Bacterial Manipulation of Host Hyaluronan Degradation for Immune Evasion

描述（由申请方提供）：宿主透明质酸酶对透明质酸的片段化被认为会引发危险信号，警告宿主存在潜在伤害。然而，如果这种信号与增强的细菌杀灭有关，那么为什么大多数病原体继续表达这种酶就违反直觉了。在这里，我们表明，由病原体B组链球菌表达的透明质酸酶，与真核生物和非致病性链霉菌表达的透明质酸酶不同，是抗炎的，并且通过将透明质酸降解到不仅不能刺激TLR激活，而且可以抑制Toll样受体的大小来调节炎症 信号这导致炎症的抑制和感染期间病原体的存活增强。基于我们的研究结果，我们假设病原体已经进化出透明质酸酶，其功能不同于来自环境非病原体的透明质酸酶。为了解决这一假设，我们将研究几种病原体（GBS，S. pneumoniae和S. aureus）、非病原体（天蓝色链霉菌（Streptomycescoelicolor））和条件致病菌（Peptostreptomycepervotii、E.粪便）。我们将确定其透明质酸降解产物的大小以及这些产物对TLR2、TLR4和Myd88信号传导的影响。我们的研究旨在揭示一种新的基于跨物种进化的免疫逃避机制。

DESCRIPTION (provided by applicant): Fragmentation of hyaluronan by host hyaluronidases are thought to elicit a danger signal that alert the host to the presence of potential harm. However, if such a signal is linked to enhanced killing of bacteria, it is counterintuitive why mos pathogens continue to express the enzyme. Here we show that hyaluronidase expressed by the pathogen Group B Streptococcus, unlike those express by eukaryotes and nonpathogenic Streptomyces, are anti-inflammatory and modulate inflammation by degrading hyaluronan down to sizes that not only fail to stimulate TLR activation, but which could inhibit Toll-like receptor signaling. This leads to the suppression of inflammation and enhanced survival of the pathogen during infection. Based on our findings, we hypothesize that pathogens have evolved hyaluronidases that are functionally different from hyaluronidases from environmental non-pathogens. To address the hypothesis, we will study the in vitro and in vivo immunomodulatory and virulence properties of hyaluronidases elaborated by several pathogens (GBS, S. pneumoniae, and S. aureus), non-pathogen (Streptomyces coelicolor), and opportunistic pathogens (Peptostreptococcus prevotii, E. faecalis). We will determine the size of their hyaluronan degradation products and the effect of these products on TLR2, TLR4, and Myd88 signaling. Our study aims to unravel a novel cross-species evolution-based immune evasion mechanism.