Human genetics influence a range of pathological and clinical phenotypes in respiratory infections; however, the contributions of disease modifiers remain underappreciated. We exploited the Collaborative Cross (CC) mouse genetic-reference population to map genetic modifiers that affect the severity of Pseudomonas aeruginosa lung infection. Screening for P. aeruginosa respiratory infection in a cohort of 39 CC lines exhibits distinct disease phenotypes ranging from complete resistance to lethal disease. Based on major changes in the survival times, a quantitative-trait locus (QTL) was mapped on murine chromosome 3 to the genomic interval of Mb 110.4 to 120.5. Within this locus, composed of 31 protein-coding genes, two candidate genes, namely, dihydropyrimidine dehydrogenase (Dpyd) and sphingosine-1-phosphate receptor 1 (S1pr1), were identified according to the level of genome-wide significance and disease gene prioritization. Functional validation of the S1pr1 gene by pharmacological targeting in C57BL/6NCrl mice confirmed its relevance in P. aeruginosa pathophysiology. However, in a cohort of Canadian patients with cystic fibrosis (CF) disease, regional genetic-association analysis of the syntenic human locus on chromosome 1 (Mb 97.0 to 105.0) identified two single-nucleotide polymorphisms (rs10875080 and rs11582736) annotated to the Dpyd gene that were significantly associated with age at first P. aeruginosa infection. Thus, there is evidence that both genes might be implicated in this disease. Our results demonstrate that the discovery of murine modifier loci may generate information that is relevant to human disease progression.IMPORTANCE Respiratory infection caused by P. aeruginosa is one of the most critical health burdens worldwide. People affected by P. aeruginosa infection include patients with a weakened immune system, such as those with cystic fibrosis (CF) genetic disease or non-CF bronchiectasis. Disease outcomes range from fatal pneumonia to chronic life-threatening infection and inflammation leading to the progressive deterioration of pulmonary function. The development of these respiratory infections is mediated by multiple causes. However, the genetic factors underlying infection susceptibility are poorly known and difficult to predict. Our study employed novel approaches and improved mouse disease models to identify genetic modifiers that affect the severity of P. aeruginosa lung infection. We identified candidate genes to enhance our understanding of P. aeruginosa infection in humans and provide a proof of concept that could be exploited for other human pathologies mediated by bacterial infection.

中文翻译：

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铜绿假单胞菌感染人类肺部疾病的协同交叉小鼠产量遗传修饰因子。

人类遗传学影响呼吸道感染的一系列病理和临床表型。然而，疾病改良剂的贡献仍然未被重视。我们利用了协作十字（CC）小鼠遗传参考种群来定位影响铜绿假单胞菌肺部感染严重程度的遗传修饰因子。在39个CC品系队列中筛选铜绿假单胞菌呼吸道感染表现出明显的疾病表型，从完全耐药到致死性疾病不等。基于生存时间的重大变化，在小鼠染色体3上将定量性状基因座（QTL）定位到Mb 110.4至120.5的基因组间隔。在这个由31个蛋白质编码基因组成的基因座中，有两个候选基因，即二氢嘧啶脱氢酶（Dpyd）和鞘氨醇-1-磷酸受体1（S1pr1），根据全基因组重要性水平和疾病基因优先次序进行鉴定。通过药理靶向在C57BL / 6NCrl小鼠中对S1pr1基因进行功能验证，证实了其在铜绿假单胞菌病理生理学中的相关性。但是，在加拿大的一组囊性纤维化（CF）疾病患者中，对第1号染色体上同性人类基因座（Mb 97.0至105.0）的区域遗传关联分析确定了标注为Dpyd的两个单核苷酸多态性（rs10875080和rs11582736）与首次铜绿假单胞菌感染时的年龄显着相关的基因。因此，有证据表明这两种基因都可能与这种疾病有关。我们的结果表明，鼠修饰基因座的发现可能产生与人类疾病进展相关的信息。重要铜绿假单胞菌引起的呼吸道感染是全世界最关键的健康负担之一。受到铜绿假单胞菌感染的人包括免疫系统较弱的患者，例如患有囊性纤维化（CF）基因疾病或非CF支气管扩张的患者。疾病的后果范围从致命的肺炎到威胁生命的慢性感染和炎症，导致肺功能的逐步恶化。这些呼吸道感染的发生是由多种原因介导的。但是，感染易感性的遗传因素知之甚少且难以预测。我们的研究采用新颖的方法和改进的小鼠疾病模型来鉴定影响铜绿假单胞菌肺部感染严重程度的遗传修饰因子。我们鉴定了候选基因以增强我们对P的了解。