Ehrilchiacidal Mechanisms In Leukocytes

Summary

Principal Investigator: Y Rikihisa
Affiliation: The Ohio State University
Country: USA
Abstract: 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.
Funding Period: 1990-08-01 - 2011-01-31
more information: NIH RePORT

Top Publications

  1. ncbi High-cholesterol diet facilitates Anaplasma phagocytophilum infection and up-regulates macrophage inflammatory protein-2 and CXCR2 expression in apolipoprotein E-deficient mice
    Qingming Xiong
    Department of Veterinary Biosciences, College of Veterinary Medicine, Ohio State University, Columbus, OH 43210, USA
    J Infect Dis 195:1497-503. 2007
  2. ncbi Anaplasma phagocytophilum inhibits human neutrophil apoptosis via upregulation of bfl-1, maintenance of mitochondrial membrane potential and prevention of caspase 3 activation
    Yan Ge
    Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210, USA
    Cell Microbiol 7:29-38. 2005
  3. ncbi Anaplasma phagocytophilum and Ehrlichia chaffeensis type IV secretion and Ank proteins
    Yasuko Rikihisa
    Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA
    Curr Opin Microbiol 13:59-66. 2010
  4. ncbi Cholesterol-dependent anaplasma phagocytophilum exploits the low-density lipoprotein uptake pathway
    Qingming Xiong
    Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, United States of America
    PLoS Pathog 5:e1000329. 2009
  5. ncbi Ehrlichia ewingii infection delays spontaneous neutrophil apoptosis through stabilization of mitochondria
    Qingming Xiong
    Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, USA
    J Infect Dis 197:1110-8. 2008
  6. ncbi Expression and porin activity of P28 and OMP-1F during intracellular Ehrlichia chaffeensis development
    Yumi Kumagai
    Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, 1925 Coffey Road, Columbus, OH 43210 1093, USA
    J Bacteriol 190:3597-605. 2008
  7. ncbi Identification of 19 polymorphic major outer membrane protein genes and their immunogenic peptides in Ehrlichia ewingii for use in a serodiagnostic assay
    Chunbin Zhang
    Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, 1925 Coffey Rd, Columbus, OH 43210 1093, USA
    Clin Vaccine Immunol 15:402-11. 2008
  8. ncbi Subversion of cellular autophagy by Anaplasma phagocytophilum
    Hua Niu
    Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210, USA
    Cell Microbiol 10:593-605. 2008
  9. ncbi Identification of novel surface proteins of Anaplasma phagocytophilum by affinity purification and proteomics
    Yan Ge
    Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, 1925 Coffey Rd, Columbus, OH 43210, USA
    J Bacteriol 189:7819-28. 2007
  10. ncbi Anaplasma phagocytophilum AnkA secreted by type IV secretion system is tyrosine phosphorylated by Abl-1 to facilitate infection
    Mingqun Lin
    Department of Veterinary Biosciences, The Ohio State University, 1925 Coffey Road, Columbus, OH 43210, USA
    Cell Microbiol 9:2644-57. 2007

Scientific Experts

  • Y Rikihisa
  • Yan Ge
  • Qingming Xiong
  • Mingqun Lin
  • Hua Niu
  • Yumi Kumagai
  • Haibin Huang
  • Chunbin Zhang
  • Takane Kikuchi
  • Xueqi Wang
  • Vera Kozjak-Pavlovic
  • Thomas Rudel
  • Mamoru Yamaguchi
  • Weichao Bao
  • Paul J J Hooykaas
  • Amke den Dulk-Ras
  • Kiyotaka Yoshiie
  • Futoshi Kuribayashi

