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.

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