Host genetic diversity influences the severity of Pseudomonas aeruginosa pneumonia in the Collaborative Cross mice

Abstract

BackgroundPseudomonas aeruginosa is one of the top three causes of opportunistic infections in humans. Patients with a compromised immune system, due to immunosuppressive therapies or underlying diseases such as cancer, AIDS or the hereditary disease cystic fibrosis, are at risk of developing P. aeruginosa infection. However, clinical evidence indicates extremely variable outcomes of P. aeruginosa infections in individuals at risk, suggesting that host multi-complex genetic traits may influence the severity of this opportunistic infection. Here, we have used an innovative experimental model to dissect whether host genetic background, such as those found in the outbred population, could influence the risk of morbidity and mortality to P. aeruginosa pneumonia.ResultsA highly genetically-diverse mouse resource population, Collaborative Cross (CC) mice, was infected with a clinical strain of P. aeruginosa and subsequently monitored for mortality, mean survival time, and morbidity, change in body weight for seven days post infection. Disease phenotypes ranged from complete resistance and recovery of body weight to lethal disease. Initial variables, including body weight, age and gender, have limited influence on P. aeruginosa outcome, emphasizing the role of host genetic background in defining the risk of morbidity and mortality. When broad-sense heritability of phenotypic traits was evaluated, it confirmed the influence of genetic profile rather than environmental factors among the CC lines during P. aeruginosa infection.ConclusionThis innovative model system can potentially reproduce the variables responses of disease severity observed in humans during P. aeruginosa pneumonia. Our results demonstrated that a widely-marked differential response to P. aeruginosa airway infection in term of morbidity and mortality, is mainly affected by host genetic factors, as multiple genetic loci or polymorphic variations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-015-0260-6) contains supplementary material, which is available to authorized users.

Genetic susceptibility to infectious diseases: Current status and future perspectives from genome-wide approaches

“…More recently, incipient CC lines were used to identify variants in Trim55 associated with vascular cuffing after infection with a mouse adapted SARS-CoV strain (Gralinski et al, 2015) and QTLs for survival to Klebsiella pneumoniae infection (Vered et al, 2014). Importantly, CC mice have been used to create improved models of EBOV (Ebola virus) and WNV (West Nile virus) infection (Graham et al, 2016;Graham et al, 2015;Rasmussen et al, 2014) and mouse populations showing diverse susceptibility to M. tuberculosis and Pseudomonas aeruginosa (Lore et al, 2015;Smith et al, 2016). These models await genome-wide scans to unveil the genetic determinants of infection susceptibility and severity.…”

The host genetic background defines diverse immune-reactivity and susceptibility to chronic Pseudomonas aeruginosa respiratory infection

“…How the host genetic background mediates disease outcome and pathogenesis of chronic lung infection by shaping the host response to P. aeruginosa remains to be established. Phenotype/genotype correlations are difficult to approach in humans, while phylogenetically different strains of mice have been successfully used to clarify aspects of different susceptibility to P. aeruginosa infection5678910. In mouse strains presenting deviant clinical phenotypes, a faster and higher cell-mediated innate immune response sets the conditions for resistance during early P. aeruginosa infection, as opposed to susceptible phenotype9.…”

Understanding the Intersection of Environmental Pollution, Pneumonia, and Inflammation: Does Gender Play a Role?

“…In a recent study, scientists used the CC mouse model to determine whether the host genetic background could impact the risk of morbidity and mortality to pneumonia caused by infection with P. aeruginosa. In this study, the CC strain reproduced the responses of disease severity commonly observed in humans during infection, suggesting that variations in morbidity and mortality are highly affected by host genetic factors [105]. Whereas no significant gender differences on disease phenotypes were observed, it is important to note the sample size was small.…”

“…The CC combines the genomes of eight genetically diverse founder strains, such as A/J, C57BL/6 J, 129S1/SvImJ, NOD/LtJ, NZO/HlLtJ, CAST/EiJ, PWK/PhJ, and WSB/ EiJ [85]. This genetic combination is a significant element for the study on human-host susceptibility to major diseases, including infections, such as pneumonia [105]. In a recent study, scientists used the CC mouse model to determine whether the host genetic background could impact the risk of morbidity and mortality to pneumonia caused by infection with P. aeruginosa.…”