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The role of CD8 T lymphocytes in rickettsial infections

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Abstract

Arthropod-borne obligately intracellular bacteria pose a difficult challenge to the immune system. The genera Rickettsia, Orientia, Ehrlichia, and Anaplasma evolved mechanisms of immune evasion, and each interacts differently with the immune system. The roles of CD8 T cells include protective immunity and immunopathology. In Rickettsia infections, CD8 T cells are protective mediated in part by cytotoxicity toward infected cells. In contrast, TNF-α overproduction by CD8 T cells is pathogenic in lethal ehrlichiosis by induction of apoptosis/necrosis in hepatocytes. Yet, CD8 T cells, along with CD4 T cells and antibodies, also contribute to protective immunity in ehrlichial infections. In granulocytic anaplasmosis, CD8 T cells impact pathogen control modestly but could contribute to immunopathology by virtue of their dysfunction. While preliminary evidence indicates that CD8 T cells are important in protection against Orientia tsutsugamushi, mechanistic studies have been neglected. Valid animal models will enable experiments to elucidate protective and pathologic immune mechanisms. The public health need for vaccines against these agents of human disease, most clearly O. tsutsugamushi, and the veterinary diseases, canine monocytotropic ehrlichiosis (Ehrlichia canis), heartwater (Ehrlichia ruminantium), and bovine anaplasmosis (A. marginale), requires detailed immunity and immunopathology investigations, including the roles of CD8 T lymphocytes.

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References

  1. Yu X-J, Walker DH (2005) Family I. Rickettsiaceae. In: Garrity GM, Brenner DJ, Krieg NR, Staley JT (eds) Bergey’s Manual of Systematic Bacteriology, vol Volume Two: The Proteobacteria. vol Part C: The Alpha-, Beta-, Delta-, and Epsilonproteobacteria, Secondth edn. Springer, New York, pp 96–116

    Google Scholar 

  2. Dumler JS, Barbet AF, Bekker CP, Dasch GA, Palmer GH, Ray SC, Rikihisa Y, Rurangirwa FR (2001) Reorganization of genera in the families Rickettsiaceae and Anaplasmataceae in the order Rickettsiales: unification of some species of Ehrlichia with Anaplasma, Cowdria with Ehrlichia and Ehrlichia with Neorickettsia, descriptions of six new species combinations and designation of Ehrlichia equi and ‘HGE agent’ as subjective synonyms of Ehrlichia phagocytophila. Int J Syst Evol Microbiol 51:2145–2165

    Article  CAS  PubMed  Google Scholar 

  3. Walker DH, Ismail N (2008) Emerging and re-emerging rickettsioses: endothelial cell infection and early disease events. Nat Rev Microbiol 6:375–386

    Article  CAS  PubMed  Google Scholar 

  4. Herrero-Herrero JI, Walker DH, Ruiz-Beltran R (1987) Immunohistochemical evaluation of the cellular immune response to Rickettsia conorii in taches noires. J Infect Dis 155:802–805

    Article  CAS  PubMed  Google Scholar 

  5. Walker DH, Hudnall SD, Szaniawski WK, Feng H-M (1999) Monoclonal antibody-based immunohistochemical diagnosis of rickettsialpox: the macrophage is the principal target. Mod Pathol 12:529–533

    CAS  PubMed  Google Scholar 

  6. Jordan JM, Woods ME, Feng H-M, Soong L, Walker DH (2007) Rickettsiae-stimulated dendritic cells mediate protection against lethal rickettsial challenge in an animal model of spotted fever rickettsiosis. J Infect Dis 196:629–638

    Article  CAS  PubMed  Google Scholar 

  7. Fang R, Ismail N, Soong L, Popov VL, Whitworth T, Bouyer DH, Walker DH (2007) Differential interaction of dendritic cells with Rickettsia conorii: impact on host susceptibility to murine spotted fever rickettsiosis. Infect Immun 75:3112–3123

