Coxiella burnetii is a Gram-negative obligate intracellular bacterial pathogen that is the aetiological agent of Q fever, which manifests as both acute and chronic infections. The infection is a zoonosis that is most often transmitted by aerosolized dry, contaminated soil or animal products.
Genetic differences between C. burnetii isolates from acute and chronic infections have led to the hypothesis that pathotype-specific virulence exists.
After inhalation by a host, C. burnetii invades and replicates within alveolar macrophages without alerting the innate immune system and has therefore been described as a stealth pathogen. Inside macrophages, the bacterium replicates within a compartment that is very similar to a phagolysosome, termed the Coxiella-containing vacuole (CCV).
C. burnetii has a type IV secretion system that resembles the Dot/Icm (defect in organelle trafficking/intracellular multiplication) system of Legionella pneumophila and is necessary for pathogenesis. C. burnetii encodes homologues for 24 of the 27 L. pneumophila Dot/Icm proteins, and four C. burnetii Dot/Icm genes can actually complement homologous mutations in the L. pneumophila system, lending strength to the conjecture that these systems are structurally and functionally similar.
Establishment and maintenance of the CCV is dependent on protein production by C. burnetii. Although the identity of the virulence factors involved are unknown, new evidence suggests that most are effectors secreted by the type IV secretion system.
The recent development of axenic media to grow C. burnetii has enabled the development of genetic tools to identify virulence factors. These developments have started a new era of research for C. burnetii, and Koch's postulates can now be tested for the first time.
The agent of Q fever, Coxiella burnetii, is an obligate intracellular bacterium that causes acute and chronic infections. The study of C. burnetii pathogenesis has benefited from two recent fundamental advances: improved genetic tools and the ability to grow the bacterium in extracellular media. In this Review, we describe how these recent advances have improved our understanding of C. burnetii invasion and host cell modulation, including the formation of replication-permissive Coxiella-containing vacuoles. Furthermore, we describe the Dot/Icm (defect in organelle trafficking/intracellular multiplication) system, which is used by C. burnetii to secrete a range of effector proteins into the host cell, and we discuss the role of these effectors in remodelling the host cell.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Scientific Reports Open Access 21 September 2020
Novel multiparameter correlates of Coxiella burnetii infection and vaccination identified by longitudinal deep immune profiling
Scientific Reports Open Access 07 August 2020
Parasites & Vectors Open Access 14 February 2020
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Flannagan, R. S., Jaumouillé, V. & Grinstein, S. The cell biology of phagocytosis. Annu. Rev. Pathol. 7, 61–98 (2012).
Flannagan, R. S., Cosio, G. & Grinstein, S. Antimicrobial mechanisms of phagocytes and bacterial evasion strategies. Nature Rev. Microbiol. 7, 355–366 (2009).
Beron, W., Gutierrez, M. G., Rabinovitch, M. & Colombo, M. I. Coxiella burnetii localizes in a Rab7- labeled compartment with autophagic characteristics. Infect. Immun. 70, 5816–5821 (2002). The first report to show that CCV formation is disrupted by autophagy inhibitors and that LC3 localizes to the CCV.
Howe, D. & Mallavia, L. P. Coxiella burnetii exhibits morphological change and delays phagolysosomal fusion after internalization by J774A.1 cells. Infect. Immun. 68, 3815–3821 (2000).
Howe, D., Melnicâakova, J., Barâak, I. & Heinzen, R. A. Fusogenicity of the Coxiella burnetii parasitophorous vacuole. Ann. NY Acad. Sci. 990, 556–562 (2003).
Coleman, S. A., Fischer, E. R., Howe, D., Mead, D. J. & Heinzen, R. A. Temporal analysis of Coxiella burnetii morphological differentiation. J. Bacteriol. 186, 7344–7352 (2004).
Coleman, S. A. et al. Proteome and antigen profiling of Coxiella burnetii developmental forms. Infect. Immun. 75, 290–298 (2007).
Stoker, M. B. P. & Fiset, P. Phase variation of the Nine Mile and other strains of Rickettsia burnetii. Can. J. Microbiol. 2, 310–321 (1956).
