Essential Domains of Invasins Utilized to Infect Mammalian Host Cells

English version České info

Anaplasma phagocytophilum causes the potentially deadly bacterial disease granulocytic anaplasmosis. The pathogen replicates inside white blood cells and, like all other obligate intracellular organisms, must enter host cells to survive. Multiple A. phagocytophilum surface proteins called invasins cooperatively orchestrate the entry process. Identifying these proteins’ domains that are required for function, and determining the molecular basis of their interaction with host cell receptors would significantly advance understanding of A. phagocytophilum pathogenesis. In this study, the binding domains of two A. phagocytophilum surface proteins, OmpA and Asp14, were identified. The specific OmpA residues that interact with its host cell receptor were also defined. An antibody cocktail generated against the binding domains of OmpA, Asp14, and a third invasin, AipA, blocked the ability of A. phagocytophilum to infect host cells. The data presented within suggest that binding domains of OmpA, Asp14, and AipA could be exploited to develop a vaccine for granulocytic anaplasmosis.

Vyšlo v časopise: Essential Domains of Invasins Utilized to Infect Mammalian Host Cells. PLoS Pathog 11(2): e32767. doi:10.1371/journal.ppat.1004669
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004669

Souhrn

Zdroje

1. 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.

2. CDC (2013) Notice to readers: final 2012 reports of nationally notifiable infectious diseases. MMWR Morb Mortal Wkly Rep 62: 669–682. 24133698

3. Hopkins RS, Jajosky RA, Hall PA, Adams DA, Connor FJ, et al. (2005) Summary of notifiable diseases—United States, 2003. MMWR Morb Mortal Wkly Rep 52: 1–85. 15889005

4. Hao Q, Geng Z, Hou XX, Tian Z, Yang XJ, et al. (2013) Seroepidemiological investigation of lyme disease and human granulocytic anaplasmosis among people living in forest areas of eight provinces in China. Biomed Environ Sci 26: 185–189. doi: 10.3967/0895-3988.2013.03.005 23425801

5. Zhang XC, Zhang LX, Li WH, Wang SW, Sun YL, et al. (2012) Ehrlichiosis and zoonotic anaplasmosis in suburban areas of Beijing, China. Vector Borne Zoonotic Dis 12: 932–937. doi: 10.1089/vbz.2012.0961 23025695

6. Zhang S, Hai R, Li W, Li G, Lin G, et al. (2009) Seroprevalence of human granulocytotropic anaplasmosis in central and southeastern China. Am J Trop Med Hyg 81: 293–295. 19635886

7. Aguero-Rosenfeld ME, Donnarumma L, Zentmaier L, Jacob J, Frey M, et al. (2002) Seroprevalence of antibodies that react with Anaplasma phagocytophila, the agent of human granulocytic ehrlichiosis, in different populations in Westchester County, New York. J Clin Microbiol 40: 2612–2615. 12089287

8. Bakken JS, Goellner P, Van Etten M, Boyle DZ, Swonger OL, et al. (1998) Seroprevalence of human granulocytic ehrlichiosis among permanent residents of northwestern Wisconsin. Clin Infect Dis 27: 1491–1496. 9868666

9. Alhumaidan H, Westley B, Esteva C, Berardi V, Young C, et al. (2013) Transfusion-transmitted anaplasmosis from leukoreduced red blood cells. Transfusion 53: 181–186. doi: 10.1111/j.1537-2995.2012.03685.x 22563784

10. Annen K, Friedman K, Eshoa C, Horowitz M, Gottschall J, et al. (2012) Two cases of transfusion-transmitted Anaplasma phagocytophilum. Am J Clin Pathol 137: 562–565. doi: 10.1309/AJCP4E4VQQQOZIAQ 22431531

11. CDC (2008) Anaplasma phagocytophilum transmitted through blood transfusion-Minnesota. MMWR Morb Mortal Wkly Rep 57: 1145–1148. 18946461

12. Dhand A, Nadelman RB, Aguero-Rosenfeld M, Haddad FA, Stokes DP, et al. (2007) Human granulocytic anaplasmosis during pregnancy: case series and literature review. Clin Infect Dis 45: 589–593. 17682993

13. Jereb M, Pecaver B, Tomazic J, Muzlovic I, Avsic-Zupanc T, et al. (2012) Severe human granulocytic anaplasmosis transmitted by blood transfusion. Emerg Infect Dis 18: 1354–1357. doi: 10.3201/eid1808.120180 22841007

