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
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
