The gram-negative bacterium Coxiella burnetii is the causative agent of Query (Q) fever in humans and coxiellosis in livestock. Association between host genetic background and Coxiella burnetii pathogenesis has been demonstrated both in humans and animals; however, specific genes associated with severity of infection remain unknown. We employed the Drosophila Genetics Reference Panel to perform a genome-wide association study and identify host genetic variants that affect Coxiella burnetii infection outcome. The analysis resulted in 64 genome-wide suggestive (P < 10^-5) single nucleotide polymorphisms or gene variants in 25 unique genes. We examined the role of each gene in Coxiella burnetii infection using flies carrying a null mutation or RNAi knockdown of each gene and monitoring survival. Of the 25 candidate genes, 15 validated using at least one method. For many, this is the first report establishing involvement of these genes or their homologs with Coxiella burnetii susceptibility in any system. Among the validated genes, FER and tara play roles in the JAK-STAT, JNK, and decapentaplegic/TGF-β signaling pathways that are associated with the innate immune response to Coxiella burnetii infection. Two other two validated genes, CG42673 and DIP-ε, play roles in bacterial infection and synaptic signaling but no previous association with Coxiella burnetii pathogenesis. Furthermore, since the mammalian ortholog of CG13404 (PLGRKT) is an important regulator of macrophage function, CG13404 could play a role in Coxiella burnetii susceptibility through hemocyte regulation. These insights provide a foundation for further investigation of genetics of Coxiella burnetii susceptibility across a wide variety of hosts.

中文翻译：

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果蝇的自然遗传变异揭示了与柯氏杆菌感染相关的基因。

革兰氏阴性杆菌伯氏杆菌是人类Query（Q）发热和牲畜肺炎的病原体。在人类和动物中都已经证明了宿主遗传背景和伯氏柯氏杆菌发病机理之间的联系。然而，与感染严重程度有关的特定基因仍是未知的。我们利用果蝇遗传学参考小组进行了全基因组关联研究，并确定了影响伯氏柯氏杆菌感染结果的宿主遗传变异。该分析导致25个独特基因中有64个全基因组提示性（P <10 ^-5）单核苷酸多态性或基因变异。我们检查了每个基因在伯氏柯氏杆菌中的作用使用携带每个基因的无效突变或RNAi敲低并监测存活率的果蝇感染。在25个候选基因中，有15个使用至少一种方法进行了验证。对于许多人来说，这是第一个报告证明这些基因或其同源物与伯氏柯氏杆菌易感性在任何系统中都有关系。在已验证的基因中，FER和tara在JAK-STAT，JNK和去能力化/TGF-β信号传导途径中起作用，这些途径与对伯氏柯氏杆菌感染的先天免疫应答有关。另外两个经过验证的基因CG42673和DIP-ε在细菌感染和突触信号传导中起作用，但以前与柯氏杆菌无关联发病。此外，由于哺乳动物直系同源基因CG13404（PLGRKT）是巨噬细胞功能的重要调节因子，CG13404可以发挥作用贝氏柯克斯体通过血细胞调控的敏感性。这些见解为进一步研究多种宿主的伯氏克氏杆菌敏感性遗传学奠定了基础。