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Coxiella burnetii: Hiding in Plain Sight

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Defense Against Biological Attacks

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Abstract

The intracellular bacterial pathogen Coxiella burnetii causes the zoonotic disease Q fever. Due to the combined traits of a very low infectious dose, significant environmental resistance, and the debilitating consequences of infection, this pathogen is considered source material for a potential biological weapon. Q fever has non-specific clinical presentation and can include both acute and life-threatening chronic sequelae. A recent outbreak of Q fever in the Netherlands, propagated by widespread infection of farmed goats, has highlighted that C. burnetii represents an important biological threat to public health but can also have a significant economic and environmental impact on agricultural industry. C. burnetii is an intravacuolar pathogen that replicates to extremely high numbers within a membrane-bound compartment termed the Coxiella-containing vacuole (CCV). Recent studies into the metabolic requirements of C. burnetii allowed researchers to develop an axenic culture media to propagate C. burnetii in a cell-free system. This advance has revolutionized research into this neglected pathogen, paving the way for application of genetic manipulation and mutagenesis studies to identify the key virulence factors of C. burnetii. Central to the capacity of C. burnetii to replicate inside eukaryotic cells, and cause disease, is the Dot/Icm type IV secretion system. This protein translocation apparatus enables C. burnetii to introduce over 140 virulence proteins, termed effectors, into the host cell. The collective action of these effectors remodels the host to maintain viability and support intracellular replication of C. burnetii. Future functional characterization of these important effectors will facilitate understanding of how C. burnetii causes disease and may aid development of novel therapeutic and preventative actions that will minimize the impact of both natural and deliberate Q fever outbreaks.

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References

  1. Derrick EH. “Q” Fever, a new fever entity: clinical features, diagnosis and laboratory investigation. Med J Aust. 1937;2(8):281–99.

    Google Scholar 

  2. Burnet FM, Freeman M. Experimental studies on the virus of “Q” fever. Med J Aust. 1937;2:299–305.

    Google Scholar 

  3. Davis GE, Cox HR. A filter-passing infectious agent isolated from ticks. I. Isolation from Dermacentor andersoni, reactions in animals, and filtration experiments. Public Health Rep. 1938;53(52):2259–76.

    Article  Google Scholar 

  4. Dyer RE. Filter-passing infectious agent isolated from ticks. Human infection. Public Health Rep. 1938;53:2277–82.

    Google Scholar 

  5. Dyer RE. Similarity of Australian ‘Q’ fever and a disease caused by an infectious agent isolated from ticks in Montana. Public Health Rep. 1939;54:1229–37.

    Article  Google Scholar 

  6. Philip CB. Comments on the name of the Q Fever organism. Public Health Rep. 1948;63(2):58.

    Article  Google Scholar 

  7. Weisburg WG, Dobson ME, Samuel JE, Dasch GA, Mallavia LP, Baca O, Mandelco L, Sechrest JE, Weiss E, Woese CR. Phylogenetic diversity of the Rickettsiae. J Bacteriol. 1989;171(8):4202–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Fang R, Blanton LS, Walker DH. Rickettsiae as emerging infectious agents. Clin Lab Med. 2017;37(2):383–400. https://doi.org/10.1016/j.cll.2017.01.009.

    Article  PubMed  Google Scholar 

  9. Coleman SA, Fischer ER, Cockrell DC, Voth DE, Howe D, Mead DJ, Samuel JE, Heinzen RA. Proteome and antigen profiling of Coxiella burnetii developmental forms. Infect Immun. 2007;75(1):290–8. https://doi.org/10.1128/IAI.00883-06.

    Article  CAS  PubMed  Google Scholar 

  10. Coleman SA, Fischer ER, Howe D, Mead DJ, Heinzen RA. Temporal analysis of Coxiella burnetii morphological differentiation. J Bacteriol. 2004;186(21):7344–52. https://doi.org/10.1128/JB.186.21.7344-7352.2004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Eldin C, Melenotte C, Mediannikov O, Ghigo E, Million M, Edouard S, Mege JL, Maurin M, Raoult D. From Q fever to Coxiella burnetii infection: a paradigm change. Clin Microbiol Rev. 2017;30(1):115–90. https://doi.org/10.1128/cmr.00045-16.

    Article  PubMed  Google Scholar 

  12. CDC|Bioterrorism Agents/Diseases (by category)|Emergency Preparedness & Response, 2017. https://emergency.cdc.gov/agent/agentlist-category.asp

  13. Rotz LD, Khan AS, Lillibridge SR, Ostroff SM, Hughes JM. Public health assessment of potential biological terrorism agents. Emerg Infect Dis. 2002;8(2):225–30. https://doi.org/10.3201/eid0802.010164.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Federal Select Agent Program – Select Agents and Toxins List, 2018. https://www.selectagents.gov/selectagentsandtoxinslist.html

  15. NIAID Emerging Infectious Diseases/Pathogens|NIH: National Institute of Allergy and Infectious Diseases, 2018. https://www.niaid.nih.gov/research/emerging-infectious-diseases-pathogens.

  16. Madariaga MG, Rezai K, Trenholme GM, Weinstein RA. Q fever: a biological weapon in your backyard. Lancet Infect Dis. 2003;3(11):709–21.

    Article  PubMed  Google Scholar 

  17. Leitenberg M, Zilinskas RA, with Kuhn JH. The Soviet biological wepons program – a history. Cambridge, MA: Harvard University Press; 2012. https://doi.org/10.4159/harvard.9780674065260.

    Book  Google Scholar 

  18. Pittman PR, Norris SL, Coonan KM, KT MK Jr. An assessment of health status among medical research volunteers who served in the Project Whitecoat program at Fort Detrick, Maryland. Mil Med. 2005;170(3):183–7.

    Article  PubMed  Google Scholar 

  19. Tigertt WD, Benenson AS, Gochenour WS. Airborne Q fever. Bacteriol Rev. 1961;25:285–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Oyston PC, Davies C. Q fever: the neglected biothreat agent. J Med Microbiol. 2011;60(Pt 1):9–21. https://doi.org/10.1099/jmm.0.024778-0.

    Article  CAS  PubMed  Google Scholar 

  21. Olson KB. Aum Shinrikyo: once and future threat? Emerg Infect Dis. 1999;5(4):413–6.

    Article  Google Scholar 

  22. Maurin M, Raoult D. Q fever. Clin Microbiol Rev. 1999;12(4):518–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Amano K, Williams JC. Chemical and immunological characterization of lipopolysaccharides from phase I and phase II Coxiella burnetii. J Bacteriol. 1984;160(3):994–1002.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Kersh GJ, Oliver LD, Self JS, Fitzpatrick KA, Massung RF. Virulence of pathogenic Coxiella burnetii strains after growth in the absence of host cells. Vector Borne Zoonotic Dis. 2011;11(11):1433–8. https://doi.org/10.1089/vbz.2011.0670.