Baca, O. G., Klassen, D. A. & Aragon, A. S. Entry of Coxiella burnetii into host cells. Acta Virol. 37, 143–155 (1993).
Tujulin, E., Macellaro, A., Lilliehook, B. & Norlander, L. Effect of endocytosis inhibitors on Coxiella burnetii interaction with host cells. Acta Virol. 42, 125–131 (1998).
Seshadri, R. et al. Complete genome sequence of the Q-fever pathogen Coxiella burnetii. Proc. Natl Acad. Sci. USA 100, 5455–5460 (2003).
Beare, P. A. et al. Dot/Icm type IVB secretion system requirements for Coxiella burnetii growth in human macrophages. mBio 2, e00175–11 (2011). Work that determines the essential role of the T4SS and the temporal control of the C. burnetii T4SS.
Carey, K. L., Newton, H. J., Luhrmann, A. & Roy, C. R. 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. 7, e1002056 (2011). A paper which demonstrates that CCV biogenesis and C. burnetii intracellular replication require a functional T4SS.
Capo, C. et al. Subversion of monocyte functions by Coxiella burnetii: impairment of the cross-talk between αvβ3 integrin and CR3. J. Immunol. 163, 6078–6085 (1999).
Dellacasagrande, J. et al. αvβ3 integrin and bacterial lipopolysaccharide are involved in Coxiella burnetii-stimulated production of tumor necrosis factor by human monocytes. Infect. Immun. 68, 5673–5678 (2000).
Dupuy, A. G. & Caron, E. Integrin-dependent phagocytosis – spreading from microadhesion to new concepts. J. Cell Sci. 121, 1773–1783 (2008).
De Fougerolles, A. R. & Koteliansky, V. E. Regulation of monocyte gene expression by the extracellular matrix and its functional implications. Immunol. Rev. 186, 208–220 (2002).
Damjanovich, L., Albelda, S. M., Mette, S. A. & Buck, C. A. Distribution of integrin cell adhesion receptors in normal and malignant lung tissue. Am. J. Respir. Cell Mol. Biol. 6, 197–206 (1992).
Russell-Lodrigue, K. E., Zhang, G. Q., McMurray, D. N. & Samuel, J. E. Clinical and pathologic changes in a guinea pig aerosol challenge model of acute Q fever. Infect. Immun. 74, 6085–6091 (2006).
Moos, A. & Hackstadt, T. Comparative virulence of intra-and interstrain lipopolysaccharide variants of Coxiella burnetii in the guinea pig model. Infect. Immun. 55, 1144–1150 (1987).
Howe, D., Shannon, J. G., Winfree, S., Dorward, D. W. & Heinzen, R. A. Coxiella burnetii phase I and II variants replicate with similar kinetics in degradative phagolysosome-like compartments of human macrophages. Infect. Immun. 78, 3465–3474 (2010). An article showing that phase I and phase II C. burnetii cells replicate within similar vacuoles in human-derived macrophages and THP-1 cells, indicating that differences in virulence are not determined by the terminal compartment that these bacteria reside in.
Romano, P. S., Gutierrez, M. G., Beron, W., Rabinovitch, M. & Colombo, M. I. The autophagic pathway is actively modulated by phase II Coxiella burnetii to efficiently replicate in the host cell. Cell. Microbiol. 9, 891–909 (2007).
Fu, Y. & Galan, J. E. A Salmonella protein antagonizes Rac-1 and Cdc42 to mediate host-cell recovery after bacterial invasion. Nature 401, 293–297 (1999).
Subtil, A., Wyplosz, B., Balana, M. E. & Dautry-Varsat, A. Analysis of Chlamydia caviae entry sites and involvement of Cdc42 and Rac activity. J. Cell Sci. 117, 3923–3933 (2004).
Meconi, S. et al. Activation of protein tyrosine kinases by Coxiella burnetii: role in actin cytoskeleton reorganization and bacterial phagocytosis. Infect. Immun. 69, 2520–2526 (2001).
Meconi, S. et al. Coxiella burnetii induces reorganization of the actin cytoskeleton in human monocytes. Infect. Immun. 66, 5527–5533 (1998).
