Skip to main content
×
×
Home

Molecular and cellular pathobiology of Ehrlichia infection: targets for new therapeutics and immunomodulation strategies

  • Jere W. McBride (a1) and David H. Walker (a1)
Abstract

Ehrlichia are small obligately intracellular bacteria in the order Rickettsiales that are transmitted by ticks and associated with emerging life-threatening human zoonoses. Vaccines are not available for human ehrlichiosis, and therapeutic options are limited to a single antibiotic class. New technologies for exploring host–pathogen interactions have yielded recent advances in understanding the molecular interactions between Ehrlichia and the eukaryotic host cell and identified new targets for therapeutic and vaccine development, including those that target pathogen virulence mechanisms or disrupt the processes associated with ehrlichial effector proteins. Animal models have also provided insight into immunopathological mechanisms that contribute significantly to understanding severe disease manifestations, which should lead to the development of immunomodulatory approaches for treating patients nearing or experiencing severe disease states. In this review, we discuss the recent advances in our understanding of molecular and cellular pathobiology and the immunobiology of Ehrlichia infection. We identify new molecular host–pathogen interactions that can be targets of new therapeutics, and discuss prospects for treating the immunological dysregulation during acute infection that leads to life-threatening complications.

Copyright
Corresponding author
*Corresponding author: David H. Walker, Department of Pathology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0609, USA. E-mail: dwalker@utmb.edu
References
Hide All
1Donatien, A. and Lestoquard, F. (1935) Existence en Algerie d'une rickettsia du chien. Bulletin of the Exotic Pathology Society 28, 418-419
2Cowdry, E.V. (1925) Studies on the etiology of heartwater. Journal of Experimental Medicine 42, 231-252
3Anderson, B.E. et al. (1992) Detection of the etiologic agent of human ehrlichiosis by polymerase chain reaction. Journal of Clinical Microbiology 30, 775-780
4Buller, R.S. et al. (1999) Ehrlichia ewingii, a newly recognized agent of human ehrlichiosis. New England Journal of Medicine 341, 148-155
5Paddock, C.D. et al. (2001) Infections with Ehrlichia chaffeensis and Ehrlichia ewingii in persons coinfected with human immunodeficiency virus. Clinical Infectious Diseases 33, 1586-1594
6Breitschwerdt, E.B., Hegarty, B.C. and Hancock, S.I. (1998) Sequential evaluation of dogs naturally infected with Ehrlichia canis, Ehrlichia chaffeensis, Ehrlichia equi, Ehrlichia ewingii, or Bartonella vinsonii. Journal of Clinical Microbiology 36, 2645-2651
7Goldman, E.E. et al. (1998) Granulocytic ehrlichiosis in dogs from North Carolina and Virginia. Journal of Veterinary Internal Medicine 12, 61-70
8Perez, M. et al. (2006) Human infection with Ehrlichia canis accompanied by clinical signs in Venezuela. Annals of the New York Academy of Sciences 1078, 110-117
9Keefe, T.J. et al. (1982) Distribution of Ehrlichia canis among military working dogs in the world and selected civilian dogs in the United States. Journal of the American Veterinary Medical Association 181, 236-238
10Uilenberg, G. (1983) Heartwater (Cowdria ruminantium infection): current status. Advances in Veterinary Science and Comparative Medicine 27, 427-480
11Koh, Y.S. et al. (2010) MyD88-dependent signaling contributes to host defense against ehrlichial infection. PLoS One 5, e11758