14. Stuen S, Granquist EG, Silaghi C (2013) Anaplasma phagocytophilum—a widespread multi-host pathogen with highly adaptive strategies. Front Cell Infect Microbiol 3: 31. doi: 10.3389/fcimb.2013.00031 23885337

15. Bastidas RJ, Elwell CA, Engel JN, Valdivia RH (2013) Chlamydial intracellular survival strategies. Cold Spring Harb Perspect Med 3: a010256. doi: 10.1101/cshperspect.a010256 23637308

16. Minnick MF, Raghavan R (2012) Developmental biology of Coxiella burnetii. Adv Exp Med Biol 984: 231–248. doi: 10.1007/978-94-007-4315-1_12 22711635

17. Zhang JZ, Popov VL, Gao S, Walker DH, Yu XJ (2007) The developmental cycle of Ehrlichia chaffeensis in vertebrate cells. Cell Microbiol 9: 610–618. 16987329

18. 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. doi: 10.1128/IAI.00527-09 19596771

19. Ojogun N, Kahlon A, Ragland SA, Troese MJ, Mastronunzio JE, et al. (2012) Anaplasma phagocytophilum outer membrane protein A interacts with sialylated glycoproteins to promote infection of mammalian host cells. Infect Immun 80: 3748–3760. doi: 10.1128/IAI.00654-12 22907813

20. Sperandio M (2006) Selectins and glycosyltransferases in leukocyte rolling in vivo. FEBS J 273: 4377–4389. 16956372

21. Goodman JL, Nelson CM, Klein MB, Hayes SF, Weston BW (1999) Leukocyte infection by the granulocytic ehrlichiosis agent is linked to expression of a selectin ligand. J Clin Invest 103: 407–412. 9927502

22. Karakantza M, Gibson FM, Cavenagh JD, Ball SE, Gordon MY, et al. (1994) SLe(x) expression of normal CD34 positive bone marrow haemopoietic progenitor cells. Br J Haematol 86: 883–886. 7522525

23. Symington FW, Hedges DL, Hakomori S (1985) Glycolipid antigens of human polymorphonuclear neutrophils and the inducible HL-60 myeloid leukemia line. J Immunol 134: 2498–2506. 3855933

24. Fukuda M, Spooncer E, Oates JE, Dell A, Klock JC (1984) Structure of sialylated fucosyl lactosaminoglycan isolated from human granulocytes. J Biol Chem 259: 10925–10935. 6432790

25. Herron MJ, Nelson CM, Larson J, Snapp KR, Kansas GS, et al. (2000) Intracellular parasitism by the human granulocytic ehrlichiosis bacterium through the P-selectin ligand, PSGL-1. Science 288: 1653–1656. 10834846

26. Carlyon JA, Akkoyunlu M, Xia L, Yago T, Wang T, et al. (2003) Murine neutrophils require alpha1,3-fucosylation but not PSGL-1 for productive infection with Anaplasma phagocytophilum. Blood 102: 3387–3395. 12869507

27. Yago T, Leppanen A, Carlyon JA, Akkoyunlu M, Karmakar S, et al. (2003) Structurally distinct requirements for binding of P-selectin glycoprotein ligand-1 and sialyl Lewis x to Anaplasma phagocytophilum and P-selectin. J Biol Chem 278: 37987–37997. 12847092

28. Huang B, Ojogun N, Ragland SA, Carlyon JA (2012) Monoubiquitinated proteins decorate the Anaplasma phagocytophilum-occupied vacuolar membrane. FEMS Immunol Med Microbiol 64: 32–41. doi: 10.1111/j.1574-695X.2011.00873.x 22066989

29. Kahlon A, Ojogun N, Ragland SA, Seidman D, Troese MJ, et al. (2013) Anaplasma phagocytophilum Asp14 is an invasin that interacts with mammalian host cells via its C terminus to facilitate infection. Infect Immun 81: 65–79. doi: 10.1128/IAI.00932-12 23071137

30. Mastronunzio JE, Kurscheid S, Fikrig E (2012) Postgenomic analyses reveal development of infectious Anaplasma phagocytophilum during transmission from ticks to mice. J Bacteriol 194: 2238–2247. doi: 10.1128/JB.06791-11 22389475