  8. Jordan JM, Woods ME, Soong L, Walker DH (2009) Rickettsiae stimulate dendritic cells through TLR4, leading to enhanced NK cell activation in vivo. J Infect Dis 199:236–242

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Feng H-M, Olano JP, Whitworth T, Popov VL, Walker DH (2004) Fc-dependent polyclonal antibodies and antibodies to outer membrane proteins A and B, but not to lipopolysaccharide, protect SCID mice against fatal Rickettsia conorii infection. Infect Immun 72:2222–2228

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Feng H-M, Walker DH (2000) Mechanisms of intracellular killing of Rickettsia conorii in infected human endothelial cells, hepatocytes, and macrophages. Infect Immun 68:6729–6736

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Walker DH, Olano JP, Feng H-M (2001) Critical role of cytotoxic T lymphocytes in immune clearance of rickettsial infection. Infect Immun 69:1841–1846

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Feng H-M, Popov VL, Yuoh G, Walker DH (1997) Role of T-lymphocyte subsets in immunity to spotted fever group rickettsiae. J Immunol 158:5314–5320

    CAS  PubMed  Google Scholar 

  13. Walker DH, Popov VL, Wen J, Feng H-M (1994) Rickettsia conorii infection of C3H/HeN mice. A model of endothelial-target rickettsiosis. Lab Investig 70:358–368

    CAS  PubMed  Google Scholar 

  14. Rollwagen FM, Bakun AJ, Dorsey CH, Dasch GA (1985) Mechanisms of immunity to infection with typhus rickettsiae: infected fibroblasts bear rickettsial antigens on their surfaces. Infect Immun 50:911–916

    PubMed Central  CAS  PubMed  Google Scholar 

  15. Gazi M, Caro-Gomez E, Goez Y, Cespedes MA, Hidalgo M, Correa P, Valbuena G (2013) Discovery of a protective Rickettsia prowazekii antigen recognized by CD8+ T cells, RP884, using an in vivo screening platform. PLoS ONE 8:e76253

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Cho N-H, Kim H-R, Lee J-H, Kim S-Y, Kim J, Cha S, Darby AC, Fuxelius H-H, Yin J, Kim JH, Kim J, Lee SJ, Koh Y-S, Jang W-J, Park K-H, Andersson SGE, Choi M-S, Kim I-S (2007) The Orientia tsutsugamushi genome reveals massive proliferation of conjugative type IV secretion system and host-cell interaction genes. Proc Natl Acad Sci 104:7981–7986

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Kim I-S, Walker DH (2011) Scrub typhus. In: Guerrant RL, Walker DH, Weller PF (eds) Tropical infectious diseases, principles, pathogens and practice, 3rd edn. Elsevier Saunders, London, pp 334–338

    Chapter  Google Scholar 

  18. Paris DH, Shelite TR, Day NP, Walker DH (2013) Unresolved problems related to scrub typhus: a seriously neglected life-threatening disease. Am J Trop Med Hyg 89:301–307

    Article  PubMed Central  PubMed  Google Scholar 

  19. Moron CG, Popov VL, Feng H-M, Wear D, Walker DH (2001) Identification of the target cells of Orientia tsutsugamushi in human cases of scrub typhus. Mod Pathol 14:752–759

    Article  CAS  PubMed  Google Scholar 

  20. Shirai A, Catanzaro PJ, Phillips SM, Osterman JV (1976) Host defenses in experimental scrub typhus: role of cellular immunity in heterologous protection. Infect Immun 14:39–46

    PubMed Central  CAS  PubMed  Google Scholar 

  21. Kodama K, Kawamura S, Yasukawa M, Kobayashi Y (1987) Establishment and characterization of a T-cell line specific for Rickettsia tsutsugamushi. Infect Immun 55:2490–2495

