Studies on the pathogenesis of the infections caused by streptococcus suis

猪链球菌是引起败血症、猝死和脑膜炎的主要病原菌之一。血清2型和血清14型被认为是重要的新出现的人畜共患病病原体，加拿大已描述了人间病例。在过去的几年里，我们对猪链球菌感染的毒力因素和发病机制的了解有了很大的进步，但仍然不完整。细菌可能通过扁桃体或上呼吸道进入并在血液中传播，通过与加剧的炎症反应相关的机制引起感染性休克。如果宿主存活下来，细菌可以到达中枢神经系统，在那里它们可能会引发强烈的炎症反应。这会导致白细胞浸润和颅内压增加，导致脑膜炎/脑炎的临床症状。我们研究计划的长期目标是更好地了解革兰氏阳性细菌与宿主细胞之间的相互作用，从而帮助推动有效控制细菌疾病，特别是感染性休克和脑膜炎的策略的发展。在接下来的五年里，我们有三个短期目标：1.进一步表征猪链球菌的毒力因子及其在感染发病机制中的作用，具体研究a)囊多糖的唾液酸部分；b)表面蛋白，即F岛和G岛编码的保护表面蛋白SaO和菌毛；c)中性粒细胞在“细胞外陷阱”中抵抗中性粒细胞的杀伤，这可能是通过包裹、LTA的D-脱氨基和具有DNA酶和/或IL-8丝氨酸酶活性的酶的分泌来实现的；2.进一步阐明猪链球菌与中枢神经系统细胞的相互作用，重点是小胶质细胞和星形胶质细胞；3.利用我们新建立的小鼠感染模型，研究导致感染性休克和脑膜炎的炎症相关受体。来自NSERC的财政支持将使我们能够实现这项提案中提出的目标，扩大现有的合作，开发新的合作，并保持我们在这种病原体方面的国际知名研究。

Streptococcus suis is one of the most important swine pathogens causing mainly septicemia, sudden death and meningitis. Serotype 2 and, to a lesser extent, serotype 14 are considered important emerging zoonotic agents and human cases have been described in Canada. Our understanding of the virulence factors and pathogenesis of S. suis infection has improved considerably in the last years but remains incomplete. Bacteria may enter via the tonsils or upper respiratory tract and disseminate in the bloodstream to cause septic shock through mechanisms related to an exacerbated inflammatory response. If the host survives, bacteria can reach the central nervous system, where they may induce a strong inflammatory response. This leads to an increase of leukocyte infiltration and intracranial pressure, causing the clinical signs of meningitis/encephalitis. The long-term objective of our research program is to better understand the interactions between Gram positive bacteria and host cells, thereby helping to advance the development of strategies for effective control of bacterial diseases, especially septic shock and meningitis. For the next five years we have three short-term objectives: 1. To further characterize S. suis virulence factors and their role in the pathogenesis of the infection, with specific studies on a) the sialic acid moiety of capsular polysaccharide; b) surface proteins, namely the protective surface protein SAO and the pili encoded by islands F and G; and c) resistance to killing by neutrophils in "neutrophils extracellular traps" as possibly conferred by encapsulation, D-alanylation of the LTA and secretion of enzymes with DNase and/or IL-8 serine protease activities; 2. To further delineate the interactions between S. suis and cells from the central nervous system, with emphasis on microglial cells and astrocytes; and 3. To study the receptors involved in inflammation leading to septic shock and meningitis, using our newly developed mouse model of infection. Financial support from NSERC will allow us to accomplish the objectives presented in this proposal, expand existing collaborations, develop new collaborations and maintain our internationally renowned research on this pathogen.