31. Munderloh UG, Lynch MJ, Herron MJ, Palmer AT, Kurtti TJ, et al. (2004) Infection of endothelial cells with Anaplasma marginale and A. phagocytophilum. Vet Microbiol 101: 53–64. 15201033

32. Schaff UY, Trott KA, Chase S, Tam K, Johns JL, et al. (2010) Neutrophils exposed to A. phagocytophilum under shear stress fail to fully activate, polarize, and transmigrate across inflamed endothelium. Am J Physiol Cell Physiol 299: C87–96. doi: 10.1152/ajpcell.00165.2009 20392928

33. Sukumaran B, Mastronunzio JE, Narasimhan S, Fankhauser S, Uchil PD, et al. (2011) Anaplasma phagocytophilum AptA modulates Erk1/2 signalling. Cell Microbiol 13: 47–61. doi: 10.1111/j.1462-5822.2010.01516.x 20716207

34. Xiong Q, Rikihisa Y (2011) The prenylation inhibitor manumycin A reduces the viability of Anaplasma phagocytophilum. J Med Microbiol 60: 744–749. doi: 10.1099/jmm.0.029231-0 21349982

35. Ojogun N, Barnstein B, Huang B, Oskeritzian CA, Homeister JW, et al. (2011) Anaplasma phagocytophilum infects mast cells via alpha1,3-fucosylated but not sialylated glycans and inhibits IgE-mediated cytokine production and histamine release. Infect Immun 79: 2717–2726. doi: 10.1128/IAI.00181-11 21536789

36. Seidman D, Ojogun N, Walker NJ, Mastronunzio J, Kahlon A, et al. (2014) Anaplasma phagocytophilum surface protein AipA mediates invasion of mammalian host cells. Cell Microbiol 16: 1133–1145. doi: 10.1111/cmi.12286 24612118

37. Xia L, Ramachandran V, McDaniel JM, Nguyen KN, Cummings RD, et al. (2003) N-terminal residues in murine P-selectin glycoprotein ligand-1 required for binding to murine P-selectin. Blood 101: 552–559. 12393631

38. Kelley LA, Sternberg MJ (2009) Protein structure prediction on the Web: a case study using the Phyre server. Nat Protoc 4: 363–371. doi: 10.1038/nprot.2009.2 19247286

39. Baker NA, Sept D, Joseph S, Holst MJ, McCammon JA (2001) Electrostatics of nanosystems: application to microtubules and the ribosome. Proc Natl Acad Sci U S A 98: 10037–10041. 11517324

40. Chung MC, Wines BD, Baker H, Langley RJ, Baker EN, et al. (2007) The crystal structure of staphylococcal superantigen-like protein 11 in complex with sialyl Lewis X reveals the mechanism for cell binding and immune inhibition. Mol Microbiol 66: 1342–1355. 18045383

41. Hermans SJ, Baker HM, Sequeira RP, Langley RJ, Baker EN, et al. (2012) Structural and functional properties of staphylococcal superantigen-like protein 4. Infect Immun 80: 4004–4013. doi: 10.1128/IAI.00764-12 22949551

42. Dormitzer PR, Sun ZY, Wagner G, Harrison SC (2002) The rhesus rotavirus VP4 sialic acid binding domain has a galectin fold with a novel carbohydrate binding site. EMBO J 21: 885–897. 11867517

43. Stein PE, Boodhoo A, Armstrong GD, Heerze LD, Cockle SA, et al. (1994) Structure of a pertussis toxin-sugar complex as a model for receptor binding. Nat Struct Biol 1: 591–596. 7634099

44. Varghese JN, McKimm-Breschkin JL, Caldwell JB, Kortt AA, Colman PM (1992) The structure of the complex between influenza virus neuraminidase and sialic acid, the viral receptor. Proteins 14: 327–332. 1438172

45. Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31: 455–461. doi: 10.1002/jcc.21334 19499576

46. Somers WS, Tang J, Shaw GD, Camphausen RT (2000) Insights into the molecular basis of leukocyte tethering and rolling revealed by structures of P- and E-selectin bound to SLe(X) and PSGL-1. Cell 103: 467–479. 11081633

47. Kolbert CP, Bruinsma ES, Abdulkarim AS, Hofmeister EK, Tompkins RB, et al. (1997) Characterization of an immunoreactive protein from the agent of human granulocytic ehrlichiosis. J Clin Microbiol 35: 1172–1178. 9114402

