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Rickettsia-host interface and multiple paths to invasion

立克次体-宿主界面和多种入侵途径

基本信息

批准号：
10626741
负责人：
Mohammed Sayeedur Rahman
金额：
$ 66.25万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-15 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10626741
关键词：
Address Africa Anti-Inflammatory Agents Antibodies Arizona Arthropods Autophagocytosis Autophagosome Bacteria Bite Blood Bone Marrow Boutonneuse Fever California Cd68 Cells Central America Complex Cytokine Signaling Cytosol Data Development Disease Outbreaks Distant Endemic Flea-Borne Typhus Endothelial Cells Environment Epidemic Etiology Europe Goals Growth Host Defense Human Immune Infection Inflammasome Inflammatory Inflammatory Response Pathway Interleukin-1 Interleukin-1 alpha Interleukin-1 beta Interleukin-10 Invaded Knowledge Life Cycle Stages Life Style Link Macrophage Middle East Organ PIK3CG gene Pathogenicity Pathway interactions Play Proteins Publishing Reporting Research Rickettsia Rickettsia Infections Rickettsia conorii Rickettsia prowazekii Rickettsia rickettsii Rickettsia typhi Risk Rocky Mountain Spotted Fever Role Signal Transduction Site Skin South America Spleen Stream Structure Systemic disease TNF gene Testing Texas Time Tissues Transforming Growth Factor beta Typhus Ubiquitination United States Up-Regulation Vaccines Virulence Virulent Wild Type Mouse arthropod-borne cytokine draining lymph node effective intervention flea-borne host colonization human pathogen inhibition of autophagy member microbial microbicide monocyte pathogen pathogenic bacteria prevent programs recruit response spotted fever therapeutically effective tick-borne trafficking

项目摘要

PROJECT SUMMARY Species in the genus Rickettsia are Gram-negative obligate intracellular bacteria with both symbiotic and pathogenic lifecycles. The global impact of rickettsial infections is illustrated by the resurgence of infections of humans with R. rickettsia (etiologic agent of Rocky Mountain Spotted Fever) in South and Central America, or R. conorii (Boutonneuse fever) in Europe, the Middle East, and Africa. Strikingly, tick- and flea-borne rickettsial diseases are also on the rise in the United States, as exemplified by recent outbreaks of R. rickettsii in Arizona and R. typhi (etiologic agent of murine typhus) in California and Texas, further highlighting the threats of rickettsial diseases. There are currently no vaccines to prevent rickettsioses and our insufficient understanding of rickettsial intracellular lifestyle hinders the progression towards the development of effective therapeutics against these increasingly recognized bacterial pathogens. Over the past four years, we identified a complex mechanism by which pathogenic rickettsiae utilize secreted effectors to facilitate colonization by manipulating ER structures or by modulating intracellular trafficking to subvert host defense pathways. However, the precise mechanisms by which virulent Rickettsia species utilize this effector arsenal to subvert host innate defense pathways to support intracellular lifestyle in endothelial cells or macrophages (MΦ) remains ill-defined. To address these knowledge gaps, this renewal application proposes to: i) decipher how virulent Rickettsia species utilize their effector repertoire to manipulate autophagic responses to colonize host cells, and ii) determine the mechanism(s) by which effectors of virulent, but not avirulent, Rickettsia species suppress inflammasome activation and manipulate MΦ polarization to promote host dissemination. Our overall goal is to test the hypothesis that effectors from virulent species of Rickettsia, like Risk1, induce autophagy to negatively regulate inflammasome activation and skews MΦ polarization from a M1 to M2 bias to facilitate host colonization. To test our hypothesis, in Aim 1, we will define the mechanism(s) by which pathogenic Rickettsia subvert autophagosomal maturation to promote host colonization. In Aim 2, we will decipher the mechanism(s) underlying subversion of inflammasome responses and manipulation of MΦ polarization by pathogenic Rickettsia species. These Aims are intended to unveil a link by which effectors of pathogenic Rickettsia species manipulate autophagy to subvert inflammasome-dependent proinflammatory cytokine signaling and skew MΦ polarization from a microbicidal milieu (M1-MΦ) to a more favorable pro- microbial environment (M2-MΦ). These studies will lead to the identification of a link that could be exploited for anti-virulence strategy.

项目总结

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Rickettsia-host interaction: strategies of intracytosolic host colonization.

DOI：
10.1093/femspd/ftab015
发表时间：
2021-04-05
期刊：
Pathogens and disease
影响因子：
3.3
作者：
Voss OH;Rahman MS
通讯作者：
Rahman MS

Risk1, a Phosphatidylinositol 3-Kinase Effector, Promotes Rickettsia typhi Intracellular Survival.

Risk1 是一种磷脂酰肌醇 3 激酶效应器，可促进伤寒立克次体细胞内存活。

DOI：
10.1128/mbio.00820-20
发表时间：
2020
期刊：
mBio
影响因子：
6.4
作者：
Voss,OliverH;Gillespie,JosephJ;Lehman,StephanieS;Rennoll,SherriA;Beier-Sexton,Magda;Rahman,MSayeedur;Azad,AbduF
通讯作者：
Azad,AbduF

Pathogenic, but Not Nonpathogenic, Rickettsia spp. Evade Inflammasome-Dependent IL-1 Responses To Establish an Intracytosolic Replication Niche.