Honstettre, A. et al. Lipopolysaccharide from Coxiella burnetii is involved in bacterial phagocytosis, filamentous actin reorganization, and inflammatory responses through Toll-like receptor 4. J. Immunol. 172, 3695–3703 (2004).
Kinchen, J. M. & Ravichandran, K. S. Phagosome maturation: going through the acid test. Nature Rev. Mol. Cell Biol. 9, 781–795 (2008).
Voth, D. E. & Heinzen, R. A. Lounging in a lysosome: the intracellular lifestyle of Coxiella burnetii. Cell. Microbiol. 9, 829–840 (2007).
Howe, D., Melnicâakovâa, J., Barâak, I. & Heinzen, R. A. Maturation of the Coxiella burnetii parasitophorous vacuole requires bacterial protein synthesis but not replication. Cell. Microbiol. 5, 469–480 (2003). The first report indicating that maturation of the CCV is a bacterially driven process.
Levine, B., Mizushima, N. & Virgin, H. W. Autophagy in immunity and inflammation. Nature 469, 323–335 (2011).
Gutierrez, M. G. et al. Autophagy induction favours the generation and maturation of the Coxiella-replicative vacuoles. Cell. Microbiol. 7, 981–993 (2005).
McDonough, J. A. et al. Host pathways important for Coxiella burnetii infection revealed by genome-wide RNA interference screening. mBio 4, e00606–12 (2013).
Roman, M. J., Crissman, H. A., Samsonoff, W. A., Hechemy, K. E. & Baca, O. G. Analysis of Coxiella burnetii isolates in cell culture and the expression of parasite-specific antigens on the host membrane surface. Acta Virol. 35, 503–510 (1991).
Aguilera, M. et al. Actin dynamics and Rho GTPases regulate the size and formation of parasitophorous vacuoles containing Coxiella burnetii. Infect. Immun. 77, 4609–4620 (2009).
Hussain, S. K., Broederdorf, L. J., Sharma, U. M. & Voth, D. E. Host kinase activity is required for Coxiella burnetii parasitophorous vacuole formation. Front. Microbiol. 1, 137 (2010). The first evidence that host cell kinases are involved in CCV maturation, further defining the host–pathogen interface.
Campoy, E. M., Zoppino, F. C. & Colombo, M. I. The early secretory pathway contributes to the growth of the Coxiella-replicative niche. Infect. Immun. 79, 402–413 (2011). An article demonstrating that the CCV interacts with the ER at late time points during infection.
Howe, D. & Heinzen, R. A. Coxiella burnetii inhabits a cholesterol-rich vacuole and influences cellular cholesterol metabolism. Cell. Microbiol. 8, 496–507 (2006).
Howe, D. & Heinzen, R. A. Replication of Coxiella burnetii is inhibited in CHO K-1 cells treated with inhibitors of cholesterol metabolism. Ann. NY Acad. Sci. 1063, 123–129 (2005).
Espenshade, P. J. & Hughes, A. L. Regulation of sterol synthesis in eukaryotes. Annu. Rev. Genet. 41, 401–427 (2007).
Akporiaye, E. T., Rowatt, J. D., Aragon, A. A. & Baca,O. G. Lysosomal response of a murine macrophage-like cell line persistently infected with Coxiella burnetii. Infect. Immun. 40, 1155–1162 (1983).
Voth, D. E., Howe, D. & Heinzen, R. A. Coxiella burnetii inhibits apoptosis in human THP-1 cells and monkey primary alveolar macrophages. Infect. Immun. 75, 4263–4271 (2007).
Baca, O. G., Scott, T. O., Akporiaye, E. T., DeBlassie, R. & Crissman, H. A. Cell cycle distribution patterns and generation times of L929 fibroblast cells persistently infected with Coxiella burnetii. Infect. Immun. 47, 366–369 (1985).
Luhrmann, A. & Roy, C. R. Coxiella burnetii inhibits activation of host cell apoptosis through a mechanism that involves preventing cytochrome c release from mitochondria. Infect. Immun. 75, 5282–5289 (2007).
