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Immune Modulation by Bacterial Autolysins

细菌自溶素的免疫调节

基本信息

批准号：
7795786
负责人：
Laurel L Lenz
金额：
$ 36.78万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7795786
关键词：
ARHGEF5 gene Acute Address Affect Animals Anti-Bacterial Agents Anti-Inflammatory Agents Anti-inflammatory Antibacterial Response Applications Grants Attenuated Autolysin Bacillus anthracis Bacteria Bacterial Infections Biochemical Biological Process Bioterrorism Categories Cell surface Cells Cellular Immunity Chronic Complement Cultured Cells Cytokine Gene Development Digestion Disease Effectiveness Elements Endopeptidases Engineering Family Gene Expression Generations Goals Grant Growth Human IFNAR1 gene Immune Immune response Immunity Infection Inflammation Inflammatory Inflammatory Response Interleukin-6 Length Listeria monocytogenes Macrophage Activation Mammalian Cell Maps Mediating Meningitis Microbe Modeling Modification Molecular Mus Natural Immunity Peptides Peptidoglycan Phylogenetic Analysis Protein Family Protein Secretion Proteins Septicemia Side Specificity Spontaneous abortion Stimulus Structure System Testing Therapeutic Tissues Vaccination Vacuole Virulence adaptive immunity antimicrobial base cell type cytokine cytosolic receptor immunoregulation macrophage microbial mutant novel novel therapeutics pathogen pathogenic bacteria receptor response small molecule sugar tissue/cell culture vector vaccine

项目摘要

The SecA2 auxiliary protein secretion system is required for secretion of virulence promoting proteins from a number of Gram-positive pathogens, including Bacillus anthracis (category A) and Listeria monocytogenes (category B). We identified two SecA2-dependent autolytic proteins that promote virulence of L. monocytogenes in infected animals, yet do not affect the growth of this bacterium in tissue culture cells. The virulence of engineered bacterial mutants lacking p60 was restored by expression of full-length p60, but not by expression of a truncated, catalytically inactive protein. The catalytic specificity of p60 predicts that it digests peptidoglycan (PGN) to generate or destroy immune modulating PGN fragments (muropeptides), including respectively muramyl di- and tri-peptides (MDP and MTP). MDP and MTP influence mammalian cell cytokine responses by acting on cytosolic proteins of the Nod family. We have found that p60- expressing bacteria and small molecules released from these bacteria enhance the induction of specific immune-regulatory cytokines by macrophages. In this grant proposal we investigate how p60 promotes virulence and affects host innate immune responses to infection. Our first Aim will identify features of p60 that are required for PGN digestion and for its effects on bacterial virulence and cytokine gene expression. Our second Aim investigates the structure and phylogenetic distribution of a p60-dependent biologically active muropeptide or small molecule and tests whether responses to this molecule require known muropeptide-responsive Nod family proteins. For our third Aim, we investigate a potential mechanism for p60's effects on bacterial virulence by determining how expression of p60 and cytokines induced by p60 affect macrophage responses to activating stimuli. Our studies will define the mechanisms by which this bacterial autolysin contributes to the virulence of a clinically important bacterial pathogen and begin to explore whether similar mechanisms promote virulence of other Gram-positive pathogens, including potential agents of bioterrorism. The mechanisms used by pathogenic bacteria to cause disease include strategies to subvert host immune responses. A subversive strategy that may be common to a number of deadly bacteria is studied in this grant. Our studies will define the molecular basis for this strategy of immune subversion and may thus reveal novel therapeutic avenues to modulate inflammation during bacterial infection, vaccination, and chronic inflammatory diseases.

SecA2辅助蛋白分泌系统是促毒蛋白分泌所必需的