12Barnewall, R.E., Rikihisa, Y. and Lee, E.H. (1997) Ehrlichia chaffeensis inclusions are early endosomes which selectively accumulate transferrin receptor. Infection and Immunity 65, 1455-1461
13Popov, V.L., Yu, X.J. and Walker, D.H. (2000) The 120-kDa outer membrane protein of Ehrlichia chaffeensis: preferential expression on dense-core cells and gene expression in Escherichia coli associated with attachment and entry. Microbial Pathogenesis 28, 71-80
14Doyle, C.K. et al. (2006) Differentially expressed and secreted major immunoreactive protein orthologs of Ehrlichia canis and E. chaffeensis elicit early antibody responses to epitopes on glycosylated tandem repeats. Infection and Immunity 74, 711-720
15Popov, V.L. et al. (1995) Ultrastructural variation of cultured Ehrlichia chaffeensis. Journal of Medical Microbiology 43, 411-421
16Zhang, J.Z. et al. (2007) The developmental cycle of Ehrlichia chaffeensis in vertebrate cells. Cellular Microbiology 9, 610-618
17Dunning Hotopp, J.C. et al. (2006) Comparative genomics of emerging human ehrlichiosis agents. PLoS Genetics 2, e21
18Mavromatis, K. et al. (2006) The genome of the obligately intracellular bacterium Ehrlichia canis reveals themes of complex membrane structure and immune evasion strategies. Journal of Bacteriology 188, 4015-4023
19Collins, N.E. et al. (2005) The genome of the heartwater agent Ehrlichia ruminantium contains multiple tandem repeats of actively variable copy number. Proceedings of the National Academy of Sciences of the United States of America 102, 838-843
20Frutos, R. et al. (2006) Comparative genomic analysis of three strains of Ehrlichia ruminantium reveals an active process of genome size plasticity. Journal of Bacteriology 188, 2533-2542
21Andersson, J.O. and Andersson, S.G. (1999) Insights into the evolutionary process of genome degradation. Current Opinion in Genetics and Development 9, 664-671
22Andersson, J.O. and Andersson, S.G. (1999) Genome degradation is an ongoing process in Rickettsia. Molecular Biology and Evolution 16, 1178-1191
23Andersson, S.G. et al. (1998) The genome sequence of Rickettsia prowazekii and the origin of mitochondria. Nature 396, 133-140
24Frutos, R. et al. (2007) Ehrlichia ruminantium: genomic and evolutionary features. Trends in Parasitology 23, 414-419
25Kumagai, Y. et al. (2010) Cyclic di-GMP signaling regulates invasion of Ehrlichia chaffeensis into human monocytes. Journal of Bacteriology 192, 4122-4133
26Jewett, T.J. et al. (2006) Chlamydial TARP is a bacterial nucleator of actin. Proceedings of the National Academy of Sciences of the United States of America 103, 15599-15604
27Gravekamp, C. et al. (1996) Variation in repeat number within the alpha C protein of group B streptococci alters antigenicity and protective epitopes. Infection and Immunity 64, 3576-3583
28Luo, T. et al. (2008) A variable-length PCR target protein of Ehrlichia chaffeensis contains major species-specific antibody epitopes in acidic serine-rich tandem repeats. Infection and Immunity 76, 1572-1580
29Luo, T., Zhang, X. and McBride, J.W. (2009) Major species-specific antibody epitopes of the Ehrlichia chaffeensis p120 and E. canis p140 orthologs in surface-exposed tandem repeat regions. Clinical and Vaccine Immunology 16, 982-990
30McBride, J.W. et al. (2007) Identification of a glycosylated Ehrlichia canis 19-kilodalton major immunoreactive protein with a species-specific serine-rich glycopeptide epitope. Infection and Immunity 75, 74-82
31Wakeel, A. et al. (2009) Investigation of Ehrlichia chaffeensis secreted tandem repeat and Ank proteins in a type IV secretion system model. Presented at the 23rd Meeting of the American Society for Rickettsiology, Hilton Head, SC, 10, August 15–18, 2009.