    PubMed Central  CAS  PubMed  Google Scholar 

  22. Soong L, Wang H, Shelite TR, Liang Y, Mendell NL, Sun J, Gong B, Valbuena GA, Bouyer DH, Walker DH (2014) Strong type 1, but impaired type 2, immune responses contribute to Orientia tsutsugamushi-induced pathology in mice. PLoS Negl Trop Dis 8:e3191

    Article  PubMed Central  PubMed  Google Scholar 

  23. McBride JW, Walker DH (2011) Molecular and cellular pathobiology of Ehrlichia infection: targets for new therapeutics and immunomodulation strategies. Expert Rev Mol Med 13:e3–e21

    Article  PubMed Central  PubMed  Google Scholar 

  24. Pritt BS, Sloan LM, Johnson DKH, Munderloh UG, Paskewitz SM, McElroy KM, McFadden JD, Binnicker MJ, Neitzel DF, Liu G, Nicholson WL, Nelson CM, Franson JJ, Martin SA, Cunningham SA, Steward CR, Bogumill K, Bjorgaard ME, David JP, McQuiston JH, Warshauer DM, Wilhelm MP, Patel R, Trivedi VA, Eremeeva ME (2011) Emergence of a new pathogenic Ehrlichia species, Wisconsin and Minnesota, 2009. New Engl J Med 365:422–429

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Zhang J-Z, Sinha M, Luxon BA, Yu X (2004) Survival strategy of obligately intracellular Ehrlichia chaffeensis: novel modulation of immune response and host cell cycles. Infect Immun 72:498–507

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Lee EH, 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. Infect Immun 66:2514–2619

    PubMed Central  CAS  PubMed  Google Scholar 

  27. Lin M, Rikihisa Y (2004) Ehrlichia chaffeensis downregulates surface toll-like receptors 2/4, CD14 and transcription factors PU.1 and inhibits lipopolysaccharide activation of NF-kB, ERK 1/2 and p38 MAPK in host monocytes. Cell Microbiol 6:175–186

    Article  CAS  PubMed  Google Scholar 

  28. Zhang J-Z, Popov VL, Gao S, Walker DH, Yu X-J (2007) The developmental cycle of Ehrlichia chaffeensis in vertebrate cells. Cell Microbiol 9:610–618

    Article  CAS  PubMed  Google Scholar 

  29. Olano JP, Wen G, Feng H-M, McBride JW, Walker DH (2004) Histologic, serologic, and molecular analysis of persistent ehrlichiosis in a murine model. Am J Pathol 165:997–1006

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Sotomayor E, Popov V, Feng H-M, Walker DH, Olano JP (2001) Animal model of fatal human monocytotropic ehrlichiosis. Am J Pathol 158:757–769

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Stevenson HL, Jordan JM, Peerwani Z, Wang H-Q, Walker DH, Ismail N (2006) An intradermal environment promotes a protective type-1 response against lethal systemic monocytotropic ehrlichial infection. Infect Immun 74:4856–4864

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Feng H-M, Walker DH (2004) Mechanisms of immunity to Erhlichia muris: a model of monocytotropic ehrlichiosis. Infect Immun 72:966–971

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. du Plessis JL, Berche P, Van Gas L (1991) T cell-mediated immunity to Cowdria ruminantium mice: the protective role of LYT-2+ T cells. Onderstepoort J Vet Res 58:171–179

  34. Ismail N, Soong L, McBride JW, Valbuena G, Olano JP, Feng H-M, Walker DH (2004) Overproduction of TNF-a by CD8+ type 1 cells and down-regulation of IFN-γ production by CD4+ Th1 cells contribute to toxic shock-like syndrome in an animal model of fatal monocytotropic ehrlichiosis. J Immunol 172:1786–1800

  35. Ismail N, Crossley EC, Stevenson HL, Walker DH (2007) Relative importance of T-cell subsets in monocytotropic ehrlichiosis: a novel effector mechanism involved in Ehrlichia-induced immunopathology in murine ehrlichiosis. Infect Immun 75:4608–4620