48. Madigan JE, Gribble D (1987) Equine ehrlichiosis in northern California: 49 cases (1968–1981). J Am Vet Med Assoc 190: 445–448. 3558086

49. Gribble DH (1969) Equine ehrlichiosis. J Am Vet Med Assoc 155: 462–469. 5819585

50. Rikihisa Y, Zhi N, Wormser GP, Wen B, Horowitz HW, et al. (1997) Ultrastructural and antigenic characterization of a granulocytic ehrlichiosis agent directly isolated and stably cultivated from a patient in New York state. J Infect Dis 175: 210–213. 8985223

51. Massung RF, Levin ML, Munderloh UG, Silverman DJ, Lynch MJ, et al. (2007) Isolation and propagation of the Ap-Variant 1 strain of Anaplasma phagocytophilum in a tick cell line. J Clin Microbiol 45: 2138–2143. 17475757

52. Johnson RC, Kodner C, Jarnefeld J, Eck DK, Xu Y (2011) Agents of human anaplasmosis and Lyme disease at Camp Ripley, Minnesota. Vector Borne Zoonotic Dis 11: 1529–1534. doi: 10.1089/vbz.2011.0633 21867420

53. Al-Khedery B, Lundgren AM, Stuen S, Granquist EG, Munderloh UG, et al. (2012) Structure of the type IV secretion system in different strains of Anaplasma phagocytophilum. BMC Genomics 13: 678. doi: 10.1186/1471-2164-13-678 23190684

54. Goodman JL, Nelson C, Vitale B, Madigan JE, Dumler JS, et al. (1996) Direct cultivation of the causative agent of human granulocytic ehrlichiosis. N Engl J Med 334: 209–215. 8531996

55. Carlyon JA (2012) Establishing intracellular infection: modulation of host cell functions (Anaplasmataceae). In: Palmer GH, Azad A, editors. Intracellular Pathogens II: Rickettsiales. Washington, D. C.: ASM Press.

56. Mansueto P, Vitale G, Cascio A, Seidita A, Pepe I, et al. (2012) New insight into immunity and immunopathology of Rickettsial diseases. Clin Dev Immunol 2012: 967852. doi: 10.1155/2012/967852 21912565

57. Suarez CE, Noh S (2011) Emerging perspectives in the research of bovine babesiosis and anaplasmosis. Vet Parasitol 180: 109–125. doi: 10.1016/j.vetpar.2011.05.032 21684084

58. Anton BP, Raleigh EA (2004) Transposon-mediated linker insertion scanning mutagenesis of the Escherichia coli McrA endonuclease. J Bacteriol 186: 5699–5707. 15317774

59. Grande KK, Gustin JK, Kessler E, Ohman DE (2007) Identification of critical residues in the propeptide of LasA protease of Pseudomonas aeruginosa involved in the formation of a stable mature protease. J Bacteriol 189: 3960–3968. 17351039

60. Okoye ME, Sexton GL, Huang E, McCaffery JM, Desai P (2006) Functional analysis of the triplex proteins (VP19C and VP23) of herpes simplex virus type 1. J Virol 80: 929–940. 16378995

61. Yamashita K, Kochibe N, Ohkura T, Ueda I, Kobata A (1985) Fractionation of L-fucose-containing oligosaccharides on immobilized Aleuria aurantia lectin. J Biol Chem 260: 4688–4693. 3988732

62. Chandrasekaran EV, Chawda R, Rhodes JM, Locke RD, Piskorz CF, et al. (2003) The binding characteristics and utilization of Aleuria aurantia, Lens culinaris and few other lectins in the elucidation of fucosyltransferase activities resembling cloned FT VI and apparently unique to colon cancer cells. Carbohydr Res 338: 887–901. 12681913

63. Wang WC, Cummings RD (1988) The immobilized leukoagglutinin from the seeds of Maackia amurensis binds with high affinity to complex-type Asn-linked oligosaccharides containing terminal sialic acid-linked alpha-2,3 to penultimate galactose residues. J Biol Chem 263: 4576–4585. 3350806

64. Akahori T, Yuzawa Y, Nishikawa K, Tamatani T, Kannagi R, et al. (1997) Role of a sialyl Lewis(x)-like epitope selectively expressed on vascular endothelial cells in local skin inflammation of the rat. J Immunol 158: 5384–5392. 9164959