32Wakeel, A., Kuriakose, J.A. and McBride, J.W. (2009) An Ehrlichia chaffeensis tandem repeat protein interacts with multiple host targets involved in cell signaling, transcriptional regulation, and vesicle trafficking. Infection and Immunity 77, 1734-1745
33Wakeel, A., Zhang, X. and McBride, J.W. (2010) Mass spectrometric analysis of Ehrlichia chaffeensis tandem repeat proteins reveals evidence of phosphorylation and absence of glycosylation. PLoS One 5, e9552
34Zhu, B. and McBride, J.W. (2010) Ehrlichia chaffeensis tandem repeat protein binds GC-rich host DNA. Presented at the 110th Meeting of the American Society for Microbiology, San Diego, CA, B2524, May 23–27, 2010.
35Luo, T. et al. (2010) Molecular characterization of antibody epitopes of Ehrlichia chaffeensis ankyrin protein 200 and tandem repeat protein 47 and evaluation of synthetic immunodeterminants for serodiagnosis of human monocytotropic ehrlichiosis. Clinical and Vaccine Immunology 17, 87-97
36Nethery, K.A. et al. (2007) Ehrlichia canis gp200 contains dominant species-specific antibody epitopes in terminal acidic domains. Infection and Immunity 75, 4900-4908
37Lin, M. et al. (2007) Anaplasma phagocytophilum AnkA secreted by type IV secretion system is tyrosine phosphorylated by Abl-1 to facilitate infection. Cellular Microbiology 9, 2644-2657
38Mott, J., Barnewall, R.E. and Rikihisa, Y. (1999) Human granulocytic ehrlichiosis agent and Ehrlichia chaffeensis reside in different cytoplasmic compartments in HL-60 cells. Infection and Immunity 67, 1368-1378
39Webster, P. et al. (1998) The agent of human granulocytic ehrlichiosis resides in an endosomal compartment. Journal of Clinical Investigation 101, 1932-1941
40Barbet, A.F. et al. (2000) Antigenic variation of Anaplasma marginale by expression of MSP2 mosaics. Infection and Immunity 68, 6133-6138
41Barbet, A.F. et al. (2003) Expression of multiple outer membrane protein sequence variants from a single genomic locus of Anaplasma phagocytophilum. Infection and Immunity 71, 1706-1718
42Wang, X. et al. (2004) Rapid sequential changeover of expressed p44 genes during the acute phase of Anaplasma phagocytophilum infection in horses. Infection and Immunity 72, 6852-6859
43Alvarez-Martinez, C.E. and Christie, P.J. (2009) Biological diversity of prokaryotic type IV secretion systems. Microbiology and Molecular Biology Reviews 73, 775-808
44Ohashi, N., Rikihisa, Y. and Unver, A. (2001) Analysis of transcriptionally active gene clusters of major outer membrane protein multigene family in Ehrlichia canis and E. chaffeensis. Infection and Immunity 69, 2083-2091
45Unver, A. et al. (2002) The omp-1 major outer membrane multigene family of Ehrlichia chaffeensis is differentially expressed in canine and tick hosts. Infection and Immunity 70, 4701-4704
46Seo, G.M. et al. (2008) Total, membrane, and immunogenic proteomes of macrophage- and tick cell-derived Ehrlichia chaffeensis evaluated by liquid chromatography-tandem mass spectrometry and MALDI-TOF methods. Infection and Immunity 76, 4823-4832
47Unver, A. et al. (2001) Transcriptional analysis of p30 major outer membrane multigene family of Ehrlichia canis in dogs, ticks, and cell culture at different temperatures. Infection and Immunity 69, 6172-6178
48Zhang, J.Z. et al. (2004) Expression of members of the 28-kilodalton major outer membrane protein family of Ehrlichia chaffeensis during persistent infection. Infection and Immunity 72, 4336-4343
