Studies on bacteriophages in respiratory diseases

项目总结 博利基博士是一名职业生涯中期的研究人员，他开发了一个成功的翻译研究项目 重点放在噬菌体--感染细菌的病毒--以及细菌伤口和呼吸道感染上。他也是 一位高生产率的研究导师，担任 医学住院医师计划以及在他自己的实验室培训大量的住院医师、研究员和医学生。 K24的目标是为博利基博士提供有保护的时间，以发展他的以患者为导向的研究 计划和指导更多的临床研究员，初级教员和其他以患者为中心的研究实习生。这个 提案还提供了专门的时间和资源来帮助博利基博士提高自己的指导技能， 从咨询委员会获得科学和职业指导，提高他在疫苗接种方面的技能和 微生物学，并扩大他在人类临床研究方面的知识和技术技能。 这项工作的科学重点是噬菌体--感染细菌的病毒--及其对细菌的影响 感染。噬菌体在人体内含量丰富，但它们对人类健康的影响在很大程度上是未知的。 Bollyky实验室最近报告说，主要细菌病原体假单胞菌产生的噬菌体 铜绿假单胞菌可促进慢性铜绿假单胞菌感染。特别是，他们确定了一种新的机制，通过它 由PA产生的丝状PF噬菌体通过作为结构元件在抗生素耐受中发挥作用 PA生物膜-细菌和聚合物的粘性群落，使细菌能够在呼吸道和其他地方定居 表面。PF噬菌体以产生强大的生物膜的方式组织宿主和微生物聚合物，从而抵抗 被抗生素渗透，导致抗生素耐药性。他们的团队最近发表了Pf噬菌体是 囊性纤维化(CF)患者的抗生素耐药性升高相关，这是一种与遗传性疾病相关的疾病 有粘稠的痰和慢性肺部感染的PA。 有可能通过靶向PF噬菌体来预防PA感染。博利基实验室最近开发了 一种针对PF噬菌体以防止PA感染的疫苗。然而，目前还不清楚是否有针对PF的抗体 自然产生的噬菌体，以及这些噬菌体是否对PA感染具有保护作用。 在这里，博利基博士将检验PF噬菌体有助于抗生素耐药性和慢性 感染，而PF抗体则可预防这种感染。在目标1中，他们将定义PF噬菌体对抗生素的贡献 铜绿假单胞菌生物膜的耐受性。在目标2中，他们将定义PF抗体如何预防PA感染。最后，在AIM中 3他们将确定PF和抗PF噬菌体抗体是否会影响CF患者的临床结果。 总之，这些研究将产生针对PA生物被膜的新的治疗靶点和治疗策略。 并开始了多名年轻内科科学家的职业生涯。受保护的职业发展时间 辅导将使博利基博士扩大他和他的受训人员工作的范围和影响，并帮助 支撑和壮大NIAID和NHLBI以患者为中心的研究事业。

PROJECT SUMMARY Dr. Bollyky is a mid-career investigator who has developed a successful, translational research program focused on bacteriophages – viruses that infect bacteria - and bacterial wound and airway infections. He is also a highly productive research mentor, serving as a director of the physician-scientist training program for the medical residency program as well as training numerous residents, fellows, and medical students in his own lab. The goal of this K24 is to provide Dr. Bollyky with protected time to grow his patient-oriented research program and mentor additional clinical fellows, junior faculty and other trainees in patient-oriented research. The proposal also provides for dedicated time and resources to help Dr. Bollyky enhance his own mentoring skills, obtain scientific and career guidance from an advisory committee, sharpen his skills in vaccinology and microbiology, and expand his knowledge and technical skills in human clinical studies. The scientific focus of this work is bacteriophages – viruses that infect bacteria – and their impact on bacterial infections. Phages are abundant in the human body but their impact on human health is largely unknown. The Bollyky lab has recently reported that phages produced by the major bacterial pathogen Pseudomonas aeruginosa (Pa) promote chronic Pa infections. In particular, they have identified a novel mechanism by which filamentous Pf phages produced by Pa contribute to antibiotic tolerance by functioning as structural elements in Pa biofilms – slimy communities of bacteria and polymers that allow bacteria to colonize airways and other surfaces. Pf phages organize host and microbial polymers in ways that produce a robust biofilm that resists penetration by antibiotics, leading to antibiotic resistance. Their team recently published that Pf phages are associated with heightened antibiotic resistance in patients with cystic fibrosis (CF), a genetic disease associated with thick, tenacious sputum and chronic lung infections with Pa. It may be possible to protect against Pa infection by targeting Pf phages. The Bollyky Lab recently developed a vaccine that targets Pf phages to prevent Pa infections. However, it is unclear whether antibodies against Pf phages naturally occur and whether these are protective against Pa infection. Here, Dr. Bollyky will test the hypothesis that Pf phages contribute to antibiotic resistance and chronic infections while Pf antibodies protect against this. In Aim 1 they will define how Pf phages contribute to antibiotic tolerance in Pa biofilms. In Aim 2 they will define how Pf antibodies protect against Pa infections. Finally, in Aim 3 they will determine whether Pf and anti-Pf phage antibodies influence clinical outcomes in patients with CF. Together, these studies will give rise to novel therapeutic targets and treatment strategies against Pa biofilm infections and launch the careers of multiple young physician scientists. Protected time for career development and mentoring will allow Dr. Bollyky to broaden the scope and influence of his and his trainees’ work and help to sustain and grow the patient-oriented research enterprise of the NIAID and the NHLBI.