Detail Information

Publications16

  1. ncbi High-cholesterol diet facilitates Anaplasma phagocytophilum infection and up-regulates macrophage inflammatory protein-2 and CXCR2 expression in apolipoprotein E-deficient mice
    Qingming Xiong
    Department of Veterinary Biosciences, College of Veterinary Medicine, Ohio State University, Columbus, OH 43210, USA
    J Infect Dis 195:1497-503. 2007
    ..This bacterium requires cholesterol for host cell infection in vitro and incorporates exogenous cholesterol into its membrane...
  2. ncbi Anaplasma phagocytophilum inhibits human neutrophil apoptosis via upregulation of bfl-1, maintenance of mitochondrial membrane potential and prevention of caspase 3 activation
    Yan Ge
    Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210, USA
    Cell Microbiol 7:29-38. 2005
    ..These results suggest that A. phagocytophilum inhibits human neutrophil apoptosis via transcriptional upregulation of bfl-1 and inhibition of mitochondria-mediated activation of caspase 3...
  3. ncbi Anaplasma phagocytophilum and Ehrlichia chaffeensis type IV secretion and Ank proteins
    Yasuko Rikihisa
    Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA
    Curr Opin Microbiol 13:59-66. 2010
    ..The recent discovery of several ankyrin repeat proteins secreted via the type IV secretion system of different intracellular bacteria suggests that a common strategy evolved to subvert host-cell functions...
  4. ncbi Cholesterol-dependent anaplasma phagocytophilum exploits the low-density lipoprotein uptake pathway
    Qingming Xiong
    Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, United States of America
    PLoS Pathog 5:e1000329. 2009
    ..phagocytophilum. These data reveal that A. phagocytophilum exploits the host LDL uptake pathway and LDLR mRNA regulatory system to accumulate cholesterol in inclusions to facilitate its replication...
  5. ncbi Ehrlichia ewingii infection delays spontaneous neutrophil apoptosis through stabilization of mitochondria
    Qingming Xiong
    Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, USA
    J Infect Dis 197:1110-8. 2008
    ..These results suggest that E. ewingii delays spontaneous apoptosis of neutrophils via stabilization of host cell mitochondria...
  6. ncbi Expression and porin activity of P28 and OMP-1F during intracellular Ehrlichia chaffeensis development
    Yumi Kumagai
    Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, 1925 Coffey Road, Columbus, OH 43210 1093, USA
    J Bacteriol 190:3597-605. 2008
    ..chaffeensis development at both temperatures...
  7. ncbi Identification of 19 polymorphic major outer membrane protein genes and their immunogenic peptides in Ehrlichia ewingii for use in a serodiagnostic assay
    Chunbin Zhang
    Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, 1925 Coffey Rd, Columbus, OH 43210 1093, USA
    Clin Vaccine Immunol 15:402-11. 2008
    ..The results support the utility of the tailored OMP-1 peptides as E. ewingii serologic test antigens...
  8. ncbi Subversion of cellular autophagy by Anaplasma phagocytophilum
    Hua Niu
    Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210, USA
    Cell Microbiol 10:593-605. 2008
    ..phagocytophilum subverts this system to establish itself in an early autophagosome-like compartment segregated from lysosomes to facilitate its proliferation...
  9. ncbi Identification of novel surface proteins of Anaplasma phagocytophilum by affinity purification and proteomics
    Yan Ge
    Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, 1925 Coffey Rd, Columbus, OH 43210, USA
    J Bacteriol 189:7819-28. 2007
    ..phagocytophilum and the host. These proteins may serve as targets for development of chemotherapy, diagnostics, and vaccines...
  10. ncbi Anaplasma phagocytophilum AnkA secreted by type IV secretion system is tyrosine phosphorylated by Abl-1 to facilitate infection
    Mingqun Lin
    Department of Veterinary Biosciences, The Ohio State University, 1925 Coffey Road, Columbus, OH 43210, USA
    Cell Microbiol 9:2644-57. 2007
    ....
  11. ncbi Surface-exposed proteins of Ehrlichia chaffeensis
    Yan Ge
    Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, 1925 Coffey Road, Columbus, OH 43210, USA
    Infect Immun 75:3833-41. 2007
    ..The identification of E. chaffeensis surface-exposed proteins provides novel insights into the E. chaffeensis surface and lays the foundation for rational studies on pathogen-host interactions and vaccine development...
  12. ncbi Porin activity of Anaplasma phagocytophilum outer membrane fraction and purified P44
    Haibin Huang
    Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210, USA
    J Bacteriol 189:1998-2006. 2007
    ....
  13. ncbi Degradation of p22phox and inhibition of superoxide generation by Ehrlichia chaffeensis in human monocytes
    Mingqun Lin
    Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210, USA
    Cell Microbiol 9:861-74. 2007
    ..These findings point to a unique survival mechanism of ROS-sensitive obligate intraleucocytic bacteria that involves the destabilization of p22(phox) following the binding of bacteria to host cell surface proteins...
  14. ncbi Anaplasma phagocytophilum delays spontaneous human neutrophil apoptosis by modulation of multiple apoptotic pathways
    Yan Ge
    Department of Veterinary Biosciences, The Ohio State University, Columbus, 43210, USA
    Cell Microbiol 8:1406-16. 2006
    ..These data point to a novel mechanism induced by A. phagocytophilum involving both extrinsic and intrinsic pathways to ensure to delay the apoptosis of host neutrophils...
  15. ncbi Ehrlichia subversion of host innate responses
    Yasuko Rikihisa
    Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, 1925 Coffey Road, Columbus, OH 43210, USA
    Curr Opin Microbiol 9:95-101. 2006
    ..They offer a fascinating example of how pathogens employ intricate strategies to usurp and subvert host cell function...
  16. ncbi Anaplasma phagocytophilum Ats-1 is imported into host cell mitochondria and interferes with apoptosis induction
    Hua Niu
    Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, USA
    PLoS Pathog 6:e1000774. 2010
    ..Bax redistribution was inhibited in both etoposide-induced and Bax-induced apoptosis by Ats-1. Taken together, Ats-1 is the first example of a bacterial protein that traverses five membranes and prevents apoptosis at the mitochondria...