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Byrom B, Barbet AF, Obwolo M, Mahan SM (2000) CD8+ T cell knockout mice are less susceptible to Cowdria ruminantium infection than athymic, CD4+ T cell knockout, and normal C57BL/6 mice. Vet Parasitol 93:159–172

    Article  CAS  PubMed  Google Scholar 

  37. Ismail N, Stevenson HL, Walker DH (2006) Role of tumor necrosis factor 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. Infect Immun 74:1846–1856

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Dumler JS, Rikihisa Y, Dasch GA (2005) Genus I. Anaplasma. In: Garrity GM, Brenner DJ, Krieg NR, Staley JT (eds) Bergey’s manual of systematic bacteriology, volume 2. the Proteobacteria; Part C The Alpha-, Beta-, Delta-, and Epsilon proteobacteria, Secondth edn. Springer, East Lansing, pp 117–125

    Google Scholar 

  39. Dunning Hotopp JC, Lin M, Madupu R, Crabtree J, Angiuoli SV, Eisen J, Seshadri R, Ren Q, Wu M, Utterback TR, Smith S, Lewis M, Khouri H, Zhang C, Niu H, Lin Q, Ohashi N, Zhi N, Nelson W, Brinkac LM, Dodson RJ, Rosovitz MJ, Sundaram J, Daugherty SC, Davidsen T, Durkin AS, Gwinn M, Haft DH, Selengut JD, Sullivan SA, Zafar N, Zhou L, Benahmed F, Forberger H, Halpin R, Mulligan S, Robinson J, White O, Rikihisa Y, Tettelin H (2006) Comparative genomics of emerging human ehrlichiosis agents. PLoS Genet 2:e21

    Article  PubMed Central  PubMed  Google Scholar 

  40. Brayton KA, Kappmeyer LS, Herndon DR, Dark MJ, Tibbals DL, Palmer GH, McGuire TC, Knowles DP Jr (2005) Complete genome sequencing of Anaplasma marginale reveals that the surface is skewed to two superfamilies of outer membrane proteins. Proc Natl Acad Sci U S A 102:844–849

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. NCBI (2015) Genome information by organism. http://www.ncbi.nlm.nih.gov/genome/. Anaplasma (taxid:768) Prokaryotes [724]. February 27, 2015.

  42. Futse JE, Brayton KA, Knowles DP, Palmer GH (2005) Structural basis for segmental gene conversion in generation of Anaplasma marginale outer membrane protein variants. Mol Microbiol 57:212–221

    Article  CAS  PubMed  Google Scholar 

  43. Rejmanek D, Foley P, Barbet A, Foley J (2012) Antigen variability in Anaplasma phagocytophilum during chronic infection of a reservoir host. Microbiology 158:2632–2641

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Truchan HK, Seidman D, Carlyon JA (2013) Breaking in and grabbing a meal: Anaplasma phagocytophilum cellular invasion, nutrient acquisition, and promising tools for their study. Microbes Infect Inst Pasteur 15:1017–1025

    Article  CAS  Google Scholar 

  45. Huang B, Troese MJ, Howe D, Ye S, Sims JT, Heinzen RA, Borjesson DL, Carlyon JA (2010) Anaplasma phagocytophilum APH_0032 is expressed late during infection and localizes to the pathogen-occupied vacuolar membrane. Microb Pathog 49:273–284

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Huang B, Hubber A, McDonough JA, Roy CR, Scidmore MA, Carlyon JA (2010) The Anaplasma phagocytophilum-occupied vacuole selectively recruits Rab-GTPases that are predominantly associated with recycling endosomes. Cell Microbiol 12:1292–1307

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Niu H, Rikihisa Y (2013) Ats-1: a novel bacterial molecule that links autophagy to bacterial nutrition. Autophagy 9:787–788

