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Humanized lung implant mouse model to study Staphylococcus aureus airway interactions

人性化肺植入小鼠模型研究金黄色葡萄球菌气道相互作用

基本信息

批准号：
10171773
负责人：
Dane Parker
金额：
$ 19.61万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10171773
关键词：
Acute Animal Model Antibiotic Resistance Antibiotics Bacteria Bacterial RNA Cells Data Disease Environment Epithelial Failure Flow Cytometry Genes Genetic Genetic Transcription Goals Human Human Cell Line Immune Immune response Immune system Implant In Vitro Incidence Infection Innate Immune Response Insertion Mutation Lead Libraries Lung Lung infections Methods Modeling Morbidity - disease rate Mus Pathogenesis Pharmaceutical Preparations Proteins Research Respiratory Tract Infections Role Signal Pathway Signaling Molecule Site Staphylococcus aureus Staphylococcus aureus infection Structure of parenchyma of lung Study models Therapeutic Intervention Transcript Translating Vaccines Virulence Factors cytokine experience gene product genetic element genome wide screen human model human pathogen human subject humanized mouse improved in vivo inhibitor/antagonist innovation mortality mouse model multi-drug resistant pathogen mutant new therapeutic target novel novel therapeutics pathogen pneumonia model response therapeutic candidate transcriptome sequencing transcriptomics transposon sequencing vaccine candidate vaccine trial

项目摘要

Summary Staphylococcus aureus in an important Gram positive human pathogen that is capable of infecting numerous bodily sites including the lung. It leads to significant morbidity and mortality, has a high incidence of antibiotic resistance and is a pathogen identified as needing increased research to discovery new therapeutics. The long term goal of our research is to better understand the host-pathogen interaction between S. aureus and the host immune system. It is hoped that an improved understanding of this interaction could lead to novel therapies targeting the bacterium or modulating the host to thwart this multidrug resistant pathogen. The objective of this proposal is to characterize the innate immune response of the human lung as well as the initial response of S. aureus to the airway and identify the genetic factors important for causing infection. The rationale for this approach is that new targets are needed to either develop antibiotics/inhibitors or vaccines against S. aureus. This is due to its high level of antibiotic resistance and previously promising vaccine candidates in murine models have failed to translate to efficacious human vaccines. Our preliminary data shows that humanized mice represent an improved model for the study of S. aureus infection in the lung, allowing the role of human specific virulence factors to be studied and understand the immune response to infection. We present a novel model of humanized mice whereby mice are implanted with human lung tissue. We have also demonstrated the use of a Tn-seq library to identify new factors important for infection in the airway. This contribution is significant as it will provide an understanding of how the human immune system, including the epithelium responds to S. aureus, as well as how S. aureus reacts to this environment and the factors that it employs to sustain infection. The innovation of this research is the utilization of a new model of infection that leverages our experience with humanized models of infection. This model incorporates human lung tissue to better replicate the human lung. We will characterize this response at multiple levels, at the transcriptional, protein and cellular level. Global approaches to understand the pathogen response, RNA-seq and Tn-seq will be combined to identify new genetic elements important in pathogenesis. Given present failure with vaccines and current drug pipelines, investigating gene products in the context of human model outside of ell-characterized virulence factors might lead to novel discoveries.

总结

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Capsule of Acinetobacter baumannii Protects against the Innate Immune Response.

鲍曼尼杆菌的囊囊可预防先天的免疫反应。

DOI：
10.1159/000522232
发表时间：
2022
期刊：
Journal of innate immunity
影响因子：
5.3
作者：
通讯作者：

Staphylococcal DNA Repair Is Required for Infection.

DOI：
10.1128/mbio.02288-20
发表时间：
2020-11-17
期刊：
mBio
影响因子：
6.4
作者：
Ha KP;Clarke RS;Kim GL;Brittan JL;Rowley JE;Mavridou DAI;Parker D;Clarke TB;Nobbs AH;Edwards AM
通讯作者：
Edwards AM

Impact of the pentose phosphate pathway on metabolism and pathogenesis of Staphylococcus aureus.