Targeting T3SA proteins as protective antigens against Yersinia

将 T3SA 蛋白作为针对耶尔森氏菌的保护性抗原

基本信息

批准号：
10645989
负责人：
DEBORAH M ANDERSON
金额：
$ 23.14万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-24 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10645989
关键词：
Adjuvant Antibiotic Resistance Antibiotics Antibodies Antigens Area Bacteria Bubonic Plague Case Fatality Rates Cells Cessation of life Classification Cytoplasm Data Disease Disease Outbreaks Formulation Genetic Health Hazards Human IL17 gene Immune response Infection Intranasal Administration Investigation Methods Mus Nature Needles Parents Pathogenesis Pathogenicity Plague Pneumonic Plague Predisposition Production Proteins Pseudomonas Pseudomonas aeruginosa Public Health Reporting Resources Rodent Route Salmonella Salmonella enterica Septicemic plague Shigella Subunit Vaccines System Testing Toxin Type III Secretion System Pathway United States Vaccines Virulence Yersinia Yersinia enterocolitica Yersinia pestis animal data bioweapon capsule cell mediated immune response combat cost cytokine efficacy evaluation enterotoxigenic Escherichia coli enzootic high risk human pathogen mortality mouse model mucosal site mutant pathogen prevent protective efficacy response vaccine development

Adjuvant Antibiotic Resistance Antibiotics Antibodies Antigens Area Bacteria Bubonic Plague Case Fatality Rates Cells Cessation of life Classification Cytoplasm Data Disease Disease Outbreaks Formulation Genetic Health Hazards Human IL17 gene Immune response Infection Intranasal Administration Investigation Methods Mus Nature Needles Parents Pathogenesis Pathogenicity Plague Pneumonic Plague Predisposition Production Proteins Pseudomonas Pseudomonas aeruginosa Public Health Reporting Resources Rodent Route Salmonella Salmonella enterica Septicemic plague Shigella Subunit Vaccines System Testing Toxin Type III Secretion System Pathway United States Vaccines Virulence Yersinia Yersinia enterocolitica Yersinia pestis animal data bioweapon capsule cell mediated immune response combat cost cytokine efficacy evaluation enterotoxigenic Escherichia coli enzootic high risk human pathogen mortality mouse model mucosal site mutant pathogen prevent protective efficacy response vaccine development

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项目摘要

Summary Yersinia pestis causes bubonic, septicemic and pneumonic plague with high rates of mortality in the absence of immediate treatment. Although Y. pestis is susceptible to many antibiotics and outbreaks have been contained in present day, plague continues to cause lethal human infections in areas where Y. pestis has established persistent enzootic cycles in wild rodents. In 2015, 15 plague cases were reported in the United States, several occurring in National Parks, with a case fatality rate of ~33%. This underscores the challenges associated with combatting this devastating disease. Additionally, Y. pestis has been deployed as a biological weapon and with its genetic tractability, natural acquisition of antibiotic resistance and relative ease of acquisition from nature, Y. pestis has been classified as a weaponizable pathogen with the potential for inflicting widespread human death. Yersinia spp. that are pathogenic for humans possess a type III secretion system (T3SS) that is essential for virulence. This T3SS injects protein effectors into host cells to manipulate functions for the benefit of the bacterium. The T3SS apparatus (T3SA) provides the energized conduit for translocation of these effectors from the bacterium and into the host cell cytoplasm. The external portions of the T3SA are the needle, the tip protein and the first of two translocator proteins. For Yersinia, LcrV is the needle tip protein and YopB is the first translocator protein. These proteins are highly conserved among Yersinia spp. and are required for pathogenesis. We have demonstrated that, when administered intranasally (IN) in the presence of the appropriate adjuvant, these two proteins protect mice against a lethal challenge by Y. pestis and Y. enterocolitica. We have fused LcrV and YopB to produce YerF and have fused LTA1, the active moiety of dmLT (double mutant labile toxin) from enterotoxigenic E. coli, to the N-terminus of these fusions to produce L-YerF. Within this proposal, we intend to assess the L-YerF as a self- adjuvanting protective subunit vaccine. We hypothesize that L-YerF will provide humoral and cellular immune responses that will protect mice against infections causing pneumonic and bubonic plague.

概括耶尔森氏念珠菌会导致泡沫，败血症和肺炎鼠疫，并具有高死亡率的死亡率没有立即治疗。虽然柴油很容易受到许多抗生素和暴发的影响瘟疫在当今已包含在Y. pestis的地区继续引起致命的人类感染已经在野生啮齿动物中建立了持续的enzootic循环。 2015年，报告了15例瘟疫案件美国，几个发生在国家公园，病例死亡率约为33％。这强调了与打击这种毁灭性疾病有关的挑战。此外，佩斯蒂斯已被部署为一种生物武器及其遗传性障碍，抗生素耐药性的自然采集和相对 Y. Pestis易于从自然中获取，已被归类为具有武器的病原体为了造成广泛的人类死亡。 Yersinia spp。对人类具有病原性具有III型分泌系统（T3SS）对于毒力至关重要。该T3SS将蛋白质效应子注入宿主细胞中操纵功能是为了受益。 T3SS设备（T3SA）提供了能量这些效应子从细菌转移到宿主细胞质中的导管。外部 T3SA的一部分是针头，尖端蛋白和两个转运蛋白中的第一个。对于Yersinia， LCRV是针头蛋白，YOPB是第一个转运蛋白。这些蛋白质是高度保守的在Yersinia spp中。并且是发病机理所必需的。我们已经证明，当管理这两种蛋白质在存在适当的辅助剂的情况下（in）（in），保护小鼠免受致命侵害 Y. Pestis和Y. Enterocolitica的挑战。我们已经融合了lcrv和Yopb来产生YERF并融合 LTA1，DMLT的活性部分（双突变型不稳定毒素）从肠毒素大肠杆菌到N末端这些融合会产生L-YERF。在该提案中，我们打算评估L-YERF为自我佐剂保护性亚基疫苗。我们假设L-YERF将提供体液和细胞免疫反应，可保护小鼠免受引起肺炎和泡沫鼠疫的感染。