Yang, J. et al. Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science 275, 1129–1132 (1997).
Voth, D. E. & Heinzen, R. A. Sustained activation of Akt and Erk1/2 is required for Coxiella burnetii antiapoptotic activity. Infect. Immun. 77, 205–213 (2009).
Roman, M. J., Coriz, P. D. & Baca, O. G. A proposed model to explain persistent infection of host cells with Coxiella burnetii. J. Gen. Microbiol. 132, 1415–1422 (1986).
Tigertt, W. D., Benenson, A. S. & Gochenour, W. S. Airborne Q fever. Bacteriol. Rev. 25, 285–293 (1961).
Zhang, Y., Zhang, G., Hendrix, L. R., Tesh, V. L. & Samuel, J. E. Coxiella burnetii induces apoptosis during early stage infection via a caspase-independent pathway in human monocytic THP-1 cells. PLoS ONE 7, e30841 (2012).
Ashida, H. et al. Cell death and infection: a double-edged sword for host and pathogen survival. J. Cell Biol. 195, 931–942 (2011).
Beare, P. A. et al. Comparative genomics reveal extensive transposon-mediated genomic plasticity and diversity among potential effector proteins within the genus Coxiella. Infect. Immun. 77, 642–656 (2009).
Peabody, C. R. et al. Type II protein secretion and its relationship to bacterial type IV pili and archaeal flagella. Microbiology 149, 3051–3072 (2003).
Sexton, J. A. & Vogel, J. P. Type IVB secretion by intracellular pathogens. Traffic 3, 178–185 (2002).
Zechner, E. L., Lang, S. & Schildbach, J. F. Assembly and mechanisms of bacterial type IV secretion machines. Phil. Trans. R. Soc. B. 367, 1073–1087 (2012).
Alvarez-Martinez, C. E. & Christie, P. J. Biological diversity of prokaryotic type IV secretion systems. Microbiol. Mol. Biol. Rev. 73, 775–808 (2009).
Vincent, C. D. et al. Identification of the core transmembrane complex of the Legionella Dot/Icm type IV secretion system. Mol. Microbiol. 62, 1278–1291 (2006).
Vincent, C. D., Friedman, J. R., Jeong, K. C., Sutherland, M. C. & Vogel, J. P. Identification of the DotL coupling protein subcomplex of the Legionella Dot/Icm type IV secretion system. Mol. Microbiol. 85, 378–391 (2012).
Hiroki, N. & Tomoko, K. Type IVB secretion systems of Legionella and other Gram-negative bacteria. Front. Microbiol. 2, 136 (2011).
Zamboni, D. S., McGrath, S., Rabinovitch, M. & Roy, C. R. Coxiella burnetii express type IV secretion system proteins that function similarly to components of the Legionella pneumophila Dot/Icm system. Mol. Microbiol. 49, 965–976 (2003).
Voth, D. E. et al. The Coxiella burnetii ankyrin repeat domain-containing protein family is heterogeneous with C-terminal truncations that influence Dot/Icm-mediated secretion. J. Bacteriol. 191, 4232–4242 (2009).
Chen, C. et al. Large-scale identification and translocation of type IV secretion substrates by Coxiella burnetii. Proc. Natl Acad. Sci. USA 107, 21755–21760 (2010). Research establishing a shuttle vector and translocation assays for C. burnetii , leading to the identification of a large number of T4SS effectors and confirming the presence of a functional secretion system in C. burnetii during infection.
Morgan, J. K., Luedtke, B. E., Thompson, H. A. & Shaw, E. I. Coxiella burnetii type IVB secretion system region I genes are expressed early during the infection of host cells. FEMS Microbiol. Lett. 311, 61–69 (2010).
Morgan, J. K., Luedtke, B. E. & Shaw, E. I. Polar localization of the Coxiella burnetii type IVB secretion system. FEMS Microbiol. Lett. 305, 177–183 (2010).
Beare, P. A., Larson, C. L., Gilk, S. D. & Heinzen, R. A. Two systems for targeted gene deletion in Coxiella burnetii. Appl. Environ. Microbiol. 78, 4580–4589 (2012).
