Laboratory of Vaccine Immunology, National Institute of Animal Biotechnology, Hyderabad 500032, India.
Graduate Studies, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India.
Open Biol. 2023 Nov;13(11):230101. doi: 10.1098/rsob.230101. Epub 2023 Nov 8.
Leptospirosis is a worldwide zoonosis caused by pathogenic spp. having more than 300 serovars. These serovars can infect a variety of hosts, some being asymptomatic carriers and others showing varied symptoms of mild to severe infection. Since lipopolysaccharide (LPS) is the major antigen which defines serovar specificity, this different course of infection may be attributed to a differential innate response against this antigen. Previous studies have shown that LPS is less endotoxic. However, it is unclear whether there is a difference in the ability of LPS isolated from different serovars to modulate the innate response. In this study, we purified LPS from three widely prevalent pathogenic serovars, i.e. Icterohaemorrhagiae strain RGA, Pomona, Hardjo, and from non-pathogenic serovar semeranga strain Potac 1 collectively termed as L-LPS and tested their ability to modulate innate response in macrophages from both resistant (mice) and susceptible (human and bovine) hosts. L-LPS induced differential response being more proinflammatory in mouse and less proinflammatory in human and bovine macrophages but overall less immunostimulatory than LPS (E-LPS). Irrespective of serovar, this response was TLR2-dependent in humans, whereas TLR4-dependent/CD14-independent in mouse using MyD88 adapter and signalling through P38 and ERK-dependent MAP kinase pathway. L-LPS-activated macrophages were able to phagocytose and this effect was significantly higher or more pronounced when the macrophages were stimulated with L-LPS from the corresponding serovar. L-LPS activated both canonical and non-canonical inflammasome, producing IL-1β without inducing pyroptosis. Further, L-LPS induced both TNF-mediated early and NO-mediated late apoptosis. Altogether, these results indicate that L-LPS induces a differential innate response that is quite distinct from that induced by E-LPS and may be attributed to the structural differences and its atypical nature.
钩端螺旋体病是一种全球性的人畜共患病，由具有 300 多个血清型的致病性 spp.引起。这些血清型可以感染多种宿主，有些是无症状携带者，有些则表现出从轻到重感染的不同症状。由于脂多糖（LPS）是定义血清型特异性的主要抗原，这种不同的感染过程可能归因于对这种抗原的不同先天反应。先前的研究表明，LPS 的内毒素活性较低。然而，目前尚不清楚来自不同血清型的 LPS 分离物在调节先天反应的能力上是否存在差异。在这项研究中，我们从三种广泛流行的致病性血清型（即 Icterohaemorrhagiae 株 RGA、Pomona、Hardjo）和非致病性 血清型 semeranga 株 Potac 1 中纯化 LPS，统称为 L-LPS，并测试其在来自抗性（小鼠）和易感（人和牛）宿主的巨噬细胞中调节先天反应的能力。L-LPS 诱导了不同的反应，在小鼠中更具促炎作用，在人和牛巨噬细胞中则不那么促炎，但总体上比 LPS（E-LPS）的免疫刺激性更低。无论血清型如何，这种反应在人类中依赖于 TLR2，而在小鼠中则依赖于 TLR4/CD14 非依赖性的 MyD88 衔接子，并通过 P38 和 ERK 依赖性 MAP 激酶途径进行信号传递。L-LPS 激活的巨噬细胞能够吞噬 ，并且当巨噬细胞用来自相应血清型的 L-LPS 刺激时，这种效应显著更高或更明显。L-LPS 激活了经典和非经典的炎性小体，产生 IL-1β 而不诱导细胞焦亡。此外，L-LPS 诱导了 TNF 介导的早期和 NO 介导的晚期细胞凋亡。总之，这些结果表明，L-LPS 诱导了一种与 E-LPS 诱导的先天反应截然不同的反应，这可能归因于其结构差异和非典型性质。