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Niu H, Kozjak-Pavlovic V, Rudel T, Rikihisa Y (2010) Anaplasma phagocytophilum Ats-1 is imported into host cell mitochondria and interferes with apoptosis induction. PLoS Pathog 6:e1000774

    Article  PubMed Central  PubMed  Google Scholar 

  49. Lin M, den Dulk-Ras A, Hooykaas PJ, Rikihisa Y (2007) Anaplasma phagocytophilum AnkA secreted by type IV secretion system is tyrosine phosphorylated by Abl-1 to facilitate infection. Cell Microbiol 9:2644–2657

    Article  CAS  PubMed  Google Scholar 

  50. Caturegli P, Asanovich KM, Walls JJ, Bakken JS, Madigan JE, Popov VL, Dumler JS (2000) ankA: an Ehrlichia phagocytophila group gene encoding a cytoplasmic protein antigen with ankyrin repeats. Infect Immun 68:5277–5283

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Park J, Kim KJ, Choi KS, Grab DJ, Dumler JS (2004) Anaplasma phagocytophilum AnkA binds to granulocyte DNA and nuclear proteins. Cell Microbiol 6:743–751

    Article  CAS  PubMed  Google Scholar 

  52. Sinclair SHG, Garcia-Garcia JC, Dumler JS (2015) Bioinformatic and mass spectrometry identification of Anaplasma phagocytophilum proteins translocated into host cell nuclei. Front Microbiol 6:55

    Article  PubMed Central  PubMed  Google Scholar 

  53. Garcia-Garcia JC, Barat NC, Trembley SJ, Dumler JS (2009) Epigenetic silencing of host cell defense genes enhances intracellular survival of the rickettsial pathogen Anaplasma phagocytophilum. PLoS Pathog 5:e1000488

    Article  PubMed Central  PubMed  Google Scholar 

  54. Garcia-Garcia JC, Rennoll-Bankert KE, Pelly S, Milstone AM, Dumler JS (2009) Silencing of host cell CYBB gene expression by the nuclear effector AnkA of the intracellular pathogen Anaplasma phagocytophilum. Infect Immun 77:2385–2391

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Rennoll-Bankert KE, Sinclair SH, Lichay MA, Dumler JS (2014) Comparison and characterization of granulocyte cell models for Anaplasma phagocytophilum infection. Pathog Dis 71:55–64

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  56. Sinclair SH, Rennoll-Bankert KE, Dumler JS (2014) Effector bottleneck: microbial reprogramming of parasitized host cell transcription by epigenetic remodeling of chromatin structure. Front Genet 5:274

    Article  PubMed Central  PubMed  Google Scholar 

  57. Borjesson DL, Kobayashi SD, Whitney AR, Voyich JM, Argue CM, Deleo FR (2005) Insights into pathogen immune evasion mechanisms: Anaplasma phagocytophilum fails to induce an apoptosis differentiation program in human neutrophils. J Immunol 174:6364–6372

    Article  CAS  PubMed  Google Scholar 

  58. Dumler JS, Trigiani ER, Bakken JS, Aguero-Rosenfeld ME, Wormser GP (2000) Serum cytokine responses during acute human granulocytic ehrlichiosis. Clin Diagn Lab Immunol 7:6–8

    PubMed Central  CAS  PubMed  Google Scholar 

  59. Scorpio DG, Akkoyunlu M, Fikrig E, Dumler JS (2004) CXCR2 blockade influences Anaplasma phagocytophilum propagation but not histopathology in the mouse model of human granulocytic anaplasmosis. Clin Diagn Lab Immunol 11:963–968

    PubMed Central  CAS  PubMed  Google Scholar 

  60. Akkoyunlu M, Malawista SE, Anguita J, Fikrig E (2001) Exploitation of interleukin-8-induced neutrophil chemotaxis by the agent of human granulocytic ehrlichiosis. Infect Immun 69:5577–5588

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Ge Y, Rikihisa Y (2006) Anaplasma phagocytophilum delays spontaneous human neutrophil apoptosis by modulation of multiple apoptotic pathways. Cell Microbiol 8:1406–1416

