Abstract

: Human monocytic ehrlichiosis (HME) caused by Ehrlichia chaffeensis and human granulocytic ehrlichiosis (HGE) caused by Anaplasma phagocytophila, are emerging infectious diseases. These bacteria are fastidious obligatory intracellular bacteria that require repeated transmission between two vastly different hosts: vertebrates and invertebrates. How these bacteria enter and continue to thrive within hostile host milieu such as neutrophils or the tick vector is largely unknown. We recently characterized genes encoding a type IV secretion system (T4SS) and two component-regulatory system (2CRS) in HGE and HME agents. This proposal aims to understand the roles of T4SS and 2CRS in pathogenesis of HME and HGE.
The specific aims of this project are as follows: 1. Examine the colocalization of T4SS proteins expressed by individual E. chaffeensis and A. phagocytophila organisms with endosome-lysosome markers and signaling molecules in human leukocytes during attachment, internalization, and subsequent proliferation, and in response to environmental stimuli. 2. Characterize expression of T4SS in ticks and the skin of mammals during tick transmission. 3. Identify T4SS effector or substrate molecules. 4. Characterize the 2CRS of E. chaffeensis and A. phagocytophila by expressing recombinant proteins and studying the phosphorylation of sensor kinases and response regulators in vitro, and in vivo under controlled sets of environmental conditions; by examining the effects of 2CRS (histidine kinase) inhibitors on phenotypes of E. chaffeensis and A. phagocytophila; and by studying genes regulated by 2CRS. 5. Construct novel mutants ofA. phagocytophila and E. chaffeensis in which a predicted critical gene is disrupted, or conditionally silenced to determine the functions of T4SS and 2CRS. The data obtained from this study will provide a new perspective for understandings the dynamic signaling events between obligatory intracellular bacteria and their mammalian and tick hosts. This project will potentially provide a technical breakthrough in this field of research. The results may point to a potential target for new treatment and prevention of HME and HGE. ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI054476-01A1
Application #
6731296
Study Section
Special Emphasis Panel (ZRG1-TMP (03))
Program Officer
Perdue, Samuel S
Project Start
2004-01-01
Project End
2008-12-31
Budget Start
2004-01-01
Budget End
2004-12-31
Support Year
1
Fiscal Year
2004
Total Cost
$373,750
Indirect Cost

  Institution

Name
Ohio State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210

  Publications

Yan, Qi; Lin, Mingqun; Huang, Weiyan et al. (2018) Ehrlichia type IV secretion system effector Etf-2 binds to active RAB5 and delays endosome maturation. Proc Natl Acad Sci U S A 115:E8977-E8986
Sharma, Pratibha; Teymournejad, Omid; Rikihisa, Yasuko (2017) Peptide Nucleic Acid Knockdown and Intra-host Cell Complementation of Ehrlichia Type IV Secretion System Effector. Front Cell Infect Microbiol 7:228
Lin, Mingqun; Liu, Hongyan; Xiong, Qingming et al. (2016) Ehrlichia secretes Etf-1 to induce autophagy and capture nutrients for its growth through RAB5 and class III phosphatidylinositol 3-kinase. Autophagy 12:2145-2166
Cheng, Zhihui; Lin, Mingqun; Rikihisa, Yasuko (2014) Ehrlichia chaffeensis proliferation begins with NtrY/NtrX and PutA/GlnA upregulation and CtrA degradation induced by proline and glutamine uptake. MBio 5:e02141
Niu, Hua; Rikihisa, Yasuko (2013) Ats-1: a novel bacterial molecule that links autophagy to bacterial nutrition. Autophagy 9:787-8
Niu, Hua; Xiong, Qingming; Yamamoto, Akitsugu et al. (2012) Autophagosomes induced by a bacterial Beclin 1 binding protein facilitate obligatory intracellular infection. Proc Natl Acad Sci U S A 109:20800-7
Liu, Hongyan; Bao, Weichao; Lin, Mingqun et al. (2012) Ehrlichia type IV secretion effector ECH0825 is translocated to mitochondria and curbs ROS and apoptosis by upregulating host MnSOD. Cell Microbiol 14:1037-50
Kumagai, Yumi; Matsuo, Junji; Cheng, Zhihui et al. (2011) Cyclic dimeric GMP signaling regulates intracellular aggregation, sessility, and growth of Ehrlichia chaffeensis. Infect Immun 79:3905-12
Cheng, Zhihui; Miura, Koshiro; Popov, Vsevolod L et al. (2011) Insights into the CtrA regulon in development of stress resistance in obligatory intracellular pathogen Ehrlichia chaffeensis. Mol Microbiol 82:1217-34
Rikihisa, Yasuko (2011) Mechanisms of obligatory intracellular infection with Anaplasma phagocytophilum. Clin Microbiol Rev 24:469-89

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