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Virulence of the Opportunistic Pathogen Rhodococcis Equi

机会性病原体马红球菌的毒力

基本信息

批准号：
7343180
负责人：
MARY HONDALUS
金额：
$ 31.55万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-02-01 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7343180
关键词：
Actinobacteria class Actinomyces Address Affect Attenuated Bacteria Binding Binding Sites Biological Assay Biology Breathing Cellular biology Clinical Complex Data Defect Development Disease Disruption Epidemic Event Gene Family Genes Genetic Goals Granulomatous Growth HIV High temperature of physical object Homologous Gene Host Defense Immunity In Vitro Individual Infection Inflammation Investigation Ions Knowledge Life Light Lipoproteins Location Lysosomes Macrophage Cell Biology Malignant Neoplasms Methods Molecular Molecular Mechanisms of Action Monitor Mus Mutagenesis Mycobacterium tuberculosis Nature Obstruction Oxidative Stress Pathogenesis Pathway interactions Persons Phagocytosis Phagosomes Phenotype Physiology Plasmids Pneumonia Positioning Attribute Process Production Proteins Recombinants Regulation Regulatory Pathway Regulon Reporter Research Research Personnel Resources Rhodococcus equi Role Signal Transduction Soil Stimulus Sum Surface System Temperature Testing Time Virulence Work attenuation base chemotherapy expectation genetic analysis genetic manipulation in vivo innovation insight intracellular parasitism killings macrophage member mortality mouse model mutant novel pathogen programs promoter resistance factors response tool trafficking

项目摘要

With the arrival of the HIV epidemic and the increase in individuals undergoing chemotherapy for various cancers, the understudied zoonotic opportunistic pathogen Rhodococcus equi has emerged as cause of life- threatening pneumonia in persons of compromised immunity. Rhodococcal pneumonia is characterized by pyogranulomatous inflammation with cavitation, which can be misdiagnosed as Mycobacterium tuberculosis infection. R. equi is a common soil-borne facultative actinomycete which, when inhaled, resists innate killing mechanisms and readily multiplies in macrophages of susceptible hosts, likely by perturbation of endosomal trafficking. Little is known about the molecular basis for R. equi pathogenesis, and prior to our recent work, few tools existed to allow a thorough genetic analysis of this bacterium. Recently, we have developed the genetic methods to construct defined mutants of R. equi and have also created an efficient transposon mutagenesis system. Using these new tools, we demonstrated that vapA (virulence associated p/otein A), a gene present on the virulence plasmid of R. equi, is required for intracellular growth and full virulence. Deletion of vapA attenuates the bacterium, rendering it incapable of growth in vivo and unable to replicate in macrophages cultured in vitro. Our long-term goal is to completely dissect the genetic basis for R. equi virulence. We propose to do so by first expanding our understanding of vapA, which is to date the only known R. equi virulence determinant. The first AIM of this work is to identify the mechanism of action of vapA. To do so, we will define the intracellular events post phagocytosis of both wild type R. equi and the vapA deletion mutant. Specifically we will characterize the process of phagosomal maturation in wild type R. equi infected macrophages and test the influence of VapA on phagosome acidification and fusion with lysosomes. We will identify interacting host protein partners of VapA. The second AIM is to characterize the R. equi virulence regulon through the examination of regulators of vapA expression, VirR (yjrulence regulator) and VarA (yap regulator). We will identify the specific signals transduced by these regulators and identify additional genes controlled by them. We will establish the effects of deletion mutants of virR and varA on R. equi virulence. Finally, we will identify the binding sites of the regulators to the vapA promoter. These studies addressing the molecular mechanisms of R. equi pathogenesis will further our understanding of macrophage cell biology and will yield insight into the biology of actinomycete host-pathogen relationships in general.

随着艾滋病毒流行的到来和个体接受各种化疗的增加