UTMB Department of Pathology

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Innate Immunity and Pathobiology of Ehrlichiae

My research interests involve understanding innate immune mechanisms and host pathogen interactions of Ehrlichia spp.. Ehrlichiae are tick-transmitted obligate intracellular gram negative bacteria that reside in phagocytes (macrophage and neutrophil), primary effector cells of innate immunity. However, we know very little about how these organisms survive and thrive in the macrophage. Specific agents under investigation are E. chaffeensis and closely related E. canis, the etiologic agents of human monocytotropic ehrlichiosis (HME) and canine monocytic ehrlichiosis (CME), respectively. HME is a serious and life-threatening disease considered to be a prototypical emerging infectious disease recognized in the late 1980’s in the United States.

Vaccines and improved diagnostics for HME and CME are needed, thus we are also involved in translational research to address this deficit. In this effort, we have performed investigations to identify major immunoreactive proteins that could potentially elicit a protective immune response. We have used a variety of methods including molecular and proteomic approaches to identify eight major immunoreactive proteins that we believe are viable subunit vaccine candidates. In an effort to commercialize our laboratory discoveries, we are currently collaborating with several industry partners (Merial, Agen and Focus Technologies) to further develop and implement this intellectual property related to vaccines and diagnositics for medically important ehrlichiae.

Until recently, bacteria were considered incapable of protein glycosylation. Our laboratory has been one of the first to identify glycoproteins in a pathogenic bacterium and much of our research effort is directed at understanding the role of glycoproteins in the pathobiology and innate immune recognition. Little information is known about the glycan structure of prokaryotic glycoproteins, and we have used mass spectroscopy to define the structure and composition of glycans attached to these proteins. In addition, we are investigating the molecular basis of the strong immunoreactivity of these glycoproteins using epitope mapping. In this work we have determined that both glycan and peptide determinants contribute to the immunoreactive epitopes of ehrlichial glycoproteins.

The ability of ehrlichiae to evade the host immune mechanisms, both innate and adaptive appears to be essential for its survival in natural hosts as well as incidental hosts such as humans. We are also investigating the interaction of E. chaffeensis with the macrophage to attempt to define the pattern recognition receptors and pathogen associated molecular patterns (PAMPs) involved in innate recognition by the host. Ehrlichiae are gram-negative bacteria that lack components including lipopolysaccharide and peptidoglycan that are well characterized PAMPs among gram negative bacteria. Through these studies we have concluded that ehrlichial glycoproteins are novel PAMPs that elicit an inflammatory chemokine response without production of proinfammatory cytokines.

1. Molecular evidence for a spotted fever group Rickettsia species in the tick Amblyomma longirostre in Brazil. J. Med. Entomol. 41:533-537. 2004
2. Overproduction of TNF- by CD8+ type-1 cells and downregulation of INF- by CD4+ Th-1 cells contribute to toxic shock-like syndrome in an animal model of fatal monocytotropic ehrlichiosis. J. Immuol. 172:1786-1800. 2004
3. Histologic, serologic, and molecular analysis of persistent ehrlichiosis in a murine model.. Am. J. Pathol. 165:997-1006. 2004
4. Detection of Rickettsia africae in patients and ticks along the coastal region of Cameroon. Am. J. Trop. Med. Hyg. 71:363-366. 2004
5. Kinetics of antibody response to Ehrlichia canis immunoreactive proteins. Infect. Immun. 71:2516-24. 2003
6. L-selectin and E-selectin expressed on monocytes mediating Ehrlichia chaffeensis attachment onto host cells. FEMS Microbiol. Lett. 227:303-309. 2003
7. Rickettsia species infecting Amblyomma cooperi ticks from an area in the state of Sao Paulo, Brazil, where Brazilian spotted fever is endemic. J. Clin. Microbiol. 42:90-98. 2003
8. Identification and functional analysis of an immunoreactive DsbA-like thio-disulfide oxidoreductase of Ehrlichia spp. Infect. Immun. 70:2700-2703. 2002
9. Phylogenetic relationships of Anaplasma marginale and ‘Ehrlichia platys’ to other Ehrlichia species determined by GroEL amino acid sequences. Int. J. Syst. Evol. Microbiol. 51:1143-1146. 2001
10. Immunodiagnosis of Ehrlichia canis infection with recombinant proteins. J. Clin. Microb. 39:315-322. 2001
11. Glycosylation of homologous immunodominant proteins of Ehrlichia chaffeensis and Ehrlichia canis. Infect. Immun. 68:13-18. 2000
12. A conserved, transcriptionally active p28 multigene locus of Ehrlichia canis. Gene. 254:245-252. 2000
13. Isolation and characterization of an antigenically distinct 68-kd protein from nonviral intracytoplasmic inclusions in boa constrictors chronically infected with the inclusion body disease virus (IBDV:Retroviridae). Vet. Path. 37:449-459. 2000
14. Characterization of the complete transcriptionally active p28 multigene family of Ehrlichia chaffeensis. Gene. 248:59-68. 2000
15. Molecular cloning and characterization of 120-kilodalton protein gene of Ehrlichia canis and application of the recombinant 120-kDa protein for serodiagnosis of canine ehrlichiosis. J. Clin. Microbiol. 38: 369-374. 2000
16. Molecular cloning of a conserved major immunoreactive 28-kilodalton protein gene of Ehrlichia canis: a potential serodiagnostic antigen. Clin. Diagn. Lab. Immunol. 6:100-108. 1999
17. Primary and anamnestic responses of bovine bronchoalveolar and peripheral blood lymphocyte subsets to aerosolized Pasteurella haemolytica A1. Vet. Immunol. Immunopathol. 67:161-169. 1999
18. Evidence of Pasteurella haemolytica linked immune complex disease in natural and experimental models. Microb. Path. 26:183-193. 1999
19. Genetic diversity of the 28-kilodalton outer membrane protein gene in human isolates of Ehrlichia chaffeensis. J. Clin. Microbiol. 37:1137-1143. 1999
20. A simple purification method for Pasteurella haemolytica outer membrane proteins. J. Microbiolog. Meth. 29:201-206. 1997
21. Memory and CD8+ are the predominant bovine bronchoalveolar lymphocyte phenotypes. Vet. Immunol. Immunopathol., 58:55-62. 1997
22. PCR detection of acute Ehrlichia canis infection in dogs. J. Vet. Diagn. Invest. 8:441-4477. 1996
23. Characterization of bovine pulmonary and serum antibody responses after parenteral or intrapulmonary vaccination with live Pasteurella haemoltyica A1. Comp. Immunol. Microbiol. Infect. Dis. 19:99-115. 1996
24. Development of polymerase chain reaction for specific identification of epizootic hemorrhagic disease virus serotype 1. Arch. Virol., 140:2273-2281. 1995
25. Detection of antigenemia by enzyme-linked immunosorbent assay in horses with experimental Ehrlichia risticii infection. J. Vet. Diagn. Invest. 5:33-36. 1992
26. Systemic and pulmonary antibody responses of calves to Pasteurella haemolytica A1 after intrapulmonary inoculation. Am. J. Vet. Res. 54:1889-94. 1992
27. 1992. Detection of antigenemia and serum antibody response by ELISA in horses with experimental Ehrlichia equi infection. J. Vet. Diagn. Invest. 5:37-39. 1992
28. Evaluation of efficacy of an experimental therapeutic compound in an indwelling bronchial catheter model of pneumonic pasteurellosis. Am. J. Vet. Res. 53:122-126. 1991

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