49Kumagai, Y., Huang, H. and Rikihisa, Y. (2008) Expression and porin activity of P28 and OMP-1F during intracellular Ehrlichia chaffeensis development. Journal of Bacteriology 190, 3597-3605
50de la Fuente, J. et al. (2004) Adhesion of outer membrane proteins containing tandem repeats of Anaplasma and Ehrlichia species (Rickettsiales: Anaplasmataceae) to tick cells. Veterinary Microbiology 98, 313-322
51Zhang, J.Z., McBride, J.W. and Yu, X.J. (2003) L-selectin and E-selectin expressed on monocytes mediating Ehrlichia chaffeensis attachment onto host cells. FEMS Microbiology Letters 227, 303-309
52Lin, M. and Rikihisa, Y. (2003) Obligatory intracellular parasitism by Ehrlichia chaffeensis and Anaplasma phagocytophilum involves caveolae and glycosylphosphatidylinositol-anchored proteins. Cellular Microbiology 5, 809-820
53Lin, M., Zhu, M.X. and Rikihisa, Y. (2002) Rapid activation of protein tyrosine kinase and phospholipase C-gamma2 and increase in cytosolic free calcium are required by Ehrlichia chaffeensis for internalization and growth in THP-1 cells. Infection and Immunity 70, 889-898
54Lin, M. and Rikihisa, Y. (2004) Ehrlichia chaffeensis downregulates surface Toll-like receptors 2/4, CD14 and transcription factors PU.1 and inhibits lipopolysaccharide activation of NF-kappa B, ERK 1/2 and p38 MAPK in host monocytes. Cellular Microbiology 6, 175-186
55Zhu, B. et al. (2009) Nuclear translocated Ehrlichia chaffeensis ankyrin protein interacts with the mid A-stretch of host promoter and intronic Alu elements. Infection and Immunity 77, 4243-4255
56Zhang, J.Z. et al. (2004) Survival strategy of obligately intracellular Ehrlichia chaffeensis: novel modulation of immune response and host cell cycles. Infection and Immunity 72, 498-507
57Alvarez-Dominguez, C. et al. (1996) Phagocytosed live Listeria monocytogenes influences Rab5-regulated in vitro phagosome-endosome fusion. Journal of Biological Chemistry 271, 13834-13843
58Barnewall, R.E., Ohashi, N. and Rikihisa, Y. (1999) Ehrlichia chaffeensis and E. sennetsu, but not the human granulocytic erhlichiosis agent, colocalize with transferrin receptor and up-regulate transferrin receptor mRNA by activating iron-responsive protein 1. Infection and Immunity 67, 2258-2265
59Barnewall, R.E. and Rikihisa, Y. (1994) Abrogation of gamma interferon-induced inhibition of Ehrlichia chaffeensis infection in human monocytes with iron-transferrin. Infection and Immunity 62, 4804-4810
60Doyle, C.K. et al. (2005) An immunoreactive 38-kilodalton protein of Ehrlichia canis shares tructural homology and iron-binding capacity with the ferric ion-binding protein family. Infection and Immunity 73, 62-69
61Lin, M. and Rikihisa, Y. (2003) Ehrlichia chaffeensis and Anaplasma phagocytophilum lack genes for lipid A biosynthesis and incorporate cholesterol for their survival. Infection and Immunity 71, 5324-5331
62Lin, M. and Rikihisa, Y. (2007) Degradation of p22phox and inhibition of superoxide generation by Ehrlichia chaffeensis in human monocytes. Cellular Microbiology 9, 861-874
63Xiong, Q. et al. (2008) Ehrlichia ewingii infection delays spontaneous neutrophil apoptosis through stabilization of mitochondria. Journal of Infectious Diseases 197, 1110-1118
64Kumagai, Y. et al. (2006) Biochemical activities of three pairs of Ehrlichia chaffeensis two-component regulatory system proteins involved in inhibition of lysosomal fusion. Infection and Immunity 74, 5014-5022
65Parkinson, J.S. and Kofoid, E.C. (1992) Communication modules in bacterial signaling proteins. Annual Review of Genetics 26, 71-112
