项目来源

美国卫生和人类服务部基金(HHS)

项目主持人

HALL, ROBERT H.

项目受资助机构

UNIVERSITY OF GEORGIA

立项年度

2017

立项时间

未公开

项目编号

5R01AI076322-10

项目级别

国家级

研究期限

未知 / 未知

受资助金额

376167.00美元

学科

Biodefense; Biotechnology; Digestive Diseases; Emerging Infectious Diseases; Infectious Diseases;

学科代码

未公开

基金类别

Non-SBIR/STTR RPGs

关键词

未公开

参与者

TRENT, MICHAEL STEPHEN

参与机构

NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES

项目标书摘要：DESCRIPTION (provided by applicant): The bacterial cell envelope is a remarkable and complex structure that guards bacteria from their surrounding environment. A defining feature of Gram-negative bacteria is the presence of an outer membrane that encapsulates the peptidoglycan layer of these organisms. While the inner membrane is composed of glycerophospholipids, the outer membrane is a unique, asymmetric bilayer with glycerophospholipids confined to the inner leaflet and lipid A, a unique saccharolipid, localized to the outer leaflet. Lipid A is the lipid moiety of lipopolysaccharide (LPS) and anchors LPS to the bacterial surface. Bacteria have evolved various mechanisms to adapt to their unpredictable and often hostile surroundings, including strategies for remodeling their membrane architecture. Often these modifications provide resistance to components of the mammalian innate immune system and modulate host recognition of the invading microorganism. The lipid A domain of LPS is toxic to humans and potent stimulator of the innate immune system through via recognition by TLR4- MD2. A number of Gram-negative pathogens modify their lipid A structure to evade host detection. Additionally, structural alteration of lipid A and glycerophospholipids can directly impact bacterial resistance to innate immune effectors such as host antimicrobial peptides. The overall objective of this application is to unravel the molecular mechanisms by which Vibrio cholerae, the causative agent of the disease cholera, remodels it membrane architecture and the role this remodeling plays in virulence. The Specific Aims of the current application are: (1) biochemical and genetic analysis of glycine modification of V. cholerae LPS; (2) Biochemical and genetic analysis of phosphoethanolamine modification of V. cholerae LPS; (3) elucidation of machinery required for phospholipid remodeling in V. cholerae; and (4) impact of V. cholerae membrane remodeling on the host innate immune response. The completion of these Aims will directly contribute to our understanding of how lipid remodeling/modification machinery impacts pathogenesis. Finally, from this work will come not only a better understanding of the disease cholera, but new avenues for vaccine development and the ability to generate engineered LPS structures that could serve as potential adjuvants and/or LPS antagonists.