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: 10206412
• 负责人: Peggy A Cotter
• 金额: $ 51.64万
• 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/10206412
• 关键词: Acellular Vaccines; Address; 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.

摘要/摘要 尽管疫苗覆盖率很高，但百日咳（又名百日咳）在发达国家重新出现。 卷土重来的主要原因是青少年对致病菌百日咳博德特氏菌 (Bp) 的免疫力减弱 和年轻人接种无细胞（aP）百日咳疫苗。此外，虽然 aP 疫苗接种可以保护 至少在最初阶段，它不能预防疾病，也不能防止定植或防止传播，这使得 婴儿最容易罹患严重甚至致命的疾病，风险更大。新疫苗 需要防止定植和疾病。他们的发展需要更好的理解 Bp 毒力的分子机制。 Bp 是一种严格适应人类的病原体，与支气管败血博德特氏菌 (Bb) 密切相关， 它感染几乎所有哺乳动物。 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 可互换。 FHA 是一种关键的粘附素，是非细胞疫苗的组成部分，也是 两伴侣分泌 (TPS) 家族。使用 Bb 及其天然宿主（大鼠和小鼠），我们表明 除了介导与宿主细胞的粘附外，FHA 在控制初始炎症方面也发挥着重要作用 对感染的反应以及介导细菌抵抗吞噬细胞清除的防御， 有助于在下呼吸道（LRT）中持续存在。我们在分泌机制方面的工作 将“前体”FhaB 蛋白加工成 FHA 导致两个伙伴机制取得重大进展 我们发现 FhaB 本身（而不是 FHA）对于细菌在 LRT 中的持久存在至关重要。行为 还通过介导对吞噬细胞清除的防御来促进细菌在 LRT 中的持久存在。 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 其中 ACT 在与细菌表面的 FhaB 结合的同时，与吞噬细胞上的 CR3 结合，触发 C 端、位于周质的 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 前结构域的调节降解中，2) 研究 ACT 与 CR3，FhaB 前结构域的调节降解，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建立的影响 维持呼吸道感染。