65. Izawa M, Kumamoto K, Mitsuoka C, Kanamori C, Kanamori A, et al. (2000) Expression of sialyl 6-sulfo Lewis X is inversely correlated with conventional sialyl Lewis X expression in human colorectal cancer. Cancer Res 60: 1410–1416. 10728707

66. Majuri ML, Rabina J, Niittymaki J, Tiisala S, Mattila P, et al. (1999) High endothelial cells synthesize and degrade sLex. Putative implications for L-selectin-dependent recognition. FEBS Lett 455: 97–100. 10428480

67. Mitsuoka C, Kawakami-Kimura N, Kasugai-Sawada M, Hiraiwa N, Toda K, et al. (1997) Sulfated sialyl Lewis X, the putative L-selectin ligand, detected on endothelial cells of high endothelial venules by a distinct set of anti-sialyl Lewis X antibodies. Biochem Biophys Res Commun 230: 546–551. 9015359

68. Mitsuoka C, Sawada-Kasugai M, Ando-Furui K, Izawa M, Nakanishi H, et al. (1998) Identification of a major carbohydrate capping group of the L-selectin ligand on high endothelial venules in human lymph nodes as 6-sulfo sialyl Lewis X. J Biol Chem 273: 11225–11233. 9556613

69. Renkonen R, Mattila P, Majuri ML, Rabina J, Toppila S, et al. (1997) In vitro experimental studies of sialyl Lewis x and sialyl Lewis a on endothelial and carcinoma cells: crucial glycans on selectin ligands. Glycoconj J 14: 593–600. 9298692

70. Sawada M, Takada A, Ohwaki I, Takahashi N, Tateno H, et al. (1993) Specific expression of a complex sialyl Lewis X antigen on high endothelial venules of human lymph nodes: possible candidate for L-selectin ligand. Biochem Biophys Res Commun 193: 337–347. 7684905

71. Paavonen T, Renkonen R (1992) Selective expression of sialyl-Lewis x and Lewis a epitopes, putative ligands for L-selectin, on peripheral lymph-node high endothelial venules. Am J Pathol 141: 1259–1264. 1281614

72. Majuri ML, Pinola M, Niemela R, Tiisala S, Natunen J, et al. (1994) Alpha 2,3-sialyl and alpha 1,3-fucosyltransferase-dependent synthesis of sialyl Lewis x, an essential oligosaccharide present on L-selectin counterreceptors, in cultured endothelial cells. Eur J Immunol 24: 3205–3210. 7528675

73. Munro JM, Lo SK, Corless C, Robertson MJ, Lee NC, et al. (1992) Expression of sialyl-Lewis X, an E-selectin ligand, in inflammation, immune processes, and lymphoid tissues. Am J Pathol 141: 1397–1408. 1281620

74. Ishibashi Y, Inouye Y, Okano T, Taniguchi A (2005) Regulation of sialyl-Lewis x epitope expression by TNF-alpha and EGF in an airway carcinoma cell line. Glycoconj J 22: 53–62. 15864435

75. Toppila S, Paavonen T, Laitinen A, Laitinen LA, Renkonen R (2000) Endothelial sulfated sialyl Lewis x glycans, putative L-selectin ligands, are preferentially expressed in bronchial asthma but not in other chronic inflammatory lung diseases. Am J Respir Cell Mol Biol 23: 492–498. 11017914

76. Turunen JP, Majuri ML, Seppo A, Tiisala S, Paavonen T, et al. (1995) De novo expression of endothelial sialyl Lewis(a) and sialyl Lewis(x) during cardiac transplant rejection: superior capacity of a tetravalent sialyl Lewis(x) oligosaccharide in inhibiting L-selectin-dependent lymphocyte adhesion. J Exp Med 182: 1133–1141. 7561686

77. Fukushima K, Hirota M, Terasaki PI, Wakisaka A, Togashi H, et al. (1984) Characterization of sialosylated Lewisx as a new tumor-associated antigen. Cancer Res 44: 5279–5285. 6386148

78. Dohi T, Nemoto T, Ohta S, Shitara K, Hanai N, et al. (1993) Different binding properties of three monoclonal antibodies to sialyl Le(x) glycolipids in a gastric cancer cell line and normal stomach tissue. Anticancer Res 13: 1277–1282. 8239497

