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ROS responses during Vibrio cholerae infection

霍乱弧菌感染期间的ROS反应

基本信息

批准号：
9102467
负责人：
Jun Zhu
金额：
$ 50.33万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9102467
关键词：
Adult Animal Model Animals Cell physiology Cells Cholera Country Cysteine Disease Enzymes Escherichia coli Experimental Animal Model Feces Fimbriae Proteins Gene Expression Genes Goals Growth Haiti Human Immune Immune response Infection Inflammation Inflammatory Intestines Lead Light Minor Modeling Modification Mus NADPH Oxidase Pathogenesis Pathogenicity Pathology Patients Phase Play Post-Translational Protein Processing Post-Translational Regulation Poverty Production Property Proteins Proteomics Reactive Oxygen Species Regulation Regulatory Pathway Research Resistance Resolution Resources Role Salmonella Sampling Series Signal Pathway Signal Transduction Small Intestines Sulfhydryl Compounds Tissues Transcriptional Regulation Vibrio cholerae Virulence Virulence Factors Work base coping gut microbiome gut microbiota in vivo microbial microbiome mouse model novel novel strategies pathogen public health relevance research study resistance mechanism response tissue culture transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Vibrio cholerae is a human pathogen which colonizes small intestines of host, resulting in the onset of a severe diarrheal disease known as cholera. In order for V. cholerae to successfully colonize the host, it must express a series of virulence factors, which have been the main focus of the cholera research. However, bacterial pathogenicity is a multifactorial property in vivo that involves host response to infection, and gu microbiome interference of colonization. For example, although the pathology of cholera is not immune driven, it has been shown that minor, but significant inflammation responses in cholera patients and in experimental animal models are induced by V. cholerae infection and likely play a role in the resolution of disease. Little is known how inflammation is induced by V. cholerae and how V. cholerae copes with these signals and help its colonization. Here we performed an RNAseq analysis on mouse intestines free of V. cholerae and those that were infected to determine host responses to V. cholerae infection. One gene involved in reactive oxygen species (ROS) production, Duox2, encoding an NADPH oxidase and has been shown to be essential for controlling the growth of gut flora, was strongly upregulated. We show that both Duox2 expression and ROS production are induced by V. cholerae in a tissue culture model and in mice. Interestingly, this induction is dependent on V. cholerae virulence gene expression. Moreover, our preliminary studies indicate that V. cholerae cells in cholera patients' stool samples are highly resistant to ROS, suggesting that V. cholerae undergoes induction of ROS resistance during infection. To elucidate how V. cholerae overcome ROS produced by the host, we performed a Tn-seq experiment and found a set of V. cholerae genes that are required for ROS resistance in vivo. Together with a proteomics approach, we reveal novel transcriptional and posttranslational regulation mechanisms that are involved in regulating ROS resistance. Therefore we hypothesize that during infection, V. cholerae induces host Duox2 expression, thus ROS production, which facilitate V. cholerae colonization by modulating gut flora composition, whereas transcriptional and posttranslational regulatory pathways lead to V. cholerae inherently resistant to ROS in vivo. We will investigate the mechanism of V. cholerae-induced host ROS production and its effects on gut microbiota composition and V. cholerae colonization. We will investigate V. cholerae ROS resistance during infection of an adult mouse model. We will focus on transcriptional regulation and posttranslational modification of cellular functions of ROS resistance. Finally, we will investigate V. cholerae ROS resistance mechanisms in cholera patients by performing RNAseq and proteomic analysis of V. cholerae cells directly from cholera patient vomituses and stools.