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

Abstract

Background: Pseudomonas 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.

Results: A 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.

Conclusion: This 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.

Fig 1

Disease phenotypes in CC mice during P. aeruginosa acute respiratory infection. 17 CC lines and A/J mice of 8–14 weeks old (between 3–7 mice per Line), were inoculated with a 1×10⁶ cfu dose of the P. aeruginosa clinical isolate AA2, and monitored for survival time ST (a) and body weight BW (b) for a period of 7 days after infection

Fig 2

Evaluation of MST, CBW1 and H² of CC lines after P. aeruginosa airway infection. The CC mice resource population had a strong wide-response to P. aeruginosa airway infection in the MST (a) and CBW1 traits (b). MST and CBW1 of CC lines are arranged in increasing order of mean magnitude. Based on Bonferroni's Multiple Comparison Tests (BMCT) (Additional file 3: Table S3) three distinct groups have been identified among 17 CC strains infected with P. aeruginosa and are indicated as scales of grey. Estimates of broad sense H² (c) have been evaluated for MST and CBW1, as previously described [23]