    Article  PubMed  Google Scholar 

  25. Denison AM, Massung RF, Thompson HA. Analysis of the O-antigen biosynthesis regions of phase II isolates of Coxiella burnetii. FEMS Microbiol Lett. 2007;267(1):102–7. https://doi.org/10.1111/j.1574-6968.2006.00544.x.

    Article  CAS  PubMed  Google Scholar 

  26. Ftacek P, Skultety L, Toman R. Phase variation of Coxiella burnetii strain Priscilla: influence of this phenomenon on biochemical features of its lipopolysaccharide. J Endotoxin Res. 2000;6(5):369–76.

    Article  CAS  PubMed  Google Scholar 

  27. Toman R, Skultety L. Structural study on a lipopolysaccharide from Coxiella burnetii strain Nine Mile in avirulent phase II. Carbohydr Res. 1996;283:175–85.

    Article  CAS  PubMed  Google Scholar 

  28. Hackstadt T. Biosafety concerns and Coxiella burnetii. Trends Microbiol. 1996;4(9):341–2.

    Article  CAS  PubMed  Google Scholar 

  29. Graham JG, MacDonald LJ, Hussain SK, Sharma UM, Kurten RC, Voth DE. Virulent Coxiella burnetii pathotypes productively infect primary human alveolar macrophages. Cell Microbiol. 2013;15(6):1012–25. https://doi.org/10.1111/cmi.12096.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Howe D, Shannon JG, Winfree S, Dorward DW, Heinzen RA. Coxiella burnetii phase I and II variants replicate with similar kinetics in degradative phagolysosome-like compartments of human macrophages. Infect Immun. 2010;78(8):3465–74. https://doi.org/10.1128/IAI.00406-10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hackstadt T, Williams JC. Biochemical stratagem for obligate parasitism of eukaryotic cells by Coxiella burnetii. Proc Natl Acad Sci USA. 1981;78(5):3240–4.

    Article  CAS  PubMed  Google Scholar 

  32. Omsland A, Cockrell DC, Fischer ER, Heinzen RA. Sustained axenic metabolic activity by the obligate intracellular bacterium Coxiella burnetii. J Bacteriol. 2008;190(9):3203–12. https://doi.org/10.1128/JB.01911-07.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Omsland A, Cockrell DC, Howe D, Fischer ER, Virtaneva K, Sturdevant DE, Porcella SF, Heinzen RA. Host cell-free growth of the Q fever bacterium Coxiella burnetii. Proc Natl Acad Sci USA. 2009;106(11):4430–4. https://doi.org/10.1073/pnas.0812074106.

    Article  PubMed  Google Scholar 

  34. Omsland A, Beare PA, Hill J, Cockrell DC, Howe D, Hansen B, Samuel JE, Heinzen RA. Isolation from animal tissue and genetic transformation of Coxiella burnetii are facilitated by an improved axenic growth medium. Appl Environ Microbiol. 2011;77(11):3720–5. https://doi.org/10.1128/AEM.02826-10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Beare PA. Genetic manipulation of Coxiella burnetii. Adv Exp Med Biol. 2012;984:249–71. https://doi.org/10.1007/978-94-007-4315-1_13.

    Article  CAS  PubMed  Google Scholar 

  36. Beare PA, Gilk SD, Larson CL, Hill J, Stead CM, Omsland A, Cockrell DC, Howe D, Voth DE, Heinzen RA. Dot/Icm type IVB secretion system requirements for Coxiella burnetii growth in human macrophages. MBio. 2011;2(4):e00175-00111. https://doi.org/10.1128/mBio.00175-11.

    Article  CAS  Google Scholar 

  37. Carey KL, Newton HJ, Luhrmann A, Roy CR. The Coxiella burnetii Dot/Icm system delivers a unique repertoire of type IV effectors into host cells and is required for intracellular replication. PLoS Pathog. 2011;7(5):e1002056. https://doi.org/10.1371/journal.ppat.1002056.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Weber MM, Chen C, Rowin K, Mertens K, Galvan G, Zhi H, Dealing CM, Roman VA, Banga S, Tan Y, Luo ZQ, Samuel JE. Identification of Coxiella burnetii type IV secretion substrates required for intracellular replication and Coxiella-containing vacuole formation. J Bacteriol. 2013;195(17):3914–24. https://doi.org/10.1128/JB.00071-13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Musso D, Broult J, Parola P, Raoult D, Fournier PE. Absence of antibodies to Rickettsia spp., Bartonella spp., Ehrlichia spp. and Coxiella burnetii in Tahiti, French Polynesia. BMC Infect Dis. 2014;14:255. https://doi.org/10.1186/1471-2334-14-255.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Georgiev M, Afonso A, Neubauer H, Needham H, Thiery R, Rodolakis A, Roest H, Stark K, Stegeman J, Vellema P, van der Hoek W, More S. Q fever in humans and farm animals in four European countries, 1982 to 2010. Euro Surveill. 2013;18(8):20407.

    PubMed  Google Scholar 

  41. Richardus JH, Donkers A, Dumas AM, Schaap GJ, Akkermans JP, Huisman J, Valkenburg HA. Q fever in the Netherlands: a sero-epidemiological survey among human population groups from 1968 to 1983. Epidemiol Infect. 1987;98(2):211–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Delsing CE, Warris A, Bleeker-Rovers CP. Q fever: still more queries than answers. Adv Exp Med Biol. 2011;719:133–43. https://doi.org/10.1007/978-1-4614-0204-6_12.

    Article  PubMed  Google Scholar 

  43. Russell-Lodrigue KE, Andoh M, Poels MW, Shive HR, Weeks BR, Zhang GQ, Tersteeg C, Masegi T, Hotta A, Yamaguchi T, Fukushi H, Hirai K, McMurray DN, Samuel JE. Coxiella burnetii isolates cause genogroup-specific virulence in mouse and guinea pig models of acute Q fever. Infect Immun. 2009;77(12):5640–50. https://doi.org/10.1128/iai.00851-09.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Baumgartner W, Bachmann S. Histological and immunocytochemical characterization of Coxiella burnetii-associated lesions in the murine uterus and placenta. Infect Immun. 1992;60(12):5232–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Buhariwalla F, Cann B, Marrie TJ. A dog-related outbreak of Q fever. Clin Infect Dis. 1996;23(4):753–5.

    Article  CAS  PubMed  Google Scholar 

  46. Sanchez J, Souriau A, Buendia AJ, Arricau-Bouvery N, Martinez CM, Salinas J, Rodolakis A, Navarro JA. Experimental Coxiella burnetii infection in pregnant goats: a histopathological and immunohistochemical study. J Comp Pathol. 2006;135(2–3):108–15. https://doi.org/10.1016/j.jcpa.2006.06.003.

    Article  CAS  PubMed  Google Scholar 

  47. Bjork A, Marsden-Haug N, Nett RJ, Kersh GJ, Nicholson W, Gibson D, Szymanski T, Emery M, Kohrs P, Woodhall D, Anderson AD. First reported multistate human Q fever outbreak in the United States, 2011. Vector Borne and Zoonotic Dis. 2014;14(2):111–7. https://doi.org/10.1089/vbz.2012.1202.