Pan, X., Luhrmann, A., Satoh, A., Laskowski-Arce, M. A. & Roy, C. R. Ankyrin repeat proteins comprise a diverse family of bacterial type IV effectors. Science 320, 1651–1654 (2008). A paper that identifies ankyrin repeat proteins as T4SS effectors in C. burnetii and L. pneumophila , indicating that these proteins are conserved 4SS effectors.
Voth, D. E. & Heinzen, R. A. Coxiella type IV secretion and cellular microbiology. Curr. Opin. Microbiol. 12, 74–80 (2009).
Voth, D. E. et al. The Coxiella burnetii cryptic plasmid is enriched in genes encoding type IV secretion system substrates. J. Bacteriol. 193, 1493–1503 (2011).
Lifshitz, Z. et al. Computational modeling and experimental validation of the Legionella and Coxiella virulence-related type-IVB secretion signal. Proc. Natl Acad. Sci. USA 110, e707–e715 (2013).
de Felipe, K. S. et al. Evidence for acquisition of Legionella type IV secretion substrates via interdomain horizontal gene transfer. J. Bacteriol. 187, 7716–7726 (2005).
Kubori, T., Shinzawa, N., Kanuka, H. & Nagai, H. Legionella metaeffector exploits host proteasome to temporally regulate cognate effector. PLoS Pathog. 6, e1001216 (2011).
Newton, H. J., McDonough, J. A. & Roy, C. R. Effector protein translocation by the Coxiella burnetii Dot/Icm type IV secretion system requires endocytic maturation of the pathogen-occupied vacuole. PLoS ONE 8, e54566 (2013).
Zusman, T. et al. The response regulator PmrA is a major regulator of the icm/dot type IV secretion system in Legionella pneumophila and Coxiella burnetii. Mol. Microbiol. 63, 1508–1523 (2007). A report showing that components of the T4SS and some putative T4SS effectors are co-regulated, implying that there is a link between, and temporal regulation of, the secretion apparatus and its effectors.
McPhee, J. B., Lewenza, S. & Hancock, R. E. Cationic antimicrobial peptides activate a two-component regulatory system, PmrA-PmrB, that regulates resistance to polymyxin B and cationic antimicrobial peptides in Pseudomonas aeruginosa. Mol. Microbiol. 50, 205–217 (2003).
Sauer, J. D. et al. Specificity of Legionella pneumophila and Coxiella burnetii vacuoles and versatility of Legionella pneumophila revealed by coinfection. Infect. Immun. 73, 4494–4504 (2005).
Omsland, A. et al. Isolation from animal tissue and genetic transformation of Coxiella burnetii are facilitated by an improved axenic growth medium. Appl. Environ. Microbiol. 77, 3720–3725 (2011). The first description of the clonal isolation of transformed C. burnetii using axenic media.
Huang, L. et al. The E Block motif is associated with Legionella pneumophila translocated substrates. Cell. Microbiol. 13, 227–245 (2011).
Klingenbeck, L., Eckart, R. A., Berens, C. & Luhrmann, A. The Coxiella burnetii type IV secretion system substrate CaeB inhibits intrinsic apoptosis at the mitochondrial level. Cell. Microbiol. 15, 675–687 (2013).
Luhrmann, A., Nogueira, C. V., Carey, K. L. & Roy, C. R. Inhibition of pathogen-induced apoptosis by a Coxiella burnetii type IV effector protein. Proc. Natl Acad. Sci. USA 107, 18997–19001 (2010). An article which describes the only characterized C. burnetii T4SS effector that prevents host cell apoptosis by targeting pro-apoptotic protein p32.
Ge, J. et al. A Legionella type IV effector activates the NF-κB pathway by phosphorylating the IκB family of inhibitors. Proc. Natl Acad. Sci. USA 106, 13725–13730 (2009).
de Felipe, K. S. et al. Legionella eukaryotic-like type IV substrates interfere with organelle trafficking. PLoS Pathog. 4, e1000117 (2008).
