HOST CELL INTERACTIONS BY PATHOGENIC BORRELIAE

伯氏疏螺旋体是莱姆病的病原体，赫氏疏螺旋体和尿囊疏螺旋体是蜱传回归热的病原体。病原体-宿主细胞相互作用被认为是感染部位和严重程度的关键决定因素，我们重点研究了两类宿主细胞分子的Borrehae识别：(1)糖胺聚糖（GAGs）；(2)整合素及其相关蛋白。对于B. burgdorferi，我们发现GAG识别的差异与宿主细胞类型特异性结合的差异有关，并鉴定了一种表面蛋白Bgp，可能是B. burgdorferi的主要GAG受体。这种细菌也能识别依赖活化的血小板整合素alphaIIbbeta3，从而选择性地结合活化血小板（与静止血小板相比）。据预测，这种整合素结合活性可将莱姆病螺旋体靶向血小板粘附部位的血管壁，并可解释莱姆病的一个显著特征：动脉循环的血管病理。我们对回归热螺旋体的研究。高水平的GAG结合与血液和可变主要蛋白的高水平生长相关。VspB促进了对GAGS的依恋。此外，与伯氏疏螺旋体不同，赫氏疏螺旋体结合并激活静息血小板。这种依赖于接触的血小板活化活性显然是由整合素相关的血小板信号分子CD9介导的。回归热螺旋体也被证明与红细胞结合，我们推测，回归热螺旋体附着于循环血液细胞，如血小板和红细胞，可以促进细菌在血液中的滞留和高水平生长。螺旋体与这两种细胞类型的相互作用也可能导致回归热的两种常见表现：贫血和血小板减少症。因此，我们建立了宿主细胞结合在致病性borrae定植和疾病表达中的作用的工作模型。为了验证这些模型的预测，将解决以下问题：(1)减少螺旋体-血小板相互作用是否会影响莱姆病血管壁和心脏的定植或回归热血小板减少症？(2) CD9是否在hermsii活化血小板中起作用？(3)回归热螺旋体的gag结合活性是否影响感染动物血液中的细胞附着和生长？(4) Bgp在伯氏疏螺旋体GAG结合中是否起主导作用？提出的实验可能揭示对抗疏螺旋体感染的潜在治疗策略以及控制细菌病原体组织特异性感染的一般原理。

Borrelia burgdorferi is the causative agent of Lyme disease, and B. hermsii and B. turicatae are causative agents of tick-borne relapsing fever. Pathogen-host cell interactions are thought to be critical determinants of the site and severity of infection, and we have focused on Borrehae recognition of two classes of host cell molecules: (1) glycosaminoglycans (GAGs); and (2) integrins and their associated proteins. For B. burgdorferi, we found that differences in GAG recognition were associated with differences in host cell type-specific binding, and identified a surface protein, Bgp, that may be the major B. burgdorferi GAG receptor. This bacterium also recognizes the activation- dependent platelet integrin alphaIIbbeta3, and thereby selectively binds to activated (vs. resting) platelets. This integrin-binding activity is predicted to target the Lyme disease spirochete to the vessel wall at sites of platelet adherence, and could explain a salient feature of Lyme disease: vascular pathology of the arterial circulation. In our studies of relapsing fever spirochetes. high-level GAG- binding correlated with high-level growth in the bloodstream and a variable major protein. VspB, promoted attachment to GAGS. Additionally, to contrast to B. burgdorferi, B. hermsii bound and activated resting platelets. This contact-dependent platelet activation activity was apparently mediated by the integrin- associated platelet signaling molecule CD9. Relapsing fever spirochetes have also been shown to bind to erythrocytes, and we speculate that attachment of relapsing fever spirochetes to circulating blood cells such as platelets and erythrocytes could promote the retention and high level growth of the bacteria in the blood. Interaction of spirochetes with these two cell types could also contribute to two common manifestations of relapsing fever: anemia and thrombocytopenia. Thus, we have formulated working models for the role of host cell binding in colonization and disease expression by pathogenic Borrehae. To test predictions of these models, the following questions will be addressed: (1) does reducing the spirochete- platelet interactions affect colonization of the vessel wall and heart in Lyme disease or thrombocytopenia in relapsing fever? (2) does CD9 play a role in platelet activation by B. hermsii? (3) does the GAG-binding activity of the relapsing fever spirochete influence cell attachment and growth in the bloodstream of infected animals? (4) does Bgp play a predominant role in GAG binding by B. burgdorferi? The proposed experiments may uncover both potential therapeutic strategies for combating Borreliae infections as well as general principles that govern tissue-specific infection by bacterial pathogens.