    Article  Google Scholar 

  48. Bond KA, Vincent G, Wilks CR, Franklin L, Sutton B, Stenos J, Cowan R, Lim K, Athan E, Harris O, Macfarlane-Berry L, Segal Y, Firestone SM. One Health approach to controlling a Q fever outbreak on an Australian goat farm. Epidemiol Infect. 2016;144(6):1129–41. https://doi.org/10.1017/S0950268815002368.

    Article  CAS  PubMed  Google Scholar 

  49. Chmielewski T, Tylewska-Wierzbanowska S. Q fever outbreaks in Poland during 2005–2011. Med Sci Monit. 2013;19:1073–9. https://doi.org/10.12659/msm.889947.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Karagiannis I, Morroy G, Rietveld A, Horrevorts AM, Hamans M, Francken P, Schimmer B. Q fever outbreak in the Netherlands: a preliminary report. Euro Surveill. 2007;12(8):E070809.070802.

    Google Scholar 

  51. van der Hoek W, Morroy G, Renders NH, Wever PC, Hermans MH, Leenders AC, Schneeberger PM. Epidemic Q fever in humans in the Netherlands. Adv Exp Med Biol. 2012;984:329–64. https://doi.org/10.1007/978-94-007-4315-1_17.

    Article  CAS  PubMed  Google Scholar 

  52. Schneeberger PM, Wintenberger C, van der Hoek W, Stahl JP. Q fever in the Netherlands – 2007–2010: what we learned from the largest outbreak ever. Med Mal Infect. 2014;44(8):339–53. https://doi.org/10.1016/j.medmal.2014.02.006.

    Article  CAS  PubMed  Google Scholar 

  53. Karagiannis I, Schimmer B, Van Lier A, Timen A, Schneeberger P, Van Rotterdam B, De Bruin A, Wijkmans C, Rietveld A, Van Duynhoven Y. Investigation of a Q fever outbreak in a rural area of The Netherlands. Epidemiol Infect. 2009;137(9):1283–94. https://doi.org/10.1017/s0950268808001908.

    Article  CAS  PubMed  Google Scholar 

  54. van Asseldonk MA, Prins J, Bergevoet RH. Economic assessment of Q fever in the Netherlands. Prev Vet Med. 2013;112(1–2):27–34. https://doi.org/10.1016/j.prevetmed.2013.06.002.

    Article  PubMed  Google Scholar 

  55. Arricau Bouvery N, Souriau A, Lechopier P, Rodolakis A. Experimental Coxiella burnetii infection in pregnant goats: excretion routes. Vet Res. 2003;34(4):423–33. https://doi.org/10.1051/vetres:2003017.

    Article  PubMed  Google Scholar 

  56. Snedeker KG, Sikora C. Q fever in Alberta, Canada: 1998–2011. Zoonoses Public Health. 2014;61(2):124–30. https://doi.org/10.1111/zph.12053.

    Article  CAS  PubMed  Google Scholar 

  57. Tissot-Dupont H, Torres S, Nezri M, Raoult D. Hyperendemic focus of Q fever related to sheep and wind. Am J Epidemiol. 1999;150(1):67–74.

    Article  CAS  PubMed  Google Scholar 

  58. Welsh HH, Lennette EH, Abinanti FR, Winn JF. Air-borne transmission of Q fever: the role of parturition in the generation of infective aerosols. Ann N Y Acad Sci. 1958;70(3):528–40.

    Article  CAS  PubMed  Google Scholar 

  59. Tissot-Dupont H, Amadei MA, Nezri M, Raoult D. Wind in November, Q fever in December. Emerg Infect Dis. 2004;10(7):1264–9. https://doi.org/10.3201/eid1007.030724.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Fishbein DB, Raoult D. A cluster of Coxiella burnetii infections associated with exposure to vaccinated goats and their unpasteurized dairy products. Am J Trop Med Hyg. 1992;47(1):35–40.

    Article  CAS  PubMed  Google Scholar 

  61. Raoult D, Stein A. Q fever during pregnancy – a risk for women, fetuses, and obstetricians. N Engl J Med. 1994;330(5):371. https://doi.org/10.1056/nejm199402033300519.

    Article  Google Scholar 

  62. Duron O, Sidi-Boumedine K, Rousset E, Moutailler S, Jourdain E. The importance of ticks in Q fever transmission: what has (and has not) been demonstrated? Trends Parasitol. 2015;31(11):536–52. https://doi.org/10.1016/j.pt.2015.06.014.

    Article  PubMed  Google Scholar 

  63. Heppell CW, Egan JR, Hall I. A human time dose response model for Q fever. Epidemics. 2017; https://doi.org/10.1016/j.epidem.2017.06.001.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Tissot Dupont H, Raoult D, Brouqui P, Janbon F, Peyramond D, Weiller PJ, Chicheportiche C, Nezri M, Poirier R. Epidemiologic features and clinical presentation of acute Q fever in hospitalized patients: 323 French cases. Am J Med. 1992;93(4):427–34.

    Article  CAS  PubMed  Google Scholar 

  65. Wielders CC, Wuister AM, de Visser VL, de Jager-Leclercq MG, Groot CA, Dijkstra F, van Gageldonk-Lafeber AB, van Leuken JP, Wever PC, van der Hoek W, Schneeberger PM. Characteristics of hospitalized acute Q fever patients during a large epidemic, The Netherlands. PLoS One. 2014;9(3):e91764. https://doi.org/10.1371/journal.pone.0091764.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Carcopino X, Raoult D, Bretelle F, Boubli L, Stein A. Managing Q fever during pregnancy: the benefits of long-term cotrimoxazole therapy. Clin Infect Dis. 2007;45(5):548–55. https://doi.org/10.1086/520661.

    Article  CAS  PubMed  Google Scholar 

  67. Langley JM, Marrie TJ, Leblanc JC, Almudevar A, Resch L, Raoult D. Coxiella burnetii seropositivity in parturient women is associated with adverse pregnancy outcomes. Am J Obstet Gynecol. 2003;189(1):228–32.

    Article  PubMed  Google Scholar 

  68. Million M, Roblot F, Carles D, D’Amato F, Protopopescu C, Carrieri MP, Raoult D. Reevaluation of the risk of fetal death and malformation after Q fever. Clin Infect Dis. 2014;59(2):256–60. https://doi.org/10.1093/cid/ciu259.

    Article  PubMed  Google Scholar 

  69. Hopper B, Cameron B, Li H, Graves S, Stenos J, Hickie I, Wakefield D, Vollmer-Conna U, Lloyd AR. The natural history of acute Q fever: a prospective Australian cohort. QJM: Month J Assoc Physic. 2016;109(10):661–8. https://doi.org/10.1093/qjmed/hcw041.

    Article  CAS  Google Scholar 

  70. Schimmer B, Morroy G, Dijkstra F, Schneeberger PM, Weers-Pothoff G, Timen A, Wijkmans C, van der Hoek W. Large ongoing Q fever outbreak in the south of The Netherlands, 2008. Euro Surveill. 2008;13(31):18939.