Shen, X. et al. Targeting eEF1A by a Legionella pneumophila effector leads to inhibition of protein synthesis and induction of host stress response. Cell. Microbiol. 11, 911–926 (2009).
Banga, S. et al. Legionella pneumophila inhibits macrophage apoptosis by targeting pro-death members of the Bcl2 protein family. Proc. Natl Acad. Sci. USA 104, 5121–5126 (2007).
Campodonico, E. M., Chesnel, L. & Roy, C. R. A yeast genetic system for the identification and characterization of substrate proteins transferred into host cells by the Legionella pneumophila Dot/Icm system. Mol. Microbiol. 56, 918–933 (2005).
Ren, Q., Robertson, S. J., Howe, D., Barrows, L. F. & Heinzen, R. A. Comparative DNA microarray analysis of host cell transcriptional responses to infection by Coxiella burnetii or Chlamydia trachomatis. Ann. NY Acad. Sci. 990, 701–713 (2003).
Murata, T. et al. The Legionella pneumophila effector protein DrrA is a Rab1 guanine nucleotide-exchange factor. Nature Cell Biol. 8, 971–977 (2006).
Machner, M. P. & Isberg, R. R. Targeting of host Rab GTPase function by the intravacuolar pathogen Legionella pneumophila. Dev. Cell 11, 47–56 (2006).
Nagai, H., Kagan, J. C., Zhu, X., Kahn, R. A. & Roy, C. R. A bacterial guanine nucleotide exchange factor activates ARF on Legionella phagosomes. Science 295, 679–682 (2002).
Price, C. T., Al-Quadan, T., Santic, M., Rosenshine, I. & Abu Kwaik, Y. Host proteasomal degradation generates amino acids essential for intracellular bacterial growth. Science 334, 1553–1557 (2011).
Vishwanath, S. & Hackstadt, T. Lipopolysaccharide phase variation determines the complement-mediated serum susceptibility of Coxiella burnetii. Infect. Immun. 56, 40–44 (1988).
Shannon, J. G., Howe, D. & Heinzen, R. A. Virulent Coxiella burnetii does not activate human dendritic cells: role of lipopolysaccharide as a shielding molecule. Proc. Natl Acad. Sci. USA 102, 8722–8727 (2005). A study showing that lipopolysaccharide is used by virulent C. burnetii to evade immune surveillance.
Zamboni, D. S. et al. Stimulation of toll-like receptor 2 by Coxiella burnetii is required for macrophage production of pro-inflammatory cytokines and resistance to infection. J. Biol. Chem. 279, 54405–54415 (2004). The first report to indicate that lipid A from either phase I or phase II C. burnetii cannot stimulate TLR4.
Hirschfeld, M., Ma, Y., Weis, J. H., Vogel, S. N. & Weis, J. J. Cutting edge: repurification of lipopolysaccharide eliminates signaling through both human and murine Toll-like receptor 2. J. Immunol. 165, 618–622 (2000).
Amano, K., Williams, J. C., Missler, S. R. & Reinhold, V. N. Structure and biological relationships of Coxiella burneti i lipopolysaccharide. J. Biol. Chem. 262, 4740–4747 (1987).
Stoenner, H. G. & Lackman, D. B. The biologic properties of Coxiella burnetii isolated from rodents collected in Utah. Am. J. Hyg. 71, 45–51 (1960).
Toman, R. et al. Physicochemical characterization of the endotoxins from Coxiella burnetii strain Priscilla in relation to their bioactivities. BMC Biochem. 5, 1 (2004).
Telepnev, M. V. et al. Tetraacylated lipopolysaccharide of Yersinia pestis can inhibit multiple Toll-like receptor-mediated signaling pathways in human dendritic cells. J. Infect. Dis. 200, 1694–1702 (2009).
Benoit, M., Barbarat, B., Bernard, A., Olive, D. & Mege, J. L. Coxiella burnetii, the agent of Q fever, stimulates an atypical M2 activation program in human macrophages. Eur. J. Immunol. 38, 1065–1070 (2008).
Dellacasagrande, J., Capo, C., Raoult, D. & Mege, J. L. IFN-γ-mediated control of Coxiella burnetii survival in monocytes: the role of cell apoptosis and TNF. J. Immunol. 162, 2259–2265 (1999).
