Cooperative roles of FHA and ACT in Bordetella virulence

FHA 和 ACT 在博德特氏菌毒力中的合作作用

• 批准号: 10541178
• 负责人: Peggy A Cotter
• 金额: $ 53.61万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-20 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10541178
• 关键词: Acellular Vaccines; Adenylate Cyclase Toxin; Adherence; Adolescent and Young Adult; Affect; Animal Model; Bacteria; Bacterial Adhesins; Binding; Biochemical; Biological; Biological Assay; Bordetella; Bordetella Virulence Factors; Bordetella bronchiseptica; Bordetella pertussis; C-terminal; Cell Culture Techniques; Cell surface; Cells; Childhood; Developed Countries; Development; Disease; Epithelial Cells; Event; Family; Genetic; Goals; Hemagglutinin; Human; Immunity; Immunize; Infant; Infection; Inflammation; Inflammatory Response; Lipoprotein (a); Lower respiratory tract structure; Macrophage-1 Antigen; Maintenance; Mammalian Cell; Mammals; Mediating; Modeling; Molecular; Mus; Peptide Hydrolases; Pertussis; Pertussis Vaccine; Phagocytes; Play; Protein Secretion; Proteins; Rattus; Respiratory Tract Infections; Risk; Role; Series; Signal Transduction; Surface; System; Testing; Therapeutic; Toxin; Vaccination; Vaccines; Virulence; Virulence Factors; Work; experimental study; insight; member; novel vaccines; pathogen; periplasm; prevent; protein function; receptor; response; transmission process

Summary/Abstract Pertussis (aka whooping cough) is re-emerging in developed countries despite high vaccine coverage. Resurgence is due primarily to waning immunity to the causal bacterium Bordetella pertussis (Bp) in adolescents and young adults immunized with acellular (aP) pertussis vaccines. Moreover, while aP vaccination protects against disease, at least initially, it does not protect against colonization or prevent transmission, which puts infants, who are most vulnerable to serious and sometimes fatal disease, at greater risk. New vaccines that protect against both colonization and disease are needed. Their development requires a better understanding of the molecular mechanisms underlying Bp virulence. A strictly human-adapted pathogen, Bp is extremely closely related to Bordetella bronchiseptica (Bb), which infects nearly all mammals. Bp and Bb produce a nearly identical set of virulence factors, some of which, including filamentous hemagglutinin (FHA) and adenylate cyclase toxin (ACT), are functionally interchangeable. FHA is a critical adhesin, a component of acellular vaccines, and the prototypical member of the Two Partner Secretion (TPS) family. Using Bb and its natural hosts (rats and mice), we showed that in addition to mediating adherence to host cells, FHA plays important roles in controlling the initial inflammatory response to infection and in mediating defense of the bacteria against clearance by phagocytic cells, which contributes to persistence in the lower respiratory tract (LRT). Our work on the mechanism of secretion and processing of the “precursor” FhaB protein to FHA has led to major advances in the mechanism of two partner secretion, and we showed that FhaB itself, rather than FHA, is critical for bacterial persistence in the LRT. ACT also contributes to bacterial persistence in the LRT by mediating defense against phagocytic cell clearance. We and others have shown that ACT binds to FhaB/FHA on the bacterial surface. We propose a model in which ACT, while bound to FhaB on the bacterial surface, binds to CR3 on phagocytic cells, triggering degradation of the C-terminal, periplasmically-located, FhaB prodomain, resulting in efficient delivery of ACT to phagocytic cells and not to epithelial cells. We propose to: 1) Investigate the roles of DegP, CtpA, EnvC and LbcA in regulated degradation of the FhaB prodomain, 2) Investigate the relationship between ACT binding to CR3, regulated degradation of the FhaB prodomain, and delivery of ACT specifically to phagocytic cells, and 3) Investigate the consequences of dysregulated FhaB prodomain degradation on the establishment and maintenance of respiratory infection.

总结/摘要 百日咳（又名百日咳）在发达国家重新出现，尽管疫苗覆盖率很高。 主要是由于青少年对百日咳杆菌的免疫力下降 和用无细胞（aP）百日咳疫苗免疫的年轻成人。此外，虽然aP疫苗可以保护 至少在最初阶段，它不能防止殖民化或防止传播， 婴儿最容易患上严重的、有时是致命的疾病，他们面临的风险更大。新的疫苗， 需要防止殖民化和疾病。它们的发展需要更好地了解 Bp毒力的分子机制。 作为一种严格适应人类的病原体，Bp与支气管败血波氏杆菌（Bb）关系极为密切， 几乎感染所有哺乳动物Bp和Bb产生一组几乎相同的毒力因子，其中一些， 包括丝状血凝素（FHA）和腺苷酸环化酶毒素（ACT），在功能上是 可以互换FHA是一种重要的粘附素，是无细胞疫苗的一种组分，也是 两个伴侣分泌（TPS）家族。利用Bb及其自然宿主（大鼠和小鼠），我们发现， 除了介导对宿主细胞的粘附外，FHA在控制初始炎症反应中起重要作用。 对感染的反应和介导细菌抵抗吞噬细胞清除的防御， 有助于下呼吸道（LRT）中的持久性。我们对分泌机制的研究， 将“前体”FhaB蛋白加工成FHA导致了两个伴侣的机制的重大进展， 分泌，我们表明，FhaB本身，而不是FHA，是关键的细菌持久性在LRT。法 还通过介导对吞噬细胞清除的防御来促进细菌在LRT中的持续存在。 我们和其他人已经证明ACT与细菌表面的FhaB/FHA结合。我们提出了一个模型， ACT与细菌表面的FhaB结合，与吞噬细胞上的CR 3结合， C-末端、位于胞质周的FhaB前结构域的降解，导致ACT有效递送至 吞噬细胞而不是上皮细胞。我们建议：1）研究DegP，CtpA，EnvC和 LbcA在FhaB前结构域的调节性降解中的作用，2）研究ACT与LbcA结合之间的关系。 CR 3，FhaB前结构域的调节性降解，以及ACT特异性递送至吞噬细胞，以及3） 研究失调的FhaB前结构域降解对建立和 维持呼吸道感染。