The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Pathog Dis. 2014 Aug;71(3):357-61. doi: 10.1111/2049-632X.12154. Epub 2014 Mar 6.
Vibrio vulnificus (Vv) is a pathogenic bacterium that can cause life-threatening infections in humans. Most fatal cases are due to septic shock that results from dysregulation of cytokines, particularly TNFα, which plays a critical role in the outcome of Vv infection. The goal of this study was to investigate the Toll-like receptor (TLR)-mediated TNFα response to four Vv biotype 1 strains using mice deficient for TLR2, TLR4, and TLR2/TLR4. Ex vivo assays were performed with blood, splenocytes, and Kupffer cells (KC) from wild-type (WT) and TLR-knockout (KO) mice using formalin-inactivated Vv (f-Vv) as stimulant. All f-Vv biotype 1 strains elicited strong TNFα production by WT mouse blood and cells, which was TLR2 and TLR4 dependent. OxPAPC, an inhibitor of TLR2 and TLR4 signaling, effectively blunted the TLR-mediated TNFα response to f-Vv. Furthermore, TLR2 KO and TLR2/TLR4 KO mice were more resistant to lethal infection with Vv ATCC 27562 than WT mice, perhaps due to attenuation of the TNFα response. These data suggest that it may be possible to devise strategies to specifically target the harmful TLR-mediated TNFα response as an adjunct to antibiotic treatment of severe Vv infection.
创伤弧菌（Vv）是一种能导致人类生命受到威胁的病原菌。大多数致命病例是由于细胞因子失调引起的败血症性休克所致，其中 TNFα 起着关键作用。本研究的目的是使用 TLR2、TLR4 和 TLR2/TLR4 缺失的小鼠来研究创伤弧菌生物型 1 株的 Toll 样受体（TLR）介导的 TNFα 反应。采用福尔马林灭活的创伤弧菌（f-Vv）作为刺激物，用来自野生型（WT）和 TLR 敲除（KO）小鼠的血液、脾细胞和库普弗细胞（KC）进行离体测定。所有 f-Vv 生物型 1 株均能强烈诱导 WT 鼠血液和细胞产生 TNFα，该反应依赖于 TLR2 和 TLR4。OxPAPC，TLR2 和 TLR4 信号通路的抑制剂，能有效阻断 f-Vv 诱导的 TLR 介导的 TNFα 反应。此外，与 WT 小鼠相比，TLR2 KO 和 TLR2/TLR4 KO 小鼠对致死性感染创伤弧菌 ATCC 27562 具有更强的抵抗力，这可能是由于 TNFα 反应的减弱。这些数据表明，针对有害的 TLR 介导的 TNFα 反应设计策略，可能成为抗生素治疗严重创伤弧菌感染的辅助手段。