    Article  CAS  PubMed  Google Scholar 

  62. Choi KS, Park JT, Dumler JS (2005) Anaplasma phagocytophilum delay of neutrophil apoptosis through the p38 mitogen-activated protein kinase signal pathway. Infect Immun 73:8209–8218

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  63. Lee HC, Goodman JL (2006) Anaplasma phagocytophilum causes global induction of antiapoptosis in human neutrophils. Genomics 88:496–503

    Article  CAS  PubMed  Google Scholar 

  64. Ramabu SS, Schneider DA, Brayton KA, Ueti MW, Graça T, Futse JE, Noh SM, Baszler TV, Palmer GH (2011) Expression of Anaplasma marginale ankyrin repeat-containing proteins during infection of the mammalian host and tick vector. Infect Immun 79:2847–2855

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Troese MJ, Kahlon A, Ragland SA, Ottens AK, Ojogun N, Nelson KT, Walker NJ, Borjesson DL, Carlyon JA (2011) Proteomic analysis of Anaplasma phagocytophilum during infection of human myeloid cells identifies a protein that is pronouncedly upregulated on the infectious dense-cored cell. Infect Immun 79:4696–4707

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  66. Troese MJ, Carlyon JA (2009) Anaplasma phagocytophilum dense-cored organisms mediate cellular adherence through recognition of human P-selectin glycoprotein ligand 1. Infect Immun 77:4018–4027

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  67. Dumler JS (2012) The biological basis of severe outcomes in Anaplasma phagocytophilum infection. FEMS Immunol Med Microbiol 64:13–20

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  68. Bakken JS, Dumler S (2008) Human granulocytic anaplasmosis. Infectious Disease Clinics of North America 22:433–448, viii

  69. Dumler JS, Barat NC, Barat CE, Bakken JS (2007) Human granulocytic anaplasmosis and macrophage activation. Clin Infect Dis 45:199–204

    Article  CAS  PubMed  Google Scholar 

  70. Kocan KM, de la Fuente J, Blouin EF, Coetzee JF, Ewing SA (2010) The natural history of Anaplasma marginale. Vet Parasitol 167:95–107

    Article  CAS  PubMed  Google Scholar 

  71. Martin ME, Bunnell JE, Dumler JS (2000) Pathology, immunohistology, and cytokine responses in early phases of human granulocytic ehrlichiosis in a murine model. J Infect Dis 181:374–378

    Article  CAS  PubMed  Google Scholar 

  72. Niu H, Rikihisa Y (2014) Investigating interference with apoptosis induction by bacterial proteins. Methods Mol Biol 1197:169–184

    Article  CAS  PubMed  Google Scholar 

  73. Ge Y, Yoshiie K, Kuribayashi F, Lin M, Rikihisa Y (2005) Anaplasma phagocytophilum inhibits human neutrophil apoptosis via upregulation of bfl-1, maintenance of mitochondrial membrane potential and prevention of caspase 3 activation. Cell Microbiol 7:29–38

    Article  CAS  PubMed  Google Scholar 

  74. Banerjee R, Anguita J, Roos D, Fikrig E (2000) Cutting edge: infection by the agent of human granulocytic ehrlichiosis prevents the respiratory burst by down-regulating gp91phox. J Immunol 164:3946–3949

    Article  CAS  PubMed  Google Scholar 

  75. Carlyon JA, Chan WT, Galan J, Roos D, Fikrig E (2002) Repression of rac2 mRNA expression by Anaplasma phagocytophila is essential to the inhibition of superoxide production and bacterial proliferation. J Immunol 169:7009–7018

    Article  CAS  PubMed  Google Scholar 

  76. Bunnell JE, Trigiani ER, Srinivas SR, Dumler JS (1999) Development and distribution of pathologic lesions are related to immune status and tissue deposition of human granulocytic ehrlichiosis agent-infected cells in a murine model system. J Infect Dis 180:546–550