    PubMed  Google Scholar 

  71. Espejo E, Gil-Diaz A, Oteo JA, Castillo-Rueda R, Garcia-Alvarez L, Santana-Baez S, Bella F. Clinical presentation of acute Q fever in Spain: seasonal and geographical differences. Int J Infect Dis. 2014;26:162–4. https://doi.org/10.1016/j.ijid.2014.06.016.

    Article  PubMed  Google Scholar 

  72. Raoult D, Tissot-Dupont H, Foucault C, Gouvernet J, Fournier PE, Bernit E, Stein A, Nesri M, Harle JR, Weiller PJ. Q fever 1985–1998. Clinical and epidemiologic features of 1,383 infections. Medicine. 2000;79(2):109–23.

    Article  CAS  PubMed  Google Scholar 

  73. Kampschreur LM, Dekker S, Hagenaars JC, Lestrade PJ, Renders NH, de Jager-Leclercq MG, Hermans MH, Groot CA, Groenwold RH, Hoepelman AI, Wever PC, Oosterheert JJ. Identification of risk factors for chronic Q fever, the Netherlands. Emerg Infect Dis. 2012;18(4):563–70. https://doi.org/10.3201/eid1804.111478.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Kampschreur LM, Delsing CE, Groenwold RH, Wegdam-Blans MC, Bleeker-Rovers CP, de Jager-Leclercq MG, Hoepelman AI, van Kasteren ME, Buijs J, Renders NH, Nabuurs-Franssen MH, Oosterheert JJ, Wever PC. Chronic Q fever in the Netherlands 5 years after the start of the Q fever epidemic: results from the Dutch chronic Q fever database. J Clin Microbiol. 2014;52(5):1637–43. https://doi.org/10.1128/jcm.03221-13.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Tissot-Dupont H, Vaillant V, Rey S, Raoult D. Role of sex, age, previous valve lesion, and pregnancy in the clinical expression and outcome of Q fever after a large outbreak. Clin Infect Dis. 2007;44(2):232–7. https://doi.org/10.1086/510389.

    Article  PubMed  Google Scholar 

  76. Brouqui P, Dupont HT, Drancourt M, Berland Y, Etienne J, Leport C, Goldstein F, Massip P, Micoud M, Bertrand A, et al. Chronic Q fever. Ninety-two cases from France, including 27 cases without endocarditis. Arch Intern Med. 1993;153(5):642–8.

    Article  CAS  PubMed  Google Scholar 

  77. Palmer SR, Young SE. Q-fever endocarditis in England and Wales, 1975-81. Lancet. 1982;2(8313):1448–9.

    Article  CAS  PubMed  Google Scholar 

  78. Ledina D, Bradaric N, Milas I, Ivic I, Brncic N, Kuzmicic N. Chronic fatigue syndrome after Q fever. Med Sci Monit. 2007;13(7):Cs88–92.

    PubMed  Google Scholar 

  79. Morroy G, Keijmel SP, Delsing CE, Bleijenberg G, Langendam M, Timen A, Bleeker-Rovers CP. Fatigue following acute Q-fever: a systematic literature review. PLoS One. 2016;11(5):e0155884. https://doi.org/10.1371/journal.pone.0155884.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. van Loenhout JA, Hautvast JL, Vercoulen JH, Akkermans RP, Wijkmans CJ, van der Velden K, Paget WJ. Q-fever patients suffer from impaired health status long after the acute phase of the illness: results from a 24-month cohort study. J Infect. 2015;70(3):237–46. https://doi.org/10.1016/j.jinf.2014.10.010.

    Article  PubMed  Google Scholar 

  81. Anderson A, Bijlmer H, Fournier PE, Graves S, Hartzell J, Kersh GJ, Limonard G, Marrie TJ, Massung RF, McQuiston JH, Nicholson WL, Paddock CD, Sexton DJ. Diagnosis and management of Q fever – United States, 2013: recommendations from CDC and the Q Fever Working Group. Morbidity and Mortality Weekly Report Recommendations and Reports. 2013;62(Rr-03):1–30.

    Google Scholar 

  82. Dupuis G, Peter O, Peacock M, Burgdorfer W, Haller E. Immunoglobulin responses in acute Q fever. J Clin Microbiol. 1985;22(4):484–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Schneeberger PM, Hermans MH, van Hannen EJ, Schellekens JJ, Leenders AC, Wever PC. Real-time PCR with serum samples is indispensable for early diagnosis of acute Q fever. Clin Vaccine Immunol. 2010;17(2):286–90. https://doi.org/10.1128/cvi.00454-09.

    Article  CAS  PubMed  Google Scholar 

  84. Klee SR, Tyczka J, Ellerbrok H, Franz T, Linke S, Baljer G, Appel B. Highly sensitive real-time PCR for specific detection and quantification of Coxiella burnetii. BMC Microbiol. 2006;6:2. https://doi.org/10.1186/1471-2180-6-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Fournier PE, Raoult D. Comparison of PCR and serology assays for early diagnosis of acute Q fever. J Clin Microbiol. 2003;41(11):5094–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Tilburg JJ, Melchers WJ, Pettersson AM, Rossen JW, Hermans MH, van Hannen EJ, Nabuurs-Franssen MH, de Vries MC, Horrevorts AM, Klaassen CH. Interlaboratory evaluation of different extraction and real-time PCR methods for detection of Coxiella burnetii DNA in serum. J Clin Microbiol. 2010;48(11):3923–7. https://doi.org/10.1128/jcm.01006-10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Turra M, Chang G, Whybrow D, Higgins G, Qiao M. Diagnosis of acute Q fever by PCR on sera during a recent outbreak in rural south Australia. Ann N Y Acad Sci. 2006;1078:566–9. https://doi.org/10.1196/annals.1374.112.

    Article  CAS  PubMed  Google Scholar 

  88. Wegdam-Blans MC, Kampschreur LM, Delsing CE, Bleeker-Rovers CP, Sprong T, van Kasteren ME, Notermans DW, Renders NH, Bijlmer HA, Lestrade PJ, Koopmans MP, Nabuurs-Franssen MH, Oosterheert JJ. Chronic Q fever: review of the literature and a proposal of new diagnostic criteria. J Infect. 2012;64(3):247–59. https://doi.org/10.1016/j.jinf.2011.12.014.

    Article  CAS  PubMed  Google Scholar 

  89. Raoult D, Houpikian P, Tissot Dupont H, Riss JM, Arditi-Djiane J, Brouqui P. Treatment of Q fever endocarditis: comparison of 2 regimens containing doxycycline and ofloxacin or hydroxychloroquine. Arch Intern Med. 1999;159(2):167–73.

    Article  CAS  PubMed  Google Scholar 

  90. Sobradillo V, Zalacain R, Capelastegui A, Uresandi F, Corral J. Antibiotic treatment in pneumonia due to Q fever. Thorax. 1992;47(4):276–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. O’Neill TJ, Sargeant JM, Poljak Z. The effectiveness of Coxiella burnetii vaccines in occupationally exposed populations: a systematic review and meta-analysis. Zoonoses Public Health. 2014;61(2):81–96. https://doi.org/10.1111/zph.12054.

