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在人体挑战模型中研究伤寒毒素在急性伤寒中的作用。

Investigation of the role of typhoid toxin in acute typhoid fever in a human challenge model.

机构信息

Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the NIHR Oxford Biomedical Research Centre, Oxford, UK.

Department of Medicine, Imperial College London, London, UK.

出版信息

Nat Med. 2019 Jul;25(7):1082-1088. doi: 10.1038/s41591-019-0505-4. Epub 2019 Jul 3.

DOI:10.1038/s41591-019-0505-4
PMID:31270506
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6892374/
Abstract

Salmonella Typhi is a human host-restricted pathogen that is responsible for typhoid fever in approximately 10.9 million people annually. The typhoid toxin is postulated to have a central role in disease pathogenesis, the establishment of chronic infection and human host restriction. However, its precise role in typhoid disease in humans is not fully defined. We studied the role of typhoid toxin in acute infection using a randomized, double-blind S. Typhi human challenge model. Forty healthy volunteers were randomized (1:1) to oral challenge with 10 colony-forming units of wild-type or an isogenic typhoid toxin deletion mutant (TN) of S. Typhi. We observed no significant difference in the rate of typhoid infection (fever ≥38 °C for ≥12 h and/or S. Typhi bacteremia) between participants challenged with wild-type or TN S. Typhi (15 out of 21 (71%) versus 15 out of 19 (79%); P = 0.58). The duration of bacteremia was significantly longer in participants challenged with the TN strain compared with wild-type (47.6 hours (28.9-97.0) versus 30.3(3.6-49.4); P ≤ 0.001). The clinical syndrome was otherwise indistinguishable between wild-type and TN groups. These data suggest that the typhoid toxin is not required for infection and the development of early typhoid fever symptoms within the context of a human challenge model. Further clinical data are required to assess the role of typhoid toxin in severe disease or the establishment of bacterial carriage.

摘要

伤寒沙门氏菌是一种人类宿主受限病原体，每年导致约 1090 万人患伤寒。伤寒毒素被认为在疾病发病机制、慢性感染的建立和人类宿主限制中起核心作用。然而，其在人类伤寒病中的确切作用尚未完全确定。我们使用随机、双盲伤寒沙门氏菌人类挑战模型研究了伤寒毒素在急性感染中的作用。将 40 名健康志愿者随机（1:1）口服 10 个菌落形成单位的野生型或伤寒毒素缺失突变体（TN）的伤寒沙门氏菌。我们观察到接受野生型或 TN 伤寒沙门氏菌挑战的参与者中伤寒感染的发生率（发热≥38°C 持续 12 小时以上和/或伤寒沙门氏菌菌血症）没有显著差异（21 名参与者中的 15 名（71%）与 19 名参与者中的 15 名（79%）；P=0.58）。与野生型相比，接受 TN 菌株挑战的参与者的菌血症持续时间明显更长（47.6 小时（28.9-97.0）与 30.3 小时（3.6-49.4）；P≤0.001）。在野生型和 TN 组之间，临床综合征 otherwise 无明显区别。这些数据表明，在人类挑战模型中，伤寒毒素对于感染和伤寒早期症状的发展不是必需的。需要进一步的临床数据来评估伤寒毒素在严重疾病或细菌携带中的作用。

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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c904/6892374/7881becab85a/41591_2019_505_Fig5_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c904/6892374/4dc1d00fb6bb/41591_2019_505_Fig6_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c904/6892374/0f52979dc29a/41591_2019_505_Fig7_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c904/6892374/652ecb2abbde/41591_2019_505_Fig8_ESM.jpg
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