    Article  CAS  PubMed  Google Scholar 

  77. Birkner K, Steiner B, Rinkler C, Kern Y, Aichele P, Bogdan C, von Loewenich FD (2008) The elimination of Anaplasma phagocytophilum requires CD4+ T cells, but is independent of Th1 cytokines and a wide spectrum of effector mechanisms. Eur J Immunol 38:3395–3410

  78. Martin ME, Caspersen K, Dumler JS (2001) Immunopathology and ehrlichial propagation are regulated by interferon-gamma and interleukin-10 in a murine model of human granulocytic ehrlichiosis. Am J Pathol 158:1881–1888

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  79. Scorpio DG, von Loewenich FD, Gobel H, Bogdan C, Dumler JS (2006) Innate immune response to Anaplasma phagocytophilum contributes to hepatic injury. Clin Vaccine Immunol 13:806–809

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  80. Akkoyunlu M, Fikrig E (2000) Gamma interferon dominates the murine cytokine response to the agent of human granulocytic ehrlichiosis and helps to control the degree of early rickettsemia. Infect Immun 68:1827–1833

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  81. von Loewenich FD, Scorpio DG, Reischl U, Dumler JS, Bogdan C (2004) Frontline: control of Anaplasma phagocytophilum, an obligate intracellular pathogen, in the absence of inducible nitric oxide synthase, phagocyte NADPH oxidase, tumor necrosis factor, Toll-like receptor (TLR)2 and TLR4, or the TLR adaptor molecule MyD88. Eur J Immunol 34:1789–1797

    Article  Google Scholar 

  82. Choi KS, Webb T, Oelke M, Scorpio DG, Dumler JS (2007) Differential innate immune cell activation and proinflammatory response in Anaplasma phagocytophilum infection. Infect Immun 75:3124–3130

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  83. Sun W, Ijdo JW, Telford SR 3rd, Hodzic E, Zhang Y, Barthold SW, Fikrig E (1997) Immunization against the agent of human granulocytic ehrlichiosis in a murine model. J Clin Invest 100:3014–3018

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  84. Menasche G, Feldmann J, Fischer A, de Saint BG (2005) Primary hemophagocytic syndromes point to a direct link between lymphocyte cytotoxicity and homeostasis. Immunol Rev 203:165–179

    Article  CAS  PubMed  Google Scholar 

  85. Janka G, zur Stadt U (2005) Familial and acquired hemophagocytic lymphohistiocytosis. Hematology 2005:82–88

    Article  Google Scholar 

  86. Larroche C, Mouthon L (2004) Pathogenesis of hemophagocytic syndrome (HPS). Autoimmun Rev 3:69–75

    Article  CAS  PubMed  Google Scholar 

  87. Grom AA (2004) Natural killer cell dysfunction: a common pathway in systemic-onset juvenile rheumatoid arthritis, macrophage activation syndrome, and hemophagocytic lymphohistiocytosis? Arthritis Rheum 50:689–698

    Article  PubMed  Google Scholar 

  88. Fisman DN (2000) Hemophagocytic syndromes and infection. Emerg Infect Dis 6:601–608

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  89. Davies RS, Madigan JE, Hodzic E, Borjesson DL, Dumler JS (2011) Dexamethasone-induced cytokine changes associated with diminished disease severity in horses infected with Anaplasma phagocytophilum. Clin Vaccine Immunol 18:1962–1968

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  90. Janka GE, Lehmberg K (2013) Hemophagocytic lymphohistiocytosis: pathogenesis and treatment. ASH Educ Program Book 2013:605–611

    Google Scholar 

  91. Janka GE, Lehmberg K (2014) Hemophagocytic syndromes—an update. Blood Rev 28:135–142

    Article  PubMed  Google Scholar 

  92. Zhang K, Jordan MB, Marsh RA, Johnson JA, Kissell D, Meller J, Villanueva J, Risma KA, Wei Q, Klein PS, Filipovich AH (2011) Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. Blood 118:5794–5798

