Ehrlichia chaffeensis and Anaplasma phagocytophilum cause emerging infectious diseases, human monocytic ehrlichiosis (HME) and human granulocytic ehrlichiosis (HGE), respectively. The overall goal of the proposed study is to identify ehrlichiacidal mechanisms in the host cells, by focusing host signaling events essential (not just parallel phenomena) for intracellular parasitism. Thus, mechanisms can be potentially exploited to prevent and treat these infections. During the previous funding period this project identified several novel signaling pathways and mechanisms essential for E. chaffeensis and A. phagocytophilum infection. Blocking the host signals effectively killed these bacteria without harming the host human leukocytes in vitro. In this renewal proposal we will: 1. Elucidate mechanisms by which TG, GPI-anchored proteins, and tyrosine phosphorylated proteins are required for E. chaffeensis and A. phagocytophilum by identifying proteins involved by MALDI-TOF analysis, the gene knockdown, and immunolabeling. 2. Evaluate influences of cholesterol levels on mouse models of HGE and HME, and influences of cholesterol derivatives from ticks on E. chaffeensis and A. phagocytophilum infectivity. 3. Elucidate the mechanism by which A. phagocytophilum and E. chaffeensis block host cell NADPH oxidase activation in a cell-free system and COS-phox cells. 4. Elucidate the mechanism by which A. phagocytophilum inhibits human neutrophil apoptosis by analysis of caspases, bcl-2 family, and the mitochondrial integrity, transcriptional regulation of bcl-2 family proteins. The information to be obtained from the proposed study will point to unique mechanisms to kill E. chaffeensis and A. phagocytophilum and contribute to our understanding on host factors and signals induced by these pathogens and are essential for the obligatory intracellular parasitism. The results may point to a potential target for new treatment and prevention of HME and HGE.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI030010-18
Application #
7559699
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Perdue, Samuel S
Project Start
1990-08-01
Project End
2011-06-30
Budget Start
2009-02-01
Budget End
2011-06-30
Support Year
18
Fiscal Year
2009
Total Cost
$312,886
Indirect Cost
Name
Ohio State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Mohan Kumar, Dipu; Yamaguchi, Mamoru; Miura, Koshiro et al. (2013) Ehrlichia chaffeensis uses its surface protein EtpE to bind GPI-anchored protein DNase X and trigger entry into mammalian cells. PLoS Pathog 9:e1003666
Xiong, Qingming; Rikihisa, Yasuko (2012) Subversion of NPC1 pathway of cholesterol transport by Anaplasma phagocytophilum. Cell Microbiol 14:560-76
Xiong, Qingming; Rikihisa, Yasuko (2011) The prenylation inhibitor manumycin A reduces the viability of Anaplasma phagocytophilum. J Med Microbiol 60:744-9
Rikihisa, Yasuko (2011) Mechanisms of obligatory intracellular infection with Anaplasma phagocytophilum. Clin Microbiol Rev 24:469-89
Gibson, Kathryn; Kumagai, Yumi; Rikihisa, Yasuko (2010) Proteomic analysis of Neorickettsia sennetsu surface-exposed proteins and porin activity of the major surface protein P51. J Bacteriol 192:5898-905
Rikihisa, Yasuko; Lin, Mingqun (2010) Anaplasma phagocytophilum and Ehrlichia chaffeensis type IV secretion and Ank proteins. Curr Opin Microbiol 13:59-66
Rikihisa, Yasuko (2010) Molecular events involved in cellular invasion by Ehrlichia chaffeensis and Anaplasma phagocytophilum. Vet Parasitol 167:155-66
Niu, Hua; Kozjak-Pavlovic, Vera; Rudel, Thomas et al. (2010) Anaplasma phagocytophilum Ats-1 is imported into host cell mitochondria and interferes with apoptosis induction. PLoS Pathog 6:e1000774
Rikihisa, Yasuko; Lin, Mingqun; Niu, Hua (2010) Type IV secretion in the obligatory intracellular bacterium Anaplasma phagocytophilum. Cell Microbiol 12:1213-21
Xiong, Qingming; Lin, Mingqun; Rikihisa, Yasuko (2009) Cholesterol-dependent anaplasma phagocytophilum exploits the low-density lipoprotein uptake pathway. PLoS Pathog 5:e1000329

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