    Article  PubMed  Google Scholar 

  92. Kersh GJ, Fitzpatrick KA, Self JS, Biggerstaff BJ, Massung RF. Long-term immune responses to Coxiella burnetii after vaccination. Clin Vaccine Immunol. 2013;20(2):129–33. https://doi.org/10.1128/cvi.00613-12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Gidding HF, Wallace C, Lawrence GL, McIntyre PB. Australia’s national Q fever vaccination program. Vaccine. 2009;27(14):2037–41. https://doi.org/10.1016/j.vaccine.2009.02.007.

    Article  PubMed  Google Scholar 

  94. Gilroy N, Formica N, Beers M, Egan A, Conaty S, Marmion B. Abattoir-associated Q fever: a Q fever outbreak during a Q fever vaccination program. Aust N Z J Public Health. 2001;25(4):362–7.

    Article  CAS  PubMed  Google Scholar 

  95. Arricau-Bouvery N, Souriau A, Bodier C, Dufour P, Rousset E, Rodolakis A. Effect of vaccination with phase I and phase II Coxiella burnetii vaccines in pregnant goats. Vaccine. 2005;23(35):4392–402. https://doi.org/10.1016/j.vaccine.2005.04.010.

    Article  CAS  PubMed  Google Scholar 

  96. de Cremoux R, Rousset E, Touratier A, Audusseau G, Nicollet P, Ribaud D, David V, Le Pape M. Assessment of vaccination by a phase I Coxiella burnetii-inactivated vaccine in goat herds in clinical Q fever situation. FEMS Immunol Med Microbiol. 2012;64(1):104–6. https://doi.org/10.1111/j.1574-695X.2011.00892.x.

    Article  CAS  PubMed  Google Scholar 

  97. Hogerwerf L, van den Brom R, Roest HI, Bouma A, Vellema P, Pieterse M, Dercksen D, Nielen M. Reduction of Coxiella burnetii prevalence by vaccination of goats and sheep, The Netherlands. Emerg Infect Dis. 2011;17(3):379–86. https://doi.org/10.3201/eid1703.101157.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Baca OG, Akporiaye ET, Aragon AS, Martinez IL, Robles MV, Warner NL. Fate of phase I and phase II Coxiella burnetii in several macrophage-like tumor cell lines. Infect Immun. 1981;33(1):258–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Capo C, Lindberg FP, Meconi S, Zaffran Y, Tardei G, Brown EJ, Raoult D, Mege JL. Subversion of monocyte functions by Coxiella burnetii: impairment of the cross-talk between alphavbeta3 integrin and CR3. J Immunol. 1999;163(11):6078–85.

    CAS  PubMed  Google Scholar 

  100. Martinez E, Cantet F, Fava L, Norville I, Bonazzi M. Identification of OmpA, a Coxiella burnetii protein involved in host cell invasion, by multi-phenotypic high-content screening. PLoS Pathog. 2014;10(3):e1004013. https://doi.org/10.1371/journal.ppat.1004013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Moffatt JH, Newton P, Newton HJ. Coxiella burnetii: turning hostility into a home. Cell Microbiol. 2015;17(5):621–31. https://doi.org/10.1111/cmi.12432.

    Article  CAS  PubMed  Google Scholar 

  102. Howe D, Mallavia LP. Coxiella burnetii exhibits morphological change and delays phagolysosomal fusion after internalization by J774A.1 cells. Infect Immun. 2000;68(7):3815–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Romano PS, Gutierrez MG, Beron W, Rabinovitch M, Colombo MI. The autophagic pathway is actively modulated by phase II Coxiella burnetii to efficiently replicate in the host cell. Cell Microbiol. 2007;9(4):891–909. https://doi.org/10.1111/j.1462-5822.2006.00838.x.

    Article  CAS  PubMed  Google Scholar 

  104. Beron W, Gutierrez MG, Rabinovitch M, Colombo MI. Coxiella burnetii localizes in a Rab7-labeled compartment with autophagic characteristics. Infect Immun. 2002;70(10):5816–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. McDonough JA, Newton HJ, Klum S, Swiss R, Agaisse H, Roy CR. Host pathways important for Coxiella burnetii infection revealed by genome-wide RNA interference screening. MBio. 2013;4(1):e00606-12. https://doi.org/10.1128/mBio.00606-12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Campoy EM, Mansilla ME, Colombo MI. Endocytic SNAREs are involved in optimal Coxiella burnetii vacuole development. Cell Microbiol. 2013;15(6):922–41. https://doi.org/10.1111/cmi.12087.

    Article  CAS  PubMed  Google Scholar 

  107. Pryor PR, Mullock BM, Bright NA, Lindsay MR, Gray SR, Richardson SC, Stewart A, James DE, Piper RC, Luzio JP. Combinatorial SNARE complexes with VAMP7 or VAMP8 define different late endocytic fusion events. EMBO Rep. 2004;5(6):590–5. https://doi.org/10.1038/sj.embor.7400150.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Seshadri R, Paulsen IT, Eisen JA, Read TD, Nelson KE, Nelson WC, Ward NL, Tettelin H, Davidsen TM, Beanan MJ, Deboy RT, Daugherty SC, Brinkac LM, Madupu R, Dodson RJ, Khouri HM, Lee KH, Carty HA, Scanlan D, Heinzen RA, Thompson HA, Samuel JE, Fraser CM, Heidelberg JF. Complete genome sequence of the Q-fever pathogen Coxiella burnetii. Proc Natl Acad Sci USA. 2003;100(9):5455–60. https://doi.org/10.1073/pnas.0931379100.

    Article  CAS  PubMed  Google Scholar 

  109. Gilk SD, Cockrell DC, Luterbach C, Hansen B, Knodler LA, Ibarra JA, Steele-Mortimer O, Heinzen RA. Bacterial colonization of host cells in the absence of cholesterol. PLoS Pathog. 2013;9(1):e1003107. https://doi.org/10.1371/journal.ppat.1003107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Mulye M, Samanta D, Winfree S, Heinzen RA, Gilk SD. Elevated cholesterol in the Coxiella burnetii intracellular Niche is bacteriolytic. MBio. 2017;8(1):e02313-16. https://doi.org/10.1128/mBio.02313-16.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Justis AV, Hansen B, Beare PA, King KB, Heinzen RA, Gilk SD. Interactions between the Coxiella burnetii parasitophorous vacuole and the endoplasmic reticulum involve the host protein ORP1L. Cell Microbiol. 2017;19(1). doi:https://doi.org/10.1111/cmi.12637.

    Article  Google Scholar 

  112. Czyz DM, Potluri LP, Jain-Gupta N, Riley SP, Martinez JJ, Steck TL, Crosson S, Shuman HA, Gabay JE. Host-directed antimicrobial drugs with broad-spectrum efficacy against intracellular bacterial pathogens. MBio. 2014;5(4):e01534-01514. https://doi.org/10.1128/mBio.01534-14.

