Abstract
BackgroundInfluenza 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.ResultsWe 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.ConclusionsThe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2483-y) contains supplementary material, which is available to authorized users.
Highlights
Influenza A virus is a zoonotic pathogen that poses a major threat to human and animal health
The eight Collaborative Cross (CC) founder strains exhibited a large diversity in their response to influenza infections
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
Summary
Influenza A virus is a zoonotic pathogen that poses a major threat to human and animal health. The severe course of influenza infection is influenced by viral virulence factors and by individual differences in the host response. The course and outcome of an infection is determined by pathogen virulence, environmental and host factors. Genetic diversity of the host has been found as an important factor that strongly influences the host response and severity to influenza infections in humans [8,9,10,11,12]. Environmental and genetic factors can be well controlled in experimental animal models It has been shown in mouse models that the genetic make-up of the host strongly influences the disease outcome after influenza infections (reviewed in [11, 13]). Several genes have been described in humans that contribute to disease severity [14]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