66Cheng, Z. et al. (2006) Intra-leukocyte expression of two-component systems in Ehrlichia chaffeensis and Anaplasma phagocytophilum and effects of the histidine kinase inhibitor closantel. Cellular Microbiology 8, 1241-1252
67Collins, H.L. (2008) Withholding iron as a cellular defence mechanism – friend or foe? European Journal of Immunology 38, 1803-1806
68Collins, H.L. (2003) The role of iron in infections with intracellular bacteria. Immunology Letters 85, 193-195
69Schaible, U.E. and Kaufmann, S.H. (2004) Iron and microbial infection. Nature Reviews. Microbiology 2, 946-953
70Lee, E.H. and Rikihisa, Y. (1998) Protein kinase A-mediated inhibition of gamma interferon-induced tyrosine phosphorylation of Janus kinases and latent cytoplasmic transcription factors in human monocytes by Ehrlichia chaffeensis. Infection and Immunity 66, 2514-2520
71Wang, J.M., Lai, M.Z. and Yang-Yen, H.F. (2003) Interleukin-3 stimulation of mcl-1 gene transcription involves activation of the PU.1 transcription factor through a p38 mitogen-activated protein kinase-dependent pathway. Molecular and Cellular Biology 23, 1896-1909
72Wakeel, A. et al. (2010) New insights into molecular Ehrlichia chaffeensis-host interactions. Microbes and Infection 12, 337-345
73Herzog, S., Reth, M. and Jumaa, H. (2009) Regulation of B-cell proliferation and differentiation by pre-B-cell receptor signalling. Nature Reviews. Immunology 9, 195-205
74Lee, E.H. and Rikihisa, Y. (1998) Protein kinase A-mediated inhibition of gamma interferon-induced tyrosine phosphorylation of Janus kinases and latent cytoplasmic transcription factors in human monocytes by Ehrlichia chaffeensis. Infection and Immunity 66, 2514-2520
75Coyne, C.B. and Bergelson, J.M. (2006) Virus-induced Abl and Fyn kinase signals permit coxsackievirus entry through epithelial tight junctions. Cell 124, 119-131
76Doody, K.M., Bourdeau, A. and Tremblay, M.L. (2009) T-cell protein tyrosine phosphatase is a key regulator in immune cell signaling: lessons from the knockout mouse model and implications in human disease. Immunological Reviews 228, 325-341
77Stuible, M., Doody, K.M. and Tremblay, M.L. (2008) PTP1B and TC-PTP: regulators of transformation and tumorigenesis. Cancer Metastasis Reviews 27, 215-230
78Hubberstey, A.V. and Mottillo, E.P. (2002) Cyclase-associated proteins: CAPacity for linking signal transduction and actin polymerization. FASEB Journal 16, 487-499
79Kessels, M.M. et al. (2001) Mammalian Abp1, a signal-responsive F-actin-binding protein, links the actin cytoskeleton to endocytosis via the GTPase dynamin. Journal of Cell Biology 153, 351-366
80Wang, C. et al. (2008) Mitochondrial shuttling of CAP1 promotes actin- and cofilin-dependent apoptosis. Journal of Cell Science 121, 2913-2920
81Rikihisa, Y. and Lin, M. (2010) Anaplasma phagocytophilum and Ehrlichia chaffeensis type IV secretion and Ank proteins. Current Opinion in Microbiology 13, 59-66
82Tomilin, N.V. et al. (1992) Differential binding of human nuclear proteins to Alu subfamilies. Nucleic Acids Research 20, 2941-2945
83Matera, A.G., Hellmann, U. and Schmid, C.W. (1990) A transpositionally and transcriptionally competent Alu subfamily. Molecular and Cellular Biology 10, 5424-5432
84Polak, P. and Domany, E. (2006) Alu elements contain many binding sites for transcription factors and may play a role in regulation of developmental processes. BMC Genomics 7, 133
85Lee, E.H. and Rikihisa, Y. (1996) Absence of tumor necrosis factor alpha, interleukin-6 (IL-6), and granulocyte-macrophage colony-stimulating factor expression but presence of IL-1beta, IL-8, and IL-10 expression in human monocytes exposed to viable or killed Ehrlichia chaffeensis. Infection and Immunity 64, 4211-4219
