The Promotion of Inflammation by Bacterial Sialidases After Influenza Infection

在一些最具挑战性的传染病中，炎症已成为病原体毒力的关键调节因子，包括艾滋病、埃博拉出血热、败血症和继发于流感感染的细菌性肺炎。人们认为，对病原体相关和/或危险相关分子模式的先天识别是炎症的根本原因。然而，这些模型并不能解释细菌感染中的炎症模式，尽管病原体被清除，炎症仍然存在。我们最近报道了CD24-Siglec G/10相互作用抑制内源性危险分子的炎症。由于这种相互作用依赖于CD24上的唾液酸，并且易受细菌唾液酸酶裂解的影响，我假设细菌编码的唾液酸酶通过破坏这种对危险分子的负调控来影响毒力。我将测试中心的假设，细菌唾液酸酶诱导流感感染后致命性肺炎的遗传和化学生物学方法。该研究可能揭示病原体毒力的新机制，并为治疗肺炎相关致死性炎症提供新的治疗靶点。此外，本研究的细菌唾液酸酶小分子抑制剂可能广泛应用于感染性疾病的治疗。

Inflammation has emerged as a key regulator of pathogen virulence in some of the most challenging infectious diseases, including AIDS, Ebola hemorrhagic fever, sepsis, and bacterial pneumonia secondary to influenza infection. It is believed that innate recognition of pathogen-associated and/or danger-associated molecular patterns are the root causes of inflammation. However, these models do not explain the pattern of inflammation in bacterial infection, which often persists in spite of clearance of the pathogen. We recently reported that the CD24-Siglec G/10 interaction represses inflammation to endogenous danger molecules. Since the interaction depends on sialic acids on CD24 and is susceptible to bacterial sialidase cleavage, I hypothesize that sialidase encoded by bacteria affect virulence by disrupting this negative regulation to danger molecules. I will test the centra hypothesis that bacterial sialidases induce lethal pneumonia after influenza infection by genetic and chemical biology approaches. The proposed study may reveal a new mechanism of pathogen virulence and suggest a new therapeutic target for the treatment of fatal inflammation associated with pneumonia. Furthermore, the small-molecule inhibitors of bacterial sialidases studied here may be broadly applicable to the therapy of infectious disease.