Bacterial virulence factors contributing to virus-associated pneumonias

描述（由申请人提供）：本次导师定量研究职业发展奖（K25）的候选人将在她从数学转向微生物学的过程中获得培训和研究支持。该候选人将在微生物学领域进行严格的培训，并结合她的定量和数学技能，以深入了解与流感感染相关的细菌毒力因子。培训和研究将在圣犹达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（犹他大学理论种群生物学）和Alan Perelson博士（洛斯阿拉莫斯国家实验室理论病毒学和免疫学）共同指导。候选人的长期目标是在实验和理论微生物学领域建立独立的研究。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，其中包括强化课程、参加会议、会议和研讨会、实验微生物学的实践培训，以及一项研究计划，该计划提供详细的定量研究，以了解感染流感的宿主细菌感染期间宿主-病原体的相互作用。该框架整合了有针对性的实验研究、群体遗传学推断和严格的数学建模。本提案的具体目的是：(1)进行流感- s的体内实验研究。(2)开发/完善病毒-细菌相互作用动力学的数学模型和计算模拟，以及(3)分析数据，估计参数并测试关于流感- s的特定假设。肺炎动力学。在实验研究中，我们将测量在初发感染和流感感染背景下产生的细菌突变体的适应度、频率和致病性。利用数学模型和模拟，将对数据进行分析，以获得关于每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确定疫苗和抗菌剂开发的新靶点至关重要，预计这对对抗这些病原体很重要。

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.