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Soft Landing - TLR4 and Yersinia pestis

软着陆 - TLR4 和鼠疫耶尔森氏菌

基本信息

批准号：
7675908
负责人：
ADELINE M HAJJAR
金额：
$ 32.55万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-01 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7675908
关键词：
Agonist Alleles Aluminum Animal Model Animals Antibodies Antibody Formation Antigens Biological Biological Assay Centers of Research Excellence Code Collaborations Complex Data Development Disease Disease Progression Emerging Communicable Diseases Fleas Flow Cytometry Francisella Francisella tularensis Generations Genes Genetic Polymorphism Genetic Variation Genotype Gram-Negative Bacteria Human Immune Immune response Immunity Immunomodulators Infection Ligands Lipid A Lipopolysaccharides Mammalian Cell Mediating Modification Mus Natural Immunity Pilot Projects Predisposition Production Proteins Protocols documentation Resistance Role Salmonella Salmonella typhimurium Salts Structure T-Lymphocyte Temperature Toll-like receptors Vaccination Variant Virulence Yersinia pestis base biodefense cytokine human TLR4 protein immunogenicity in vivo interest microbial monophosphoryl lipid A mouse model mouse toll-like receptor 4 nonhuman primate protective efficacy receptor research study response toll-like receptor 4 trend vector

项目摘要

Toll-like receptor 4 (TLR4) and its coreceptor MD-2 mediate recognition of lipopolysaccharide (IPS), a component of all Gram negative bacteria. In the last few years it has become clear that differences in recognition of LPS structures between mouse and human TLR4/MD-2 exist. Interestingly, Yersinia pestis alters the structure of its LPS when it infects the mammalian host from its flea vector. It switches from a structure that is highly proinflammatory to one that is an antagonist on the human but not mouse receptor. To study the biological consequences of this modification we have generated a mouse model that expresses the human receptor instead of the mouse receptor. We predict this mouse will be more susceptible to Y. pestis infection. Human TLR4 polymorphisms have been shown to be associated with various diseases whereas similar coding variants in MD-2 have yet to be described. Data from the Wurfel/Martin project indicates that the D299G/T399I TLR4 variant is even less responsive to Y. pestis LPS at mammalian temperature. Therefore we are also generating a mouse model expressing this variant. These studies will determine the in vivo role of TLR4 in innate and adaptive responses to Y. pestis as well as Salmonella typhimurium, the first Gram negative bacterium shown to alter its LPS upon infecting mammalian cells. Finally, TLR4-mediated immunomodulators have been shown to protect mice from Francisella novicida or Y. pestis infection upon pretreatment with the compounds. We will therefore examine the response of the humanized mice to these TLR4 agonists. All together these experiments will determine the impact of species-specific differences in the recognition of various LPS structures by human and mouse TLR4.

toll样受体4 （TLR4）及其辅助受体MD-2介导脂多糖的识别