    Article  CAS  Google Scholar 

  113. Howe D, Heinzen RA. Coxiella burnetii inhabits a cholesterol-rich vacuole and influences cellular cholesterol metabolism. Cell Microbiol. 2006;8(3):496–507. https://doi.org/10.1111/j.1462-5822.2005.00641.x.

    Article  CAS  PubMed  Google Scholar 

  114. Howe D, Melnicakova J, Barak I, Heinzen RA. Fusogenicity of the Coxiella burnetii parasitophorous vacuole. Ann N Y Acad Sci. 2003;990:556–62.

    Article  PubMed  Google Scholar 

  115. Veras PS, de Chastellier C, Moreau MF, Villiers V, Thibon M, Mattei D, Rabinovitch M. Fusion between large phagocytic vesicles: targeting of yeast and other particulates to phagolysosomes that shelter the bacterium Coxiella burnetii or the protozoan Leishmania amazonensis in Chinese hamster ovary cells. J Cell Sci. 1994;107(Pt 11):3065–76.

    CAS  PubMed  Google Scholar 

  116. Kohler LJ, Reed SCO, Sarraf SA, Arteaga DD, Newton HJ, Roy CR. Effector protein Cig2 decreases host tolerance of infection by directing constitutive fusion of autophagosomes with the Coxiella-containing vacuole. MBio. 2016;7(4):e01127-16. https://doi.org/10.1128/mBio.01127-16.

    Article  PubMed  PubMed Central  Google Scholar 

  117. Martinez E, Allombert J, Cantet F, Lakhani A, Yandrapalli N, Neyret A, Norville IH, Favard C, Muriaux D, Bonazzi M. Coxiella burnetii effector CvpB modulates phosphoinositide metabolism for optimal vacuole development. Proc Natl Acad Sci USA. 2016;113(23):E3260–9. https://doi.org/10.1073/pnas.1522811113.

    Article  CAS  PubMed  Google Scholar 

  118. Newton HJ, Kohler LJ, McDonough JA, Temoche-Diaz M, Crabill E, Hartland EL, Roy CR. A screen of Coxiella burnetii mutants reveals important roles for Dot/Icm effectors and host autophagy in vacuole biogenesis. PLoS Pathog. 2014;10(7):e1004286. https://doi.org/10.1371/journal.ppat.1004286.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Winchell CG, Graham JG, Kurten RC, Voth DE. Coxiella burnetii type IV secretion-dependent recruitment of macrophage autophagosomes. Infect Immun. 2014;82(6):2229–38. https://doi.org/10.1128/IAI.01236-13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Gutierrez MG, Vazquez CL, Munafo DB, Zoppino FC, Beron W, Rabinovitch M, Colombo MI. Autophagy induction favours the generation and maturation of the Coxiella-replicative vacuoles. Cell Microbiol. 2005;7(7):981–93. https://doi.org/10.1111/j.1462-5822.2005.00527.x.

    Article  CAS  PubMed  Google Scholar 

  121. Larson CL, Beare PA, Howe D, Heinzen RA. Coxiella burnetii effector protein subverts clathrin-mediated vesicular trafficking for pathogen vacuole biogenesis. Proc Natl Acad Sci USA. 2013;110(49):E4770–9. https://doi.org/10.1073/pnas.1309195110.

    Article  CAS  PubMed  Google Scholar 

  122. Latomanski EA, Newton P, Khoo CA, Newton HJ. The effector Cig57 Hijacks FCHO-mediated vesicular trafficking to facilitate intracellular replication of Coxiella burnetii. PLoS Pathog. 2016;12(12):e1006101. https://doi.org/10.1371/journal.ppat.1006101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Luhrmann A, Roy CR. Coxiella burnetii inhibits activation of host cell apoptosis through a mechanism that involves preventing cytochrome c release from mitochondria. Infect Immun. 2007;75(11):5282–9. https://doi.org/10.1128/IAI.00863-07.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Voth DE, Howe D, Heinzen RA. Coxiella burnetii inhibits apoptosis in human THP-1 cells and monkey primary alveolar macrophages. Infect Immun. 2007;75(9):4263–71. https://doi.org/10.1128/IAI.00594-07.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Macdonald LJ, Graham JG, Kurten RC, Voth DE. Coxiella burnetii exploits host cAMP-dependent protein kinase signalling to promote macrophage survival. Cell Microbiol. 2014;16(1):146–59. https://doi.org/10.1111/cmi.12213.

    Article  CAS  PubMed  Google Scholar 

  126. Vazquez CL, Colombo MI. Coxiella burnetii modulates Beclin 1 and Bcl-2, preventing host cell apoptosis to generate a persistent bacterial infection. Cell Death Differ. 2010;17(3):421–38. https://doi.org/10.1038/cdd.2009.129.

    Article  CAS  PubMed  Google Scholar 

  127. Russell-Lodrigue KE, Zhang GQ, McMurray DN, Samuel JE. Clinical and pathologic changes in a guinea pig aerosol challenge model of acute Q fever. Infect Immun. 2006;74(11):6085–91. https://doi.org/10.1128/iai.00763-06.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Scott GH, Williams JC, Stephenson EH. Animal models in Q fever: pathological responses of inbred mice to phase I Coxiella burnetii. J Gen Microbiol. 1987;133(3):691–700. https://doi.org/10.1099/00221287-133-3-691.

    Article  CAS  PubMed  Google Scholar 

  129. Waag DM, Byrne WR, Estep J, Gibbs P, Pitt ML, Banfield CM. Evaluation of cynomolgus (Macaca fascicularis) and rhesus (Macaca mulatta) monkeys as experimental models of acute Q fever after aerosol exposure to phase-I Coxiella burnetii. Lab Anim Sci. 1999;49(6):634–8.

    CAS  PubMed  Google Scholar 

  130. Lillie RD. Pathologic histology in guinea pigs following intraperitoneal inoculation with the virus of “Q” fever. Public Health Rep. 1942;57(9):296–306.

    Article  Google Scholar 

  131. Scott GH, Burger GT, Kishimoto RA. Experimental Coxiella burnetii infection of guinea pigs and mice. Lab Anim Sci. 1978;28(6):673–5.

    CAS  PubMed  Google Scholar 

  132. Kishimoto RA, Gonder JC, Johnson JW, Reynolds JA, Larson EW. Evaluation of a killed phase I Coxiella burnetii vaccine in cynomolgus monkeys (Macaca fascicularis). Lab Anim Sci. 1981;31(1):48–51.

    CAS  PubMed  Google Scholar 

  133. Waag DM, England MJ, Tammariello RF, Byrne WR, Gibbs P, Banfield CM, Pitt ML. Comparative efficacy and immunogenicity of Q fever chloroform: methanol residue (CMR) and phase I cellular (Q-Vax) vaccines in cynomolgus monkeys challenged by aerosol. Vaccine. 2002;20(19–20):2623–34.