79. Reneer DV, Kearns SA, Yago T, Sims J, Cummings RD, et al. (2006) Characterization of a sialic acid- and P-selectin glycoprotein ligand-1-independent adhesin activity in the granulocytotropic bacterium Anaplasma phagocytophilum. Cellular microbiology 8: 1972–1984. 16869829

80. Snapp KR, Ding H, Atkins K, Warnke R, Luscinskas FW, et al. (1998) A novel P-selectin glycoprotein ligand-1 monoclonal antibody recognizes an epitope within the tyrosine sulfate motif of human PSGL-1 and blocks recognition of both P- and L-selectin. Blood 91: 154–164. 9414280

81. Baker HM, Basu I, Chung MC, Caradoc-Davies T, Fraser JD, et al. (2007) Crystal structures of the staphylococcal toxin SSL5 in complex with sialyl Lewis X reveal a conserved binding site that shares common features with viral and bacterial sialic acid binding proteins. J Mol Biol 374: 1298–1308. 17996251

82. Morschhauser J, Hoschutzky H, Jann K, Hacker J (1990) Functional analysis of the sialic acid-binding adhesin SfaS of pathogenic Escherichia coli by site-specific mutagenesis. Infect Immun 58: 2133–2138. 2194961

83. Rademacher C, Bru T, McBride R, Robison E, Nycholat CM, et al. (2012) A Siglec-like sialic-acid-binding motif revealed in an adenovirus capsid protein. Glycobiology 22: 1086–1091. doi: 10.1093/glycob/cws073 22522600

84. McGarey DJ, Allred DR (1994) Characterization of hemagglutinating components on the Anaplasma marginale initial body surface and identification of possible adhesins. Infect Immun 62: 4587–4593. 7927725

85. Cheng Z, Miura K, Popov VL, Kumagai Y, Rikihisa Y (2011) Insights into the CtrA regulon in development of stress resistance in obligatory intracellular pathogen Ehrlichia chaffeensis. Mol Microbiol 82: 1217–1234. doi: 10.1111/j.1365-2958.2011.07885.x 22014113

86. Martinez E, Cantet F, Fava L, Norville I, Bonazzi M (2014) Identification of OmpA, a Coxiella burnetii Protein Involved in Host Cell Invasion, by Multi-Phenotypic High-Content Screening. PLoS Pathog 10: e1004013. doi: 10.1371/journal.ppat.1004013 24651569

87. de la Fuente J, Garcia-Garcia JC, Blouin EF, Kocan KM (2001) Differential adhesion of major surface proteins 1a and 1b of the ehrlichial cattle pathogen Anaplasma marginale to bovine erythrocytes and tick cells. Int J Parasitol 31: 145–153. 11239934

88. Mohan Kumar D, Yamaguchi M, Miura K, Lin M, Los M, 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. doi: 10.1371/journal.ppat.1003666 24098122

89. Popov VL, Yu X, Walker DH (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. Microb Pathog 28: 71–80. 10644493

90. Cardwell MM, Martinez JJ (2009) The Sca2 autotransporter protein from Rickettsia conorii is sufficient to mediate adherence to and invasion of cultured mammalian cells. Infect Immun 77: 5272–5280. doi: 10.1128/IAI.00201-09 19805531

91. Chan YG, Cardwell MM, Hermanas TM, Uchiyama T, Martinez JJ (2009) Rickettsial outer-membrane protein B (rOmpB) mediates bacterial invasion through Ku70 in an actin, c-Cbl, clathrin and caveolin 2-dependent manner. Cell Microbiol 11: 629–644. doi: 10.1111/j.1462-5822.2008.01279.x 19134120

92. Chan YG, Riley SP, Martinez JJ (2010) Adherence to and invasion of host cells by spotted Fever group rickettsia species. Front Microbiol 1: 139. doi: 10.3389/fmicb.2010.00139 21687751

93. Hillman RD Jr, Baktash YM, Martinez JJ (2013) OmpA-mediated rickettsial adherence to and invasion of human endothelial cells is dependent upon interaction with alpha2beta1 integrin. Cell Microbiol 15: 727–741. doi: 10.1111/cmi.12068 23145974

94. Riley SP, Goh KC, Hermanas TM, Cardwell MM, Chan YG, et al. (2010) The Rickettsia conorii autotransporter protein Sca1 promotes adherence to nonphagocytic mammalian cells. Infect Immun 78: 1895–1904. doi: 10.1128/IAI.01165-09 20176791

