Royal Tropical Institute (KIT), KIT Biomedical Research, Amsterdam, The Netherlands.
PLoS One. 2011 Mar 31;6(3):e18279. doi: 10.1371/journal.pone.0018279.
Leptospirosis is caused by pathogenic spirochetes of the genus Leptospira. The bacteria enter the human body via abraded skin or mucous membranes and may disseminate throughout. In general the clinical picture is mild but some patients develop rapidly progressive, severe disease with a high case fatality rate. Not much is known about the innate immune response to leptospires during haematogenous dissemination. Previous work showed that a human THP-1 cell line recognized heat-killed leptospires and leptospiral LPS through TLR2 instead of TLR4. The LPS of virulent leptospires displayed a lower potency to trigger TNF production by THP-1 cells compared to LPS of non-virulent leptospires.
METHODOLOGY/PRINCIPAL FINDINGS: We investigated the host response and killing of virulent and non-virulent Leptospira of different serovars by human THP-1 cells, human PBMC's and human whole blood. Virulence of each leptospiral strain was tested in a well accepted standard guinea pig model. Virulent leptospires displayed complement resistance in human serum and whole blood while in-vitro attenuated non-virulent leptospires were rapidly killed in a complement dependent manner. In vitro stimulation of THP-1 and PBMC's with heat-killed and living leptospires showed differential serovar and cell type dependence of cytokine induction. However, at low, physiological, leptospiral dose, living virulent complement resistant strains were consistently more potent in whole blood stimulations than the corresponding non-virulent complement sensitive strains. At higher dose living virulent and non-virulent leptospires were equipotent in whole blood. Inhibition of different TLRs indicated that both TLR2 and TLR4 as well as TLR5 play a role in the whole blood cytokine response to living leptospires.
CONCLUSIONS/SIGNIFICANCE: Thus, in a minimally altered system as human whole blood, highly virulent Leptospira are potent inducers of the cytokine response.
钩端螺旋体病是由致病性螺旋体属钩端螺旋体引起的。细菌通过擦伤的皮肤或粘膜进入人体，并可能传播全身。一般来说，临床表现较轻，但有些患者会迅速发展为严重疾病，病死率高。目前人们对钩端螺旋体血源播散过程中的固有免疫反应知之甚少。先前的研究表明，人 THP-1 细胞系通过 TLR2 而不是 TLR4 识别热灭活的钩端螺旋体和钩端螺旋体 LPS。与非毒力钩端螺旋体的 LPS 相比，毒力钩端螺旋体的 LPS 触发 THP-1 细胞产生 TNF 的效力较低。
方法/主要发现：我们研究了不同血清型的毒力和非毒力钩端螺旋体对人 THP-1 细胞、人 PBMC 和人全血的宿主反应和杀伤作用。通过公认的标准豚鼠模型测试了每种钩端螺旋体菌株的毒力。在人血清和全血中，毒力钩端螺旋体表现出补体抗性，而体外减毒的非毒力钩端螺旋体则以补体依赖性方式迅速被杀死。用热灭活和活的钩端螺旋体体外刺激 THP-1 和 PBMC，显示细胞因子诱导的血清型和细胞类型依赖性差异。然而，在低生理剂量的钩端螺旋体时，活的毒力互补抗性菌株在全血刺激中始终比相应的非毒力互补敏感菌株更有效。在更高剂量时，活的毒力和非毒力钩端螺旋体在全血中具有同等效力。不同 TLR 的抑制表明，TLR2、TLR4 和 TLR5 均在全血对活的钩端螺旋体的细胞因子反应中发挥作用。
结论/意义：因此，在人全血这种最小改变的系统中，高度毒力的钩端螺旋体是细胞因子反应的有效诱导剂。
