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.

摘要/摘要 百日咳（又名百日咳）正在发达国家重新出现，目的地高疫苗覆盖率。 复活是由于对青少年的因果细菌（BP）的免疫力逐渐减弱 和年轻人用细胞（AP）百日咳疫苗免疫的年轻人。此外，AP疫苗接种保护 至少最初，它不能防止殖民或防止传播，这是 婴儿最容易受到严重，有时是致命疾病的攻击，面临更大的风险。新疫苗 需要预防殖民化和疾病。他们的发展需要更好地理解 BP病毒背后的分子机制。 BP是严格的人类适应的病原体，与Bordetella Oronchiseptica（BB），非常密切 感染了几乎所有哺乳动物。 BP和BB产生了几乎相同的病毒因素，其中一些因素 包括丝状血凝集素（FHA）和腺苷酸环化酶毒素（ACT）在功能上是 可互换。 FHA是一种关键的粘附素，是细胞疫苗的组成部分，是 两个伴侣分泌（TPS）家庭。使用BB及其天然寄主（大鼠和小鼠），我们在 除了介导对宿主细胞的遵守，FHA在控制初始炎症方面起着重要作用 对感染的反应和介导细菌防御吞噬细胞清除的防御，这 有助于下呼吸道（LRT）的持久性。我们在分泌机制和 将“前体” FHAB蛋白处理为FHA的处理已导致了两个合作伙伴的机制的重大进步 分泌物，我们表明FHAB本身而不是FHA对于LRT中细菌持久性至关重要。行为 还通过介导针对吞噬细胞清除的防御，导致LRT中的细菌持久性。 我们和其他人表明，ACT与细菌表面上的FHAB/FHA结合。我们提出了一个模型 虽然与细菌表面上的Fhab结合起来，但在吞噬细胞上与CR3结合，触发 C末端，周期性，Fhab Prodomain的降解，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Fhab Prodomain的调节降解中，2）研究ACT与 CR3，Fhab Prodomain的调节降解以及专门为吞噬细胞的ACT递送，3） 调查失调的Fhab Prodomain降解对机构的后果和 维持呼吸道感染。