International Respiratory and Severe Illness Center, University of Washington, Seattle, WA 98104, USA.
J Immunol. 2013 Apr 1;190(7):3373-9. doi: 10.4049/jimmunol.1202974. Epub 2013 Feb 27.
Melioidosis is infection caused by the flagellated saprophyte Burkholderia pseudomallei. TLR5 is a pathogen recognition receptor activated by bacterial flagellin. We studied a genetic variant that encodes a defective TLR5 protein, TLR5(1174C)>T, to elucidate the role of TLR5 in melioidosis. We measured NF-κB activation induced by B. pseudomallei in human embryonic kidney-293 cells transfected with TLR5 and found that B. pseudomallei induced TLR5(1174C)- but not TLR5(1174T)-dependent activation of NF-κB. We tested the association of TLR5(1174C)>T with outcome in 600 Thai subjects with melioidosis. In a dominant model, TLR5(1174C)>T was associated with protection against in-hospital death (adjusted odds ratio: 0.20; 95% confidence interval: 0.08-0.50; p = 0.001) and organ failure (adjusted odds ratio: 0.37; 95% confidence interval: 0.19-0.71; p = 0.003). We analyzed blood cytokine production induced by flagellin or heat-killed B. pseudomallei by TLR5(1174C)>T genotype in healthy subjects. Flagellin induced lower monocyte-normalized levels of IL-6, IL-8, TNF-α, IL-10, MCP-1, IL-1ra, G-CSF, and IL-1β in carriers of TLR5(1174T) compared with carriers of TLR5(1174C). B. pseudomallei induced lower monocyte-normalized levels of IL-10 in carriers of TLR5(1174T). We conclude that the hypofunctional genetic variant TLR5(1174C)>T is associated with reduced organ failure and improved survival in melioidosis. This conclusion suggests a deleterious immunoregulatory effect of TLR5 that may be mediated by IL-10 and identifies this receptor as a potential therapeutic target in melioidosis.
类鼻疽是由鞭毛腐生菌伯克霍尔德菌引起的感染。TLR5 是一种被细菌鞭毛激活的病原体识别受体。我们研究了一种编码缺陷 TLR5 蛋白的遗传变异，TLR5(1174C)>T，以阐明 TLR5 在类鼻疽中的作用。我们测量了转染 TLR5 的人胚肾 293 细胞中 B. pseudomallei 诱导的 NF-κB 激活，发现 B. pseudomallei 诱导 TLR5(1174C)-但不诱导 TLR5(1174T)-依赖性 NF-κB 激活。我们在 600 名泰国类鼻疽患者中测试了 TLR5(1174C)>T 与结局的关联。在显性模型中，TLR5(1174C)>T 与住院期间死亡的保护作用相关（调整后的优势比：0.20；95%置信区间：0.08-0.50；p=0.001）和器官衰竭（调整后的优势比：0.37；95%置信区间：0.19-0.71；p=0.003）。我们分析了健康受试者中 TLR5(1174C)>T 基因型对鞭毛蛋白或热灭活 B. pseudomallei 诱导的血液细胞因子产生的影响。与 TLR5(1174C)携带者相比，TLR5(1174T)携带者的单核细胞归一化水平的 IL-6、IL-8、TNF-α、IL-10、MCP-1、IL-1ra、G-CSF 和 IL-1β水平较低。B. pseudomallei 诱导的单核细胞归一化水平的 IL-10 水平在 TLR5(1174T)携带者中较低。我们得出结论，功能低下的遗传变异 TLR5(1174C)>T 与类鼻疽器官衰竭减少和生存率提高相关。这一结论表明 TLR5 具有有害的免疫调节作用，可能通过 IL-10 介导，并确定该受体为类鼻疽的潜在治疗靶点。
