title: Influenza H3N2 infection of the collaborative cross founder strains reveals highly divergent host responses and identifies a unique phenotype in CAST/EiJ mice.
abstract: BACKGROUND
  Influenza A virus is a zoonotic pathogen that poses a major threat to human and animal health. The severe course of influenza infection is not only influenced by viral virulence factors but also by individual differences in the host response. To determine the extent to which the genetic background can modulate severity of an infection, we studied the host responses to influenza infections in the eight genetically highly diverse Collaborative Cross (CC) founder mouse strains.
  
  
  RESULTS
  We observed highly divergent host responses between the CC founder strains with respect to survival, body weight loss, hematological parameters in the blood, relative lung weight and viral load. Mouse strain was the main factor with highest effect size on body weight loss after infection, demonstrating that this phenotype was highly heritable. Sex represented another significant main effect, although it was less strong. Analysis of survival rates and mean time to death suggested three groups of susceptibility phenotypes: highly susceptible (A/J, CAST/EiJ, WSB/EiJ), intermediate susceptible (C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ) and highly resistant strains (NZO/HlLtJ, PWK/PhJ). These three susceptibility groups were significantly different with respect to death/survival counts. Viral load was significantly different between susceptible and resistant strains but not between intermediate and highly susceptible strains. CAST/EiJ mice showed a unique phenotype. Despite high viral loads in their lungs, CAST/EiJ mice exhibited low counts of infiltrating granulocytes and showed increased numbers of macrophages in the lung. Histological studies of infected lungs and transcriptome analyses of peripheral blood cells and lungs confirmed an abnormal response in the leukocyte recruitment in CAST/EiJ mice.
  
  
  CONCLUSIONS
  The eight CC founder strains exhibited a large diversity in their response to influenza infections. Therefore, the CC will represent an ideal mouse genetic reference population to study the influence of genetic variation on the susceptibility and resistance to influenza infections which will be important to understand individual variations of disease severity in humans. The unique phenotype combination in the CAST/EiJ strain resembles human leukocyte adhesion deficiency and may thus represent a new mouse model to understand this and related abnormal immune responses to infections in humans.
authors.affiliation: Department of Infection Genetics, Helmholtz Centre for Infection Research, Braunschweig and University of Veterinary Medicine Hannover, Inhoffenstr.7, D-38124, Braunschweig, Hannover, Germany.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Leist
authors.affiliation: Department of Infection Genetics, Helmholtz Centre for Infection Research, Braunschweig and University of Veterinary Medicine Hannover, Inhoffenstr.7, D-38124, Braunschweig, Hannover, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Pilzner
authors.affiliation: Department of Viroscience, Erasmus Medical Center, Rotterdam, Netherlands.
authors.forename: Judith M A
authors.initials: JM
authors.lastname: van den Brand
authors.affiliation: Department of Infection Genetics, Helmholtz Centre for Infection Research, Braunschweig and University of Veterinary Medicine Hannover, Inhoffenstr.7, D-38124, Braunschweig, Hannover, Germany.
authors.forename: Leonie
authors.initials: L
authors.lastname: Dengler
authors.affiliation: Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Geffers
authors.affiliation: Department of Viroscience, Erasmus Medical Center, Rotterdam, Netherlands.
authors.forename: Thijs
authors.initials: T
authors.lastname: Kuiken
authors.affiliation: Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg.
authors.forename: Rudi
authors.initials: R
authors.lastname: Balling
authors.affiliation: Department of Infection Genetics, Helmholtz Centre for Infection Research, Braunschweig and University of Veterinary Medicine Hannover, Inhoffenstr.7, D-38124, Braunschweig, Hannover, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Kollmus
authors.affiliation: Department of Infection Genetics, Helmholtz Centre for Infection Research, Braunschweig and University of Veterinary Medicine Hannover, Inhoffenstr.7, D-38124, Braunschweig, Hannover, Germany. kls@helmholtz-hzi.de.|University of Tennessee Health Science Center, Memphis, TN, USA. kls@helmholtz-hzi.de.
authors.forename: Klaus
authors.initials: K
authors.lastname: Schughart
mesh_terms: D000818:Animals; D001835:Body Weight; D060467:Disease Resistance / Q000235:genetics*; D005260:Female; D053122:Influenza A Virus, H3N2 Subtype; D008168:Lung / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains / Q000235:genetics* / Q000821:virology; D009976:Orthomyxoviridae Infections / Q000235:genetics*; D010641:Phenotype; D059467:Transcriptome; D019562:Viral Load