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Defining the pathobiological roles of Orientia tsutsugamushi Ank proteins

确定恙虫病东方体 Ank 蛋白的病理生物学作用

基本信息

批准号：
10455792
负责人：
Jason A Carlyon
金额：
$ 46.57万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-12 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10455792
关键词：
ANK1 gene Africa Ankyrin Repeat Antigen-Presenting Cells Asia Bacteria Binding Biological Assay Cell Nucleus Cell physiology Cells Cellular biology Communities Complex Coupled Cowpox Cytoplasm Data Defense Mechanisms Detection Disease Etiology Event F Box Domain F-Box Motifs Fatality rate Funding Gene Expression Genetic Immune Immunity Immunology Immunoprecipitation Impairment Infection Knowledge Lysine Mass Spectrum Analysis Mediating Microbe Middle East Natural Immunity Nature Orientia tsutsugamushi Pathogen detection Pathogenesis Pathway interactions Phosphotransferases Proteins Proteomics Research Role SKP Cullin F-Box Protein Ligases Scrub Typhus South America TNF gene Time Toxic effect Trans-Activators Ubiquitin Ubiquitination Virulence Virulence Factors War Work Yeasts adaptive immunity antimicrobial cell type cohort functional outcomes gain of function global health immunoregulation in vivo inhibitor/antagonist innovation microbial mortality multicatalytic endopeptidase complex neglect novel pathogen pathogenic bacteria prevent protein protein interaction response screening

项目摘要

Orientia tsutsugamushi is an obligate intracellular bacterium and causative agent of scrub typhus, a severe illness with a high fatality rate that results in approximately 1 million new cases each year. Scrub typhus has long been considered endemic to the Asia-Pacific region, but non-travel related cases and detection of the pathogen on multiple continents signify the disease as an emerging global health threat. The ankyrin repeat is one of the most-common protein-protein interaction motifs in nature. O. tsutsugamushi subverts innate and adaptive immunity using its cadre of ankyrin repeat-containing effectors (Anks), many of which also carry a PRANC/F- box motif that co-opts SCF ubiquitin ligases. Ank1 and Ank6 inhibit NF-κB accumulation in the nucleus to impair NF-κB-dependent gene expression in an ankyrin repeat- and PRANC/F-box-dependent manner. Both effectors bind the host cell NF-κB inhibitor, p105, and prevent its TNFα-induced degradation. Conspicuously, Ank1 and Ank6 ubiquitinate Crybg3, a host kinase that influences p105 stability. Further screening revealed that 13 Anks antagonize NF-κB, some of which bind p105 and others of which do not. Thus, multiple O. tsutsugamushi Anks inhibit NF-κB by distinct, overlapping mechanisms. Ank5 promotes ubiquitination and proteasomal degradation of NLRC5, a transactivator of MHC-I gene expression, to potently reduce MHC-I levels. Our findings indicate that Ank immunomodulation enables O. tsutsugamushi to win, at least initially, its tug-of-war with host cells to establish infection. Yet, the detailed mechanisms by which Anks modulate NF-κB, NLRC5, and other targets remain poorly understood. Indeed, while our data establish that O. tsutsugamushi uses Anks to alter the host cell ubiquitome, the extent of this strategy, identity of modified targets, and specific functional outcomes are poorly defined. Due to the bacterium’s genetic intractability, Ank-mediated virulence in vivo has not been pursued. Finally, several additional Anks target unknown host pathways that also likely influence O. tsutsugamushi pathobiology. To fill these knowledge gaps, we propose to (1) decipher the mechanisms by which O. tsutsugamushi Anks inhibit NF-κB and will employ a novel in vivo screen as part of this approach; (2) dissect how Ank5 promotes NLRC5 degradation to block MHC-I expression; and (3) identify new host cell pathways and ubiquitome changes that Anks modulate. The culmination of our studies will define novel and previously unsurmised mechanisms by which intracellular pathogens modulate host immunity. Overall, this work will have a broad and powerful impact.

恙虫病东方体是一种专性细胞内细菌，是严重恙虫病的病原体