    Article  CAS  PubMed  Google Scholar 

  134. Norville IH, Hartley MG, Martinez E, Cantet F, Bonazzi M, Atkins TP. Galleria mellonella as an alternative model of Coxiella burnetii infection. Microbiology. 2014;160(Pt 6):1175–81. https://doi.org/10.1099/mic.0.077230-0.

    Article  CAS  PubMed  Google Scholar 

  135. Tsai CJ, Loh JM, Proft T. Galleria mellonella infection models for the study of bacterial diseases and for antimicrobial drug testing. Virulence. 2016;7(3):214–29. https://doi.org/10.1080/21505594.2015.1135289.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. van Schaik EJ, Case ED, Martinez E, Bonazzi M, Samuel JE. The SCID mouse model for identifying virulence determinants in Coxiella burnetii. Front Cell Infect Microbiol. 2017;7:25. https://doi.org/10.3389/fcimb.2017.00025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Weber MM, Faris R, van Schaik EJ, McLachlan JT, Wright WU, Tellez A, Roman VA, Rowin K, Case ED, Luo ZQ, Samuel JE. The type IV secretion system effector protein CirA stimulates the GTPase activity of RhoA and is required for virulence in a mouse model of Coxiella burnetii infection. Infect Immun. 2016;84(9):2524–33. https://doi.org/10.1128/iai.01554-15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Akporiaye ET, Rowatt JD, Aragon AA, Baca OG. Lysosomal response of a murine macrophage-like cell line persistently infected with Coxiella burnetii. Infect Immun. 1983;40(3):1155–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Baca OG, Scott TO, Akporiaye ET, DeBlassie R, Crissman HA. Cell cycle distribution patterns and generation times of L929 fibroblast cells persistently infected with Coxiella burnetii. Infect Immun. 1985;47(2):366–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Maurin M, Benoliel AM, Bongrand P, Raoult D. Phagolysosomes of Coxiella burnetii-infected cell lines maintain an acidic pH during persistent infection. Infect Immun. 1992;60(12):5013–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Raoult D, Vestris G, Enea M. Isolation of 16 strains of Coxiella burnetii from patients by using a sensitive centrifugation cell culture system and establishment of the strains in HEL cells. J Clin Microbiol. 1990;28(11):2482–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Zamboni DS, Mortara RA, Rabinovitch M. Infection of Vero cells with Coxiella burnetii phase II: relative intracellular bacterial load and distribution estimated by confocal laser scanning microscopy and morphometry. J Microbiol Methods. 2001;43(3):223–32.

    Article  CAS  PubMed  Google Scholar 

  143. Beare PA, Heinzen RA. Gene inactivation in Coxiella burnetii. Methods Mol Biol. 2014;1197:329–45. https://doi.org/10.1007/978-1-4939-1261-2_19.

    Article  CAS  PubMed  Google Scholar 

  144. Chen C, Banga S, Mertens K, Weber MM, Gorbaslieva I, Tan Y, Luo ZQ, Samuel JE. Large-scale identification and translocation of type IV secretion substrates by Coxiella burnetii. Proc Natl Acad Sci USA. 2010;107(50):21755–60. https://doi.org/10.1073/pnas.1010485107.

    Article  PubMed  Google Scholar 

  145. Voth DE, Beare PA, Howe D, Sharma UM, Samoilis G, Cockrell DC, Omsland A, Heinzen RA. The Coxiella burnetii cryptic plasmid is enriched in genes encoding type IV secretion system substrates. J Bacteriol. 2011;193(7):1493–503. https://doi.org/10.1128/JB.01359-10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Charpentier X, Oswald E. Identification of the secretion and translocation domain of the enteropathogenic and enterohemorrhagic Escherichia coli effector Cif, using TEM-1 beta-lactamase as a new fluorescence-based reporter. J Bacteriol. 2004;186(16):5486–95. https://doi.org/10.1128/jb.186.16.5486-5495.2004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. de Felipe KS, Glover RT, Charpentier X, Anderson OR, Reyes M, Pericone CD, Shuman HA. Legionella eukaryotic-like type IV substrates interfere with organelle trafficking. PLoS Pathog. 2008;4(8):e1000117. https://doi.org/10.1371/journal.ppat.1000117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Newton P, Latomanski EA, Newton HJ. Applying Fluorescence Resonance Energy Transfer (FRET) to examine effector translocation efficiency by Coxiella burnetii during siRNA silencing. J Vis Exp. 2016;(113). doi:https://doi.org/10.3791/54210.

  149. Beare PA, Larson CL, Gilk SD, Heinzen RA. Two systems for targeted gene deletion in Coxiella burnetii. Appl Environ Microbiol. 2012;78(13):4580–9. https://doi.org/10.1128/AEM.00881-12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Cunha LD, Ribeiro JM, Fernandes TD, Massis LM, Khoo CA, Moffatt JH, Newton HJ, Roy CR, Zamboni DS. Inhibition of inflammasome activation by Coxiella burnetii type IV secretion system effector IcaA. Nat Commun. 2015;6:10205. https://doi.org/10.1038/ncomms10205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Fielden LF, Moffatt JH, Kang Y, Baker MJ, Khoo C, Roy CR, Stojanovski D, NH J. A farnesylated Coxiella burnetii effector forms a multimeric complex at the mitochondrial outer membrane during infection. Infect Immun. 2017;85(5):e01046-16.

    Article  PubMed  PubMed Central  Google Scholar 

  152. Christie PJ, Vogel JP. Bacterial type IV secretion: conjugation systems adapted to deliver effector molecules to host cells. Trends Microbiol. 2000;8(8):354–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Feldman M, Zusman T, Hagag S, Segal G. Coevolution between nonhomologous but functionally similar proteins and their conserved partners in the Legionella pathogenesis system. Proc Natl Acad Sci USA. 2005;102(34):12206–11. https://doi.org/10.1073/pnas.0501850102.

    Article  CAS  PubMed  Google Scholar 

  154. Zamboni DS, McGrath S, Rabinovitch M, Roy CR. Coxiella burnetii express type IV secretion system proteins that function similarly to components of the Legionella pneumophila Dot/Icm system. Mol Microbiol. 2003;49(4):965–76.

    Article  CAS  PubMed  Google Scholar 

  155. Zusman T, Yerushalmi G, Segal G. Functional similarities between the icm/dot pathogenesis systems of Coxiella burnetii and Legionella pneumophila. Infect Immun. 2003;71(7):3714–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Segal G, Purcell M, Shuman HA. Host cell killing and bacterial conjugation require overlapping sets of genes within a 22-kb region of the Legionella pneumophila genome. Proc Natl Acad Sci USA. 1998;95(4):1669–74.

    Article  CAS  PubMed  Google Scholar 

  157. Vogel JP, Andrews HL, Wong SK, Isberg RR. Conjugative transfer by the virulence system of Legionella pneumophila. Science. 1998;279(5352):873–6.

