Complex Genetic Architecture Underlies Regulation of Influenza-A-Virus-Specific Antibody Responses in the Collaborative Cross

Kelsey E. Noll; Alan C. Whitmore; Ande West; Mary K. McCarthy; Clayton R. Morrison; Kenneth S. Plante; Brea K. Hampton; Heike Kollmus; Carolin Pilzner; Sarah R. Leist; Lisa E. Gralinski; Vineet D. Menachery; Alexandra Schäfer; Darla Miller; Ginger Shaw; Michael Mooney; Shannon McWeeney; Fernando Pardo-Manuel de Villena; Klaus Schughart; Thomas E. Morrison; Ralph S. Baric; Martin T. Ferris; Mark T. Heise

Cell Reports (Apr 2020)

Complex Genetic Architecture Underlies Regulation of Influenza-A-Virus-Specific Antibody Responses in the Collaborative Cross

Kelsey E. Noll,
Alan C. Whitmore,
Ande West,
Mary K. McCarthy,
Clayton R. Morrison,
Kenneth S. Plante,
Brea K. Hampton,
Heike Kollmus,
Carolin Pilzner,
Sarah R. Leist,
Lisa E. Gralinski,
Vineet D. Menachery,
Alexandra Schäfer,
Darla Miller,
Ginger Shaw,
Michael Mooney,
Shannon McWeeney,
Fernando Pardo-Manuel de Villena,
Klaus Schughart,
Thomas E. Morrison,
Ralph S. Baric,
Martin T. Ferris,
Mark T. Heise

Affiliations

Kelsey E. Noll: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Alan C. Whitmore: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Ande West: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Mary K. McCarthy: Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA
Clayton R. Morrison: StrideBio, Durham, NC, USA
Kenneth S. Plante: Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, TX, USA
Brea K. Hampton: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Heike Kollmus: Department of Infection Genetics, Helmholtz Centre for Infection Research, Braunschweig, Germany
Carolin Pilzner: Department of Infection Genetics, Helmholtz Centre for Infection Research, Braunschweig, Germany
Sarah R. Leist: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Infection Genetics, Helmholtz Centre for Infection Research, Braunschweig, Germany
Lisa E. Gralinski: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Vineet D. Menachery: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, TX, USA
Alexandra Schäfer: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Darla Miller: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Ginger Shaw: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Michael Mooney: Division of Bioinformatics and Computational Biology, Department of Medical Informatics and Clinical Epidemiology, Oregon Health and Science University, Portland, OR, USA; OHSU Knight Cancer Center Institute, Oregon Health and Science University, Portland, OR, USA
Shannon McWeeney: Division of Bioinformatics and Computational Biology, Department of Medical Informatics and Clinical Epidemiology, Oregon Health and Science University, Portland, OR, USA; OHSU Knight Cancer Center Institute, Oregon Health and Science University, Portland, OR, USA; Oregon Clinical and Translational Research Institute, Oregon Health and Science University, Portland, OR, USA
Fernando Pardo-Manuel de Villena: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
Klaus Schughart: Department of Infection Genetics, Helmholtz Centre for Infection Research, Braunschweig, Germany; University of Veterinary Medicine Hannover, Hannover, Germany; Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN, USA
Thomas E. Morrison: Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA
Ralph S. Baric: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
Martin T. Ferris: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Mark T. Heise: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA; Corresponding author

Journal volume & issue: Vol. 31, no. 4

Abstract

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Summary: Host genetic factors play a fundamental role in regulating humoral immunity to viral infection, including influenza A virus (IAV). Here, we utilize the Collaborative Cross (CC), a mouse genetic reference population, to study genetic regulation of variation in antibody response following IAV infection. CC mice show significant heritable variation in the magnitude, kinetics, and composition of IAV-specific antibody response. We map 23 genetic loci associated with this variation. Analysis of a subset of these loci finds that they broadly affect the antibody response to IAV as well as other viruses. Candidate genes are identified based on predicted variant consequences and haplotype-specific expression patterns, and several show overlap with genes identified in human mapping studies. These findings demonstrate that the host antibody response to IAV infection is under complex genetic control and highlight the utility of the CC in modeling and identifying genetic factors with translational relevance to human health and disease. : Noll et al. use the Collaborative Cross, a mouse genetic reference population, to map genetic loci associated with variation in the humoral response to influenza virus infection. Cross-dataset comparison shows that mapped loci are important for antibody response to multiple pathogens, and candidate genes with likely translational relevance are identified. Keywords: Collaborative Cross, humoral immunity, influenza, influenza virus, antibody, host genetics, genetic architecture, genetic mapping, genetic reference population, complex trait

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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