Role of Pertussis Toxin in Bordetella pertussis infection

百日咳杆菌是一种革兰氏阴性细菌，会感染人类呼吸道， 导致一种称为百日咳的严重阵发性咳嗽，这种疾病在 婴儿。这种病原体用来确定感染和引起疾病的机制是 仍然相对默默无闻。此外，尽管在体外已经有了广泛的表征 几种推测的百日咳毒力因子的结构和功能，这些因子在其中的作用 在宿主-病原体的相互作用中促进感染和疾病的作用还知之甚少。这个 这个项目的总体目标是确定这些因素之一百日咳毒素(PT)所起的作用 百日咳杆菌呼吸道感染。PT是一种由该病原体专属产生的外毒素。 并可在培养中毒化多种哺乳动物细胞，但其作用是8.百日咳感染 很大程度上是未知的。通过比较野生型菌株(WT)和突变菌株(APT) 编码PT的基因在小鼠鼻内感染模型中，我们有初步数据表明PT在 8.百日咳在呼吸道定植中的重要和早期作用至少有三种不同 免疫反应(肺早期中性粒细胞募集、早期细胞因子和趋化因子 呼吸道产生，以及对感染WT的血清抗体反应)似乎 相对于APT感染后的抑制作用。因此，我们假设一个重要的角色是 PT的作用是抑制对8.百日咳的抗菌免疫反应，允许建立 感染与随后的疾病发病机制有关。为了检验这一假设，我们提出了四个具体的 目的：(1)确定抑制中性粒细胞向肺部募集的机制；(2) 利用化学改变和基因改变的小鼠确定PT活性的相关靶点； 确定PT是否抑制8.百日咳感染后的肺抗体和T细胞反应；以及 (4)确定百日咳感染后PT对免疫功能的抑制作用是否增强。 对二次感染的易感性。PT在8.百日咳中的特殊作用 感染将增加我们对这种有机体致病机制的了解，并可能 导致抗击百日咳感染和疾病的新治疗方法。

Bordetella pertussis is a gram-negative bacterial pathogen that infects the human respiratory tract, leading to a severe paroxysmal coughing disease known as whooping cough that can be fatal in infants. The mechanisms that this pathogen employs to establish an infection and cause disease are still relatively obscure. In addition, although there has been extensive characterization in vitro of the structure and function of several putative 8. pertussis virulence factors, the roles that these factors play in the host-pathogen interaction to promote infection and disease are poorly understood. The overall goal of this project is to determine the role that one of these factors, pertussis toxin (PT), plays in respiratory tract infection by B. pertussis. PT is an exotoxin produced exclusively by this pathogen and can intoxicate a wide range of mammalian cells in culture, but its role in 8. pertussis infection is largely unknown. By comparing a wild type strain (WT) to a mutant strain (APT) with a deletion of the genes encoding PT in a mouse intranasal infection model, we have preliminary data that PT plays an important and early role in colonization of the respiratory tract by 8. pertussis. At least three different immune responses (early neutrophil recruitment to the lungs, early cytokine and chemokine production in the respiratory tract, and serum antibody responses) to infection with WT appear to be suppressed relative to those after infection with APT. Therefore, we hypothesize that an important role of PT is to suppress the antibacterial immune responsesto 8. pertussis, allowing establishment of the infection with subsequent disease pathogenesis. To test this hypothesis we propose four specific aims: (1) to determine the mechanism of inhibition of neutrophil recruitment to the lungs; (2) to determine the relevant targets of PT activity using chemically- and genetically-altered mice; (3) to determine whether PT suppresses lung antibody and T cell responses after 8. pertussis infection; and (4) to determine whether immunosuppression by PT after 8. pertussis infection enhances susceptibility to secondary infections. Elucidation of the specific roles of PT during 8. pertussis infection will increase our understanding of the pathogenic mechanisms of this organism, and may lead to novel therapeutic approaches to combat pertussis infection and disease.