Bacterial virulence factors contributing to virus-associated pneumonias

描述（由申请人提供）：在这个指导定量研究职业发展奖（K25）的候选人将在培训和研究支持，因为她使从数学到微生物学的过渡。该候选人将联合收割机严格的微生物学培训与她的定量和数学技能相结合，以深入了解与流感感染相关的细菌毒力因子。培训和研究将在St. Jude儿童研究医院传染病科进行，由Jonathan McCullers博士（实验微生物学）指导，Frederick Adler博士（理论种群生物学，犹他州大学）和Alan Perelson博士（理论病毒学和免疫学，洛斯阿拉莫斯国家实验室）共同指导。候选人的长期目标是在实验和理论微生物学的界面上建立研究独立性。本研究计划的目的和目标是通过实验和理论方法和工具确定肺炎链球菌基因对流感感染发病机制的相对贡献。K25奖将支持一项研究和培训计划，包括强化课程，参加会议，会议和研讨会，实验微生物学的实践培训，以及提供详细定量研究以了解流感感染宿主细菌感染期间宿主-病原体相互作用的研究计划。建议的框架集成了有针对性的实验研究，群体遗传学的推理，和严格的数学建模。本提案的具体目标是：（1）进行流感-S的实验性体内研究。小鼠中的肺炎感染，（2）开发/完善病毒-细菌相互作用的动力学的数学模型和计算模拟，以及（3）分析数据、估计参数和测试关于流感-S的特定假设。肺炎动力学在实验研究中，我们将测量在初始感染和流感感染的背景下产生的细菌突变体的适应性、频率和致病性。使用数学模型和模拟，将分析数据，以获得关于每个单个细菌突变体和整个突变体群体的动力学差异的定量信息。实验，数学模型和计算模拟的迭代组合将导致对病毒-细菌共感染动力学的详细和定量的理解。这种方法对于理解病毒-细菌相互作用的复杂相互作用以及鉴定疫苗和抗菌剂开发的新靶点至关重要，这些靶点对对抗这些病原体至关重要。 公共卫生相关声明：流感和肺炎是美国第七大死亡原因。细菌定殖与S.在过去的流行病中，肺炎是住院和严重疾病的危险因素，并占流感相关死亡的很大一部分。该提案提供了必要的方法和工具，以了解感染的发病机制，并可能开发新的治疗方法，需要打击流感和S。肺炎。流感并发细菌感染是重要的公共卫生威胁，疾病的潜在机制尚不清楚。特别是S.在过去的流感大流行中，肺炎被认为是引起严重疾病的重要病原体。该研究的目的是探讨某些S。在流感感染过程中的肺炎基因，并发展感染动力学的全面理解，重点是理论模型的发展和对这一重要疾病的新疗法。

DESCRIPTION (provided by applicant): The candidate in this Mentored Quantitative Research Career Development Award (K25) will be supported in training and research as she makes the transition from mathematics to microbiology. This candidate will combine rigorous training in the field of microbiology with her quantitative and mathematical skills in order to gai an in-depth understanding of bacterial virulence factors associated with influenza infection. The training and research will be performed in the Department of Infectious Diseases at St. Jude Children's Research Hospital under the mentorship of Dr. Jonathan McCullers (experimental microbiology) and co-mentorships of Dr. Frederick Adler (theoretical population biology, University of Utah) and Dr. Alan Perelson (theoretical virology and immunology, Los Alamos National Laboratory). The candidate's long-term goal is to establish research independence at the interface of experimental and theoretical microbiology. The objective and goal of this research plan is to determine the relative contributions of Streptococcus pneumoniae genes to pathogenesis of influenza infections through experimental and theoretical methods and tools. The K25 award will support a research and training program that includes intensive coursework, attendance at conferences, meetings and seminars, hands-on training in experimental microbiology, and a research plan that provides detailed quantitative studies to understand the host-pathogen interactions during bacterial infections in influenza-infected hosts. The proposed framework integrates targeted experimental studies, inference of population genetics, and rigorous mathematical modeling. The specific aims of this proposal are to: (1) perform experimental in vivo studies of influenza-S. pneumoniae infections in mice, (2) develop/refine mathematical models and computational simulations of the kinetics of viral-bacterial interactions, and (3) analyze data, estimate parameters and test specific hypotheses with regard to the influenza-S. pneumoniae dynamics. In the experimental studies, we will measure the fitness, frequency, and pathogenicity of bacterial mutants produced within the contexts of naive infections and influenza infections. Using the mathematical models and simulation, the data will be analyzed in order to obtain quantitative information about the kinetic differences of each individual bacterial mutant and of the entire population of mutants. The iterative combination of experiments, mathematical models, and computational simulations will result in a detailed and quantitative understanding of the viral-bacterial co-infection dynamics. Such an approach is of critical importance to understand the complex interplay of viral-bacterial interactions and for identification of novel targets for vaccine and antimicrobial development expected to be important to combat these pathogens. PUBLIC HEALTH RELEVANCE STATEMENT: Influenza and pneumonia are the 7th leading cause of death in the United States. Bacterial colonization with S. pneumoniae has been a risk factor for hospitalization and severe disease in past pandemics and accounted for a significant portion of influenza-related deaths. This proposal provides methodologies and tools necessary to understand infection pathogenesis and possibly develop new therapeutics that are needed to combat the public health risk posed by influenza and S. pneumoniae. Bacterial infections complicating influenza are important public health threats and the underlying mechanisms of disease are not well-understood. In particular, S. pneumoniae was implicated as an important pathogen causing severe disease during past influenza pandemics. The objective of the proposed research is to investigate the role of certain S. pneumoniae genes during infection with influenza and develop a comprehensive understanding of infection dynamics, with focus on the development of theoretical models and on new therapies for this important disease.