Lorè Nicola Ivan, Iraqi Fuad A, Bragonzi Alessandra
Infection and Cystic Fibrosis Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS - San Raffaele Scientific Institute, Milan, Italy.
Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, 69978, Tel Aviv, Israel.
BMC Genet. 2015 Aug 28;16:106. doi: 10.1186/s12863-015-0260-6.
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.
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.
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.
铜绿假单胞菌是人类机会性感染的三大病因之一。由于免疫抑制疗法或潜在疾病（如癌症、艾滋病或遗传性疾病囊性纤维化）导致免疫系统受损的患者，有发生铜绿假单胞菌感染的风险。然而，临床证据表明，有风险的个体中铜绿假单胞菌感染的结果差异极大，这表明宿主的多复杂遗传特征可能会影响这种机会性感染的严重程度。在这里，我们使用了一种创新的实验模型来剖析宿主遗传背景（如在远交群体中发现的那些）是否会影响铜绿假单胞菌肺炎的发病和死亡风险。
一个高度遗传多样的小鼠资源群体——协作杂交（CC）小鼠，感染了一株临床分离的铜绿假单胞菌，随后监测其死亡率、平均存活时间和发病率，以及感染后七天的体重变化。疾病表型从完全抵抗和体重恢复到致命疾病不等。包括体重、年龄和性别在内的初始变量对铜绿假单胞菌感染结果的影响有限，这突出了宿主遗传背景在确定发病和死亡风险中的作用。当评估表型性状的广义遗传力时，证实了在铜绿假单胞菌感染期间CC品系中遗传图谱而非环境因素的影响。
这种创新的模型系统有可能重现人类在铜绿假单胞菌肺炎期间观察到的疾病严重程度的可变反应。我们的结果表明，在发病率和死亡率方面，对铜绿假单胞菌气道感染的广泛差异反应主要受宿主遗传因素影响，如多个基因位点或多态性变异。