95. Kari L, Southern TR, Downey CJ, Watkins HS, Randall LB, et al. (2014) Chlamydia trachomatis Polymorphic Membrane Protein D Is a Virulence Factor Involved in Early Host-Cell Interactions. Infect Immun 82: 2756–2762. doi: 10.1128/IAI.01686-14 24733093

96. Wuppermann FN, Molleken K, Julien M, Jantos CA, Hegemann JH (2008) Chlamydia pneumoniae GroEL1 protein is cell surface associated and required for infection of HEp-2 cells. J Bacteriol 190: 3757–3767. doi: 10.1128/JB.01638-07 18310329

97. Moelleken K, Hegemann JH (2008) The Chlamydia outer membrane protein OmcB is required for adhesion and exhibits biovar-specific differences in glycosaminoglycan binding. Mol Microbiol 67: 403–419. 18086188

98. Ting LM, Hsia RC, Haidaris CG, Bavoil PM (1995) Interaction of outer envelope proteins of Chlamydia psittaci GPIC with the HeLa cell surface. Infect Immun 63: 3600–3608. 7642297

99. Su H, Watkins NG, Zhang YX, Caldwell HD (1990) Chlamydia trachomatis-host cell interactions: role of the chlamydial major outer membrane protein as an adhesin. Infect Immun 58: 1017–1025. 2318528

100. Shimoji Y, Ng V, Matsumura K, Fischetti VA, Rambukkana A (1999) A 21-kDa surface protein of Mycobacterium leprae binds peripheral nerve laminin-2 and mediates Schwann cell invasion. Proc Natl Acad Sci U S A 96: 9857–9862. 10449784

101. Govender VS, Ramsugit S, Pillay M (2014) Mycobacterium tuberculosis adhesins: potential biomarkers as anti-tuberculosis therapeutic and diagnostic targets. Microbiology.

102. Schorey JS, Li Q, McCourt DW, Bong-Mastek M, Clark-Curtiss JE, et al. (1995) A Mycobacterium leprae gene encoding a fibronectin binding protein is used for efficient invasion of epithelial cells and Schwann cells. Infect Immun 63: 2652–2657. 7790081

103. Ha NY, Cho NH, Kim YS, Choi MS, Kim IS (2011) An autotransporter protein from Orientia tsutsugamushi mediates adherence to nonphagocytic host cells. Infect Immun 79: 1718–1727. doi: 10.1128/IAI.01239-10 21282412

104. Lee JH, Cho NH, Kim SY, Bang SY, Chu H, et al. (2008) Fibronectin facilitates the invasion of Orientia tsutsugamushi into host cells through interaction with a 56-kDa type-specific antigen. J Infect Dis 198: 250–257. doi: 10.1086/589284 18500929

105. Li F, Wilkins PP, Crawley S, Weinstein J, Cummings RD, et al. (1996) Post-translational modifications of recombinant P-selectin glycoprotein ligand-1 required for binding to P- and E-selectin. The Journal of biological chemistry 271: 3255–3264. 8621728

106. Miller DP, McDowell JV, Bell JK, Marconi RT (2011) Crystallization of the factor H-binding protein, FhbB, from the periopathogen Treponema denticola. Acta Crystallogr Sect F Struct Biol Cryst Commun 67: 678–681. doi: 10.1107/S1744309111011298 21636910

107. O'Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, et al. (2011) Open Babel: An open chemical toolbox. J Cheminform 3: 33. doi: 10.1186/1758-2946-3-33 21982300

108. 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. 12471136

109. Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ (1990) Basic local alignment search tool. J Mol Biol 215: 403–410. 2231712

110. Dunning Hotopp JC, Lin M, Madupu R, Crabtree J, Angiuoli SV, et al. (2006) Comparative genomics of emerging human ehrlichiosis agents. PLoS Genet 2: e21. 16482227

111. Granquist EG, Bardsen K, Bergstrom K, Stuen S (2010) Variant -and individual dependent nature of persistent Anaplasma phagocytophilum infection. Acta Vet Scand 52: 25. doi: 10.1186/1751-0147-52-25 20398321

112. Thompson JD, Higgins DG, Gibson TJ (1994) CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 22: 4673–4680. 7984417