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  93. Weil AA, Baron EL, Brown CM, Drapkin MS (2012) Clinical findings and diagnosis in human granulocytic anaplasmosis: a case series from Massachusetts. Mayo Clin Proc 87:233–239

    Article  PubMed Central  PubMed  Google Scholar 

  94. Brown WC, Palmer GH, Brayton KA, Meeus PF, Barbet AF, Kegerreis KA, McGuire TC (2004) CD4+ T lymphocytes from Anaplasma marginale major surface protein 2 (MSP2) vaccinees recognize naturally processed epitopes conserved in MSP3. Infect Immun 72:3688–3692

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  95. Brown WC, Palmer GH, Lewin HA, McGuire TC (2001) CD4(+) T lymphocytes from calves immunized with Anaplasma marginale major surface protein 1 (MSP1), a heteromeric complex of MSP1a and MSP1b, preferentially recognize the MSP1a carboxyl terminus that is conserved among strains. Infect Immun 69:6853–6862

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  96. Brown WC, Zhu D, Shkap V, McGuire TC, Blouin EF, Kocan KM, Palmer GH (1998) The repertoire of Anaplasma marginale antigens recognized by CD4(+) T-lymphocyte clones from protectively immunized cattle is diverse and includes major surface protein 2 (MSP-2) and MSP-3. Infect Immun 66:5414–5422

    PubMed Central  CAS  PubMed  Google Scholar 

  97. Han S, Norimine J, Brayton KA, Palmer GH, Scoles GA, Brown WC (2010) Anaplasma marginale infection with persistent high-load bacteremia induces a dysfunctional memory CD4+ T lymphocyte response but sustained high IgG titers. Clin Vaccine Immunol 17:1881–1890

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  98. Palmer GH, Eid G, Barbet AF, McGuire TC, McElwain TF (1994) The immunoprotective Anaplasma marginale major surface protein 2 is encoded by a polymorphic multigene family. Infect Immun 62:3808–3816

    PubMed Central  CAS  PubMed  Google Scholar 

  99. Abbott JR, Palmer GH, Kegerreis KA, Hetrick PF, Howard CJ, Hope JC, Brown WC (2005) Rapid and long-term disappearance of CD4+ T lymphocyte responses specific for Anaplasma marginale major surface protein-2 (MSP2) in MSP2 vaccinates following challenge with live A. marginale. J Immunol 174:6702–6715

    Article  CAS  PubMed  Google Scholar 

  100. Brown WC (2012) Adaptive immunity to Anaplasma pathogens and immune dysregulation: implications for bacterial persistence. Comp Immunol Microbiol Infect Dis 35:241–252

    Article  PubMed Central  PubMed  Google Scholar 

  101. Dierberg KL, Dumler JS (2006) Lymph node hemophagocytosis in rickettsial diseases: a pathogenetic role for CD8 T lymphocytes in human monocytic ehrlichiosis (HME)? BMC Infect Dis 6:121

    Article  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

DHW was supported in part by grants R01 AI021242, R21 AI102304, and U54 AI057156 from the National Institute of Allergy and Infectious Diseases. JSD support was provided in part by grants R01-AI044102 and R21-AI096062 from the National Institutes of Allergy and Infectious Diseases.

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Correspondence to David H. Walker.

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This article is a contribution to the Special Issue on : CD8+ T-cell Responses against Non-Viral Pathogens - Guest Editors: Fidel Zavala and Imtiaz A. Khan

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Walker, D.H., Dumler, J.S. The role of CD8 T lymphocytes in rickettsial infections. Semin Immunopathol 37, 289–299 (2015). https://doi.org/10.1007/s00281-015-0480-x

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  • DOI: https://doi.org/10.1007/s00281-015-0480-x

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