    Article  CAS  Google Scholar 

  158. Nagai H, Cambronne ED, Kagan JC, Amor JC, Kahn RA, Roy CR. A C-terminal translocation signal required for Dot/Icm-dependent delivery of the Legionella RalF protein to host cells. Proc Natl Acad Sci USA. 2005;102(3):826–31. https://doi.org/10.1073/pnas.0406239101.

    Article  CAS  PubMed  Google Scholar 

  159. Newton HJ, McDonough JA, Roy CR. Effector protein translocation by the Coxiella burnetii Dot/Icm type IV secretion system requires endocytic maturation of the pathogen-occupied vacuole. PLoS One. 2013;8(1):e54566. https://doi.org/10.1371/journal.pone.0054566.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Segal G. The Legionella pneumophila two-component regulatory systems that participate in the regulation of Icm/Dot effectors. Curr Top Microbiol Immunol. 2013;376:35–52. https://doi.org/10.1007/82_2013_346.

    Article  CAS  PubMed  Google Scholar 

  161. Beare PA, Sandoz KM, Larson CL, Howe D, Kronmiller B, Heinzen RA. Essential role for the response regulator PmrA in Coxiella burnetii type 4B secretion and colonization of mammalian host cells. J Bacteriol. 2014;196(11):1925–40. https://doi.org/10.1128/JB.01532-14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Larson CL, Martinez E, Beare PA, Jeffrey B, Heinzen RA, Bonazzi M. Right on Q: genetics begin to unravel Coxiella burnetii host cell interactions. Future Microbiol. 2016;11:919–39. https://doi.org/10.2217/fmb-2016-0044.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Lifshitz Z, Burstein D, Peeri M, Zusman T, Schwartz K, Shuman HA, Pupko T, Segal G. Computational modeling and experimental validation of the Legionella and Coxiella virulence-related type-IVB secretion signal. Proc Natl Acad Sci USA. 2013;110(8):E707–15. https://doi.org/10.1073/pnas.1215278110.

    Article  PubMed  Google Scholar 

  164. Pan X, Luhrmann A, Satoh A, Laskowski-Arce MA, Roy CR. Ankyrin repeat proteins comprise a diverse family of bacterial type IV effectors. Science. 2008;320(5883):1651–4. https://doi.org/10.1126/science.1158160.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Voth DE, Howe D, Beare PA, Vogel JP, Unsworth N, Samuel JE, Heinzen RA. The Coxiella burnetii ankyrin repeat domain-containing protein family is heterogeneous, with C-terminal truncations that influence Dot/Icm-mediated secretion. J Bacteriol. 2009;191(13):4232–42. https://doi.org/10.1128/JB.01656-08.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Kohler LJ, Roy CR. Biogenesis of the lysosome-derived vacuole containing Coxiella burnetii. Microbes Infect. 2015;17(11–12):766–71. https://doi.org/10.1016/j.micinf.2015.08.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Larson CL, Beare PA, Voth DE, Howe D, Cockrell DC, Bastidas RJ, Valdivia RH, Heinzen RA. Coxiella burnetii effector proteins that localize to the parasitophorous vacuole membrane promote intracellular replication. Infect Immun. 2015;83(2):661–70. https://doi.org/10.1128/IAI.02763-14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Lifshitz Z, Burstein D, Schwartz K, Shuman HA, Pupko T, Segal G. Identification of novel Coxiella burnetii Icm/Dot effectors and genetic analysis of their involvement in modulating a mitogen-activated protein kinase pathway. Infect Immun. 2014;82(9):3740–52. https://doi.org/10.1128/IAI.01729-14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Friedrich A, Pechstein J, Berens C, Luhrmann A. Modulation of host cell apoptotic pathways by intracellular pathogens. Curr Opin Microbiol. 2017;35:88–99. https://doi.org/10.1016/j.mib.2017.03.001.

    Article  CAS  PubMed  Google Scholar 

  170. Klingenbeck L, Eckart RA, Berens C, Luhrmann A. The Coxiella burnetii type IV secretion system substrate CaeB inhibits intrinsic apoptosis at the mitochondrial level. Cell Microbiol. 2013;15(4):675–87. https://doi.org/10.1111/cmi.12066.

    Article  CAS  PubMed  Google Scholar 

  171. Luhrmann A, Nogueira CV, Carey KL, Roy CR. Inhibition of pathogen-induced apoptosis by a Coxiella burnetii type IV effector protein. Proc Natl Acad Sci USA. 2010;107(44):18997–9001. https://doi.org/10.1073/pnas.1004380107.

    Article  PubMed  Google Scholar 

  172. Eckart RA, Bisle S, Schulze-Luehrmann J, Wittmann I, Jantsch J, Schmid B, Berens C, Luhrmann A. Antiapoptotic activity of Coxiella burnetii effector protein AnkG is controlled by p32-dependent trafficking. Infect Immun. 2014;82(7):2763–71. https://doi.org/10.1128/IAI.01204-13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Schafer W, Eckart RA, Schmid B, Cagkoylu H, Hof K, Muller YA, Amin B, Luhrmann A. Nuclear trafficking of the anti-apoptotic Coxiella burnetii effector protein AnkG requires binding to p32 and Importin-alpha1. Cell Microbiol. 2016. doi:https://doi.org/10.1111/cmi.12634.

    Article  Google Scholar 

  174. Bisle S, Klingenbeck L, Borges V, Sobotta K, Schulze-Luehrmann J, Menge C, Heydel C, Gomes JP, Luhrmann A. The inhibition of the apoptosis pathway by the Coxiella burnetii effector protein CaeA requires the EK repetition motif, but is independent of survivin. Virulence. 2016;7(4):400–12. https://doi.org/10.1080/21505594.2016.1139280.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Rodriguez-Escudero M, Cid VJ, Molina M, Schulze-Luehrmann J, Luhrmann A, Rodriguez-Escudero I. Studying Coxiella burnetii type IV substrates in the yeast Saccharomyces cerevisiae: focus on subcellular localization and protein aggregation. PLoS One. 2016;11(1):e0148032. https://doi.org/10.1371/journal.pone.0148032.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia

    Patrice Newton, Miku Kuba, Bhavna Padmanabhan, Eleanor A. Latomanski & Hayley J. Newton

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  1. Patrice Newton
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  2. Miku Kuba
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  3. Bhavna Padmanabhan
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  4. Eleanor A. Latomanski
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  5. Hayley J. Newton
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Correspondence to Hayley J. Newton .

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Editors and Affiliations

  1. Molecular Biology Unit, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India

    Sunit K. Singh

  2. NIH/NIAID, Division of Clinical Research, Integrated Research Facility at Fort Detrick, Frederick, MD, USA

    Jens H. Kuhn

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Newton, P., Kuba, M., Padmanabhan, B., Latomanski, E.A., Newton, H.J. (2019). Coxiella burnetii: Hiding in Plain Sight. In: Singh, S., Kuhn, J. (eds) Defense Against Biological Attacks. Springer, Cham. https://doi.org/10.1007/978-3-030-03071-1_9

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