Howe, D., Barrows, L. F., Lindstrom, N. M. & Heinzen, R. A. Nitric oxide inhibits Coxiella burnetii replication and parasitophorous vacuole maturation. Infect. Immun. 70, 5140–5147 (2002).
Turco, J., Thompson, H. A. & Winkler, H. Interferon-γ inhibits growth of Coxiella burnetii in mouse fibroblasts. Infect. Immun. 45, 781–783 (1984).
Zamboni, D. S. & Rabinovitch, M. Nitric oxide partially controls Coxiella burnetii phase II infection in mouse primary macrophages. Infect. Immun. 71, 1225–1233 (2003).
Brennan, R. E., Russell, K., Zhang, G. & Samuel, J. E. Both inducible nitric oxide synthase and NADPH oxidase contribute to the control of virulent phase I Coxiella burnetii infections. Infect. Immun. 72, 6666–6675 (2004).
Hill, J. & Samuel, J. E. Coxiella burnetii acid phosphatase inhibits the release of reactive oxygen intermediates in polymorphonuclear leukocytes. Infect. Immun. 79, 414–420 (2011). Work identifying a specific protein that mediates the inhibition of ROS release in infected polymorphonuclear neutrophils.
Siemsen, D. W., Kirpotina, L. N., Jutila, M. A. & Quinn,M. T. Inhibition of the human neutrophil NADPH oxidase by Coxiella burnetii. Microbes Infect. 11, 671–679 (2009).
Vila-del Sol, V., Diaz-Munoz, M. D. & Fresno, M. Requirement of tumor necrosis factor α and nuclear factor-κB in the induction by IFN-γ of inducible nitric oxide synthase in macrophages. J. Leukoc. Biol. 81, 272–283 (2007).
Vazquez, C. L. & Colombo, M. I. Coxiella burnetii modulates Beclin 1 and Bcl-2, preventing host cell apoptosis to generate a persistent bacterial infection. Cell Death Differ. 17, 421–438 (2010).
Babudieri, C. Q fever: a zoonosis. Adv. Vet. Sci. 5, 81–84 (1959).
CDC & Department of Health and Human Services. Possession, use, and transfer of select agents and toxins. Final rule. Fed. Regist. 73, 61363–61366 (2008).
Fournier, P.-E., Marrie, T. J. & Raoult, D. Diagnosis of Q fever. J. Clin. Microbiol. 36, 1823–1834 (1998).
Million, M., Thuny, F., Richet, H. & Raoult, D. Long-term outcome of Q fever endocarditis: a 26-year personal survey. Lancet Infect. Dis. 10, 527–535 (2010).
Raoult, D. et al. Treatment of Q fever endocarditis: comparison of 2 regimens containing doxycycline and ofloxacin or hydroxychloroquine. Arch. Intern. Med. 159, 167–173 (1999).
Marmion, B. P. et al. Long-term persistence of Coxiella burnetii after acute primary Q fever. QJM 98, 7–20 (2005).
Penttila, I. A. et al. Cytokine dysregulation in the post-Q-fever fatigue syndrome. QJM 91, 549–560 (1998).
Marmion, B. P., Shannon, M., Maddocks, I., Storm, P. & Penttila, I. Protracted debility and fatigue after acute Q fever. Lancet 347, 977–978 (1996).
Enserink, M. Infectious diseases. Questions abound in Q-fever explosion in the Netherlands. Science 327, 266–267 (2010).
Whelan, J. et al. Q fever among culling workers, the Netherlands, 2009–2010. Emerg. Infect. Dis. 17, 1719–1723 (2011).
Roest, H. I. et al. The Q fever epidemic in The Netherlands: history, onset, response and reflection. Epidemiol. Infect. 139, 1–12 (2011).
Glazunova, O. et al. Coxiella burnetii genotyping. Emerg. Infect. Dis. 11, 1211–1217 (2005).
