Bordetella cell surface modification and pathogenesis

博德特氏菌细胞表面修饰和发病机制

• 批准号: 10117511
• 负责人: RAJENDAR K DEORA
• 金额: $ 25.33万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-04 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10117511
• 关键词: Acellular Vaccines; Active Immunization; Adherence; Affect; Alanine; Amino Acids; Anabolism; Animal Model; Antimicrobial Resistance; Bacteria; Biochemical; Biological; Biological Assay; Blood Circulation; Bordetella; Bordetella pertussis; Cell Fractionation; Cell Line; Cell surface; Cells; Centers for Disease Control and Prevention (U.S.); Chloride Anion Exchanger; Communities; Country; Data; Development; Disease; Edetic Acid; Emerging Communicable Diseases; Enzymes; Epidemic; Epithelial Cells; Fractionation; Generations; Genes; Genomics; Glycine; Glycylglycine; Gram-Negative Bacteria; Gram-Positive Bacteria; Human; Immune; Immunity; In Vitro; Infection; Laboratories; Link; Mass Spectrum Analysis; Membrane; Microbial Biofilms; Modification; Mus; Nasopharynx; National Institute of Allergy and Infectious Disease; Organ; Outcomes Research; Pathogenesis; Pathogenicity; Pathway interactions; Peptide Hydrolases; Peptidoglycan; Pertussis; Pertussis Vaccine; Polysaccharides; Property; Proteins; Public Health; Publishing; Reagent; Research; Resistance; Resolution; Respiratory System; Respiratory Tract Infections; Role; Structure of respiratory epithelium; Surface; System; Techniques; Technology; Teichoic Acids; Testing; Therapeutic; Vaccination; Vaccines; Vibrio cholerae; Virulence; Work; antimicrobial peptide; insight; mouse model; mutant; neutrophil; new therapeutic target; next generation; novel; pathogen; pathogenic bacteria; prevent; respiratory; tool; transmission process; vaccination outcome

The Gram-negative bacterium Bordetella pertussis is a human-restricted pathogen that causes severe respiratory infections and the disease whooping cough or pertussis. Despite high levels and widespread vaccination, there has been a world-wide rise in B. pertussis infections and pertussis. This resurgence is attributed to the ineffectiveness of the current acellular pertussis vaccines to control bacterial numbers in the nasopharynx, bacterial transmission and generation of shorter-lived immunity. How B. pertussis survives effectively in the respiratory tract and circulates in the community is poorly understood. In order to control the resurgence of pertussis, it is critical to discover new strategies and identify new pathogenesis-associated loci and factors. The draABCD locus identified in our laboratory promotes in vitro (i) the resistance to killing by anti-microbial peptides and proteins (AMPs); (ii) polymorphonuclear leukocytes and (iii) the formation of biofilms. We hypothesize that dra is critical for survival of B. pertussis in the mouse respiratory tract. In Specific aim 1, we will utilize well-established mouse models of intranasal infection to examine its role in colonization and biofilm formation in the respiratory tract organs. We will also test whether dra promotes adherence to respiratory epithelium by using epithelial cells lines and respiratory explants. The Dra proteins catalyze the addition of D-alanine in an outer membrane-associated protease-susceptible component. This mechanism of surface modification is distinct from the polysaccharide modification carried out by other known bacterial loci. The Dra-modified surface factor (DMF) is unknown. In Specific Aim 2, using fractionation techniques and mass spectrometry, we will identify the DMF. This work will uncover new virulence strategies that will inform on the reasons of the resurgence of pertussis. Studies of the dra locus and discovering the identity of the DMF will provide important biochemical and biological insights resulting in advanced understanding of surface alterations in B. pertussis. Outcomes from this research will result in targeting of the dra locus and DMF for developing better vaccines and alternative therapeutics.

革兰氏阴性细菌百日咳博德特菌是一种人类限制性病原体，可引起严重的