Interferon-driven alterations of the host's amino acid metabolism in the pathogenesis of typhoid fever.
Interferon-driven alterations of the host's amino acid metabolism in the pathogenesis of typhoid fever.
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DOI：
10.1084/jem.20151025
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发表时间：
2016-05-30
期刊：
影响因子：
--
通讯作者：
Pollard AJ
中科院分区：
文献类型：
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作者：
Blohmke CJ;Darton TC;Jones C;Suarez NM;Waddington CS;Angus B;Zhou L;Hill J;Clare S;Kane L;Mukhopadhyay S;Schreiber F;Duque-Correa MA;Wright JC;Roumeliotis TI;Yu L;Choudhary JS;Mejias A;Ramilo O;Shanyinde M;Sztein MB;Kingsley RA;Lockhart S;Levine MM;Lynn DJ;Dougan G;Pollard AJ
对人类和小鼠的研究强调了色氨酸代谢在伤寒免疫发病机制中的作用，为临床疾病提供了新的见解。由伤寒沙门氏菌引起的肠热病是资源有限环境中的一个重要公共卫生问题，尽管进行了数十年的研究，但人类对该感染的反应仍知之甚少。在 41 名健康成年人中，通过实验感染野生型伤寒沙门氏菌，我们在摄入细菌后 12 小时内检测到显着的细胞因子反应。这些早期反应与随后的临床疾病结果无关，可能表明肠道粘膜中最初的宿主-病原体相互作用。在口腔感染后出现肠热的参与者中，急性疾病期间显着的转录和细胞因子反应反映了主导的 I/II 型干扰素特征，这与菌血症显着相关。使用小鼠和巨噬细胞感染模型，我们验证了沙门氏菌感染期间这种反应在宿主色氨酸代谢蛋白表达中的关键作用。伤寒参与者血清中具有免疫调节特性的色氨酸分解代谢物的相应变化证实了该途径的活性，并暗示宿主色氨酸代谢在伤寒发病机制中的核心作用。
Work in humans and mice highlights the role of tryptophan metabolism in the immunopathogenesis of typhoid fever, offering novel insight into clinical disease. Enteric fever, caused by Salmonella enterica serovar Typhi, is an important public health problem in resource-limited settings and, despite decades of research, human responses to the infection are poorly understood. In 41 healthy adults experimentally infected with wild-type S. Typhi, we detected significant cytokine responses within 12 h of bacterial ingestion. These early responses did not correlate with subsequent clinical disease outcomes and likely indicate initial host–pathogen interactions in the gut mucosa. In participants developing enteric fever after oral infection, marked transcriptional and cytokine responses during acute disease reflected dominant type I/II interferon signatures, which were significantly associated with bacteremia. Using a murine and macrophage infection model, we validated the pivotal role of this response in the expression of proteins of the host tryptophan metabolism during Salmonella infection. Corresponding alterations in tryptophan catabolites with immunomodulatory properties in serum of participants with typhoid fever confirmed the activity of this pathway, and implicate a central role of host tryptophan metabolism in the pathogenesis of typhoid fever.