Hendrix, L. R., Samuel, J. E. & Mallavia, L. P. Differentiation of Coxiella burnetii isolates by analysis of restriction-endonuclease-digested DNA separated by SDS-PAGE. J. Gen. Microbiol. 137, 269–276 (1991).
Samuel, J. E., Frazier, M. E. & Mallavia, L. P. Correlation of plasmid type and disease caused by Coxiella burnetii. Infect. Immun. 49, 775–779 (1985). The proposal that pathotype-specific differences exist between clinical isolates of C. burnetii.
Svraka, S., Toman, R., Skultety, L., Slaba, K. & Homan, W. L. Establishment of a genotyping scheme for Coxiella burnetii. FEMS Microbiol. Lett. 254, 268–274 (2006).
Thiele, D. & Willems, H. Is plasmid based differentiation of Coxiella burnetii in 'acute' and 'chronic' isolates still valid? Eur. J. Epidemiol. 10, 427–434 (1994).
Beare, P. A. et al. Genetic diversity of the Q fever agent, Coxiella burnetii, assessed by microarray-based whole-genome comparisons. J. Bacteriol. 188, 2309–2324 (2006).
Russell-Lodrigue, K. E. et al. Coxiella burnetii isolates cause genogroup-specific virulence in mouse and guinea pig models of acute Q fever. Infect. Immun. 77, 5640–5650 (2009). An investigation that clearly establishes pathotype differences in animal models of acute Q fever.
Capo, C. et al. Production of interleukin-10 and transforming growth factor β by peripheral blood mononuclear cells in Q fever endocarditis. Infect. Immun. 64, 4143–4147 (1996).
Meghari, S. et al. Persistent Coxiella burnetii infection in mice overexpressing IL-10: an efficient model for chronic Q fever pathogenesis. PLoS Pathog. 4, e23 (2008).
Chen, S. Y., Hoover, T. A., Thompson, H. A. & Williams, J. C. Characterization of the origin of DNA replication of the Coxiella burnetii chromosome. Ann. NY Acad. Sci. 590, 491–503 (1990).
Suhan, M. et al. Cloning and characterization of an autonomous replication sequence from Coxiella burnetii. J. Bacteriol. 176, 5233–5243 (1994).
Hackstadt, T. & Williams, J. C. Biochemical stratagem for obligate parasitism of eukaryotic cells by Coxiella burnetii. Proc. Natl Acad. Sci. USA 78, 3240–3244 (1981).
Omsland, A. et al. Host cell-free growth of the Q fever bacterium Coxiella burnetii. Proc. Natl Acad. Sci. USA 106, 4430–4434 (2009). Work which characterizes the cell-free growth medium of C. burnetii and determines the anaerobic and acidophilic tropism of this bacterium.
Beare, P. A. et al. Characterization of a Coxiella burnetii ftsZ mutant generated by Himar1 transposon mutagenesis. J. Bacteriol. 191, 1369–1381 (2009). An article detailing the Himar1 -based transposon system for C. burnetii , building the foundation for forward genetics screens.
Beare, P., Sandoz, K., Omsland, A., Rockey, D. & Heinzen, R. Advances in genetic manipulation of obligate intracellular bacterial pathogens. Front. Microbiol. 2, 97 (2011).
This work was supported by US National Institutes of Health grants AI037744, U54 AI057156, AI078213, AI088430, AI090142, and AI092153 (to J.E.S.). The authors thank L. R. Hendrix, K. Russell-Lodrigue and C. Farris for critical review and helpful discussions.
The authors declare no competing financial interests.
- Axenic culture media
Media used for the growth of intracellular bacteria in the absence of host cells.
- Category B select agent
An infectious disease agent of the second highest priority, as defined by the US CDC guidelines for potential misuse. These agents are usually readily transmitted by aerosol, are stable in the environment and cause moderate morbidity and low mortality.
- BL3 containment
A level of biocontainment that includes a separation from general traffic areas by double doors, airlocks and negative air flow. Access is limited to trained personnel and requires users to wear personal protective equipment. All research activities with potential exposure of the agent to the atmosphere are conducted within biosafety cabinets.
A highly conserved family of heterodimeric surface glycoproteins involved in binding to extracellular