86Lee, E.H. and Rikihisa, Y. (1997) Anti-Ehrlichia chaffeensis antibody complexed with E. chaffeensis induces potent proinflammatory cytokine mRNA expression in human monocytes through sustained reduction of IkappaB-alpha and activation of NF-kappaB. Infection and Immunity 65, 2890-2897
87Bitsaktsis, C. and Winslow, G. (2006) Fatal recall responses mediated by CD8 T cells during intracellular bacterial challenge infection. Journal of Immunology 177, 4644-4651
88Ismail, N. et al. (2004) Overproduction of TNF-alpha by CD8+ type 1 cells and down-regulation of IFN-gamma production by CD4+ Th1 cells contribute to toxic shock-like syndrome in an animal model of fatal monocytotropic ehrlichiosis. Journal of Immunology 172, 1786-1800
89Fichtenbaum, C.J., Peterson, L.R. and Weil, G.J. (1993) Ehrlichiosis presenting as a life-threatening illness with features of the toxic shock syndrome. American Journal of Medicine 95, 351-357
90Maeda, K. et al. (1987) Human infection with Ehrlichia canis, a leukocytic rickettsia. New England Journal of Medicine 316, 853-856
91Sotomayor, E. et al. (2001) Animal model of fatal human monocytotropic ehrlichiosis. American Journal of Pathology 158, 757-769
92Ismail, N. et al. (2007) Relative importance of T-cell subsets in monocytotropic ehrlichiosis: a novel effector mechanism involved in Ehrlichia-induced immunopathology in murine ehrlichiosis. Infection and Immunity 75, 4608-4620
93Ismail, N., Stevenson, H.L. and Walker, D.H. (2006) Role of tumor necrosis factor alpha (TNF-alpha) and interleukin-10 in the pathogenesis of severe murine monocytotropic ehrlichiosis: increased resistance of TNF receptor p55- and p75-deficient mice to fatal ehrlichial infection. Infection and Immunity 74, 1846-1856
94Thirumalapura, N.R. et al. (2008) Protective heterologous immunity against fatal ehrlichiosis and lack of protection following homologous challenge. Infection and Immunity 76, 1920-1930
95Stevenson, H.L. et al. (2008) Regulatory roles of CD1d-restricted NKT cells in the induction of toxic shock-like syndrome in an animal model of fatal ehrlichiosis. Infection and Immunity 76, 1434-1444
96Kuriakose, J.A. et al. (2010) Reduction of Ehrlichia chaffeensis burden by epitope specific TRP120 antibody. Presented at 24th Meeting of the American Society for Rickettsiology, Stevenson, WA, 11, July 31-August 3, 2010.
Rikihisa, Y. (2010) Molecular events involved in cellular invasion by Ehrlichia chaffeensis and Anaplasma phagocytophilum. Veterinary Parastiology 167, 155-166
Rikihisa, Y. (2010) Anaplasma phagocytophilum and Ehrlichia chaffeensis: subversive manipulators of host cells. Nature Reviews Microbiology 8, 328-339
Ganta, R.R. et al. (2009) Molecular characterization of Ehrlichia interactions with tick cells and macrophages. Frontiers in Bioscience 14, 3259-3273
McBride, J.W. and Walker, D.H. (2010) Progress and obstacles in vaccine development for the ehrlichioses. Expert Review of Vaccines 9, 1071-1082
Thomas, R.J., Dumler, J.S. and Carlyon, J.A. (2009) Current management of human granulocytic anaplasmosis, human monocytic ehrlichiosis and Ehrlichia ewingii ehrlichiosis. Expert Review of Anti-Infective Therapy 7, 709-722
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Expert Reviews in Molecular Medicine
  • ISSN: -
  • EISSN: 1462-3994
  • URL: /core/journals/expert-reviews-in-molecular-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed