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: 10331076
• 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/10331076
• 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，百日咳(又名百日咳)仍在发达国家重新出现。 复发的主要原因是青少年对百日咳杆菌(BP)的免疫力减弱。 年轻人接种无细胞(AP)百日咳疫苗。此外，虽然接种AP疫苗可以保护 抵御疾病，至少在一开始，它不能防止殖民或防止传播，这使 婴儿最容易感染严重的、有时是致命的疾病，他们面临更大的风险。新的疫苗 既要防止殖民，也要防止疾病。它们的发展需要更好地理解 BP毒力背后的分子机制。 BP是一种严格适应人类的病原体，与支气管败血波尔德氏菌(BB)关系极为密切， 它感染了几乎所有的哺乳动物。BP和BB产生一套几乎相同的毒力因子，其中一些， 包括丝状血凝素(FHA)和腺苷环化酶毒素(ACT) 可互换。FHA是一种关键的粘附素，是无细胞疫苗的组成部分，也是 两个伴侣分泌物(TPS)家族。使用BB及其自然宿主(大鼠和小鼠)，我们在 除了介导与宿主细胞的黏附外，FHA还在控制最初的炎症中发挥重要作用 对感染的反应和介导细菌对吞噬细胞清除的防御，这是 有助于下呼吸道(LRT)的持久性。我们在分泌机制和 将FhaB前体蛋白加工成FHA导致了两个伙伴的机制的重大进展 分泌，我们表明FhaB本身，而不是FHA，是细菌在LRT中持久性的关键。行动 通过介导对吞噬细胞清除的防御，也有助于细菌在LRT中的持久性。 我们和其他人已经证明ACT与细菌表面的FhaB/FHA结合。我们在文中提出了一个模型 What ACT虽然与细菌表面的FhaB结合，但与吞噬细胞上的CR3结合，触发 降解位于胞浆周围的C-末端FhaB前域，导致ACT有效地传递到 吞噬细胞，而不是上皮细胞。我们建议：1)研究DegP、CTPA、EnvC和 LbcA在调节降解FhaB前域中的作用，2)研究ACT与FhaB前域结合的关系 CR3，调节FhaB前结构域的降解，并将ACT特异性地递送到吞噬细胞，以及3) 调查失调的FhaB前结构域降解对建立和 维持呼吸道感染。