680 and U19 AI100625 from NIH, CA134240 to DWT, F32 AI084322-01 from NIH to MTF, and by the VIRGO consortium (BSIK 03012) to BLH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Genetics
                Animal Genetics
                Gene Networks
                Genetics of Disease
                Immunology
                Genetics of the Immune System
                Microbiology
                Virology
                Animal Models of Infection
                Mechanisms of Resistance and Susceptibility
                Host-Pathogen Interaction
                Model Organisms
                Animal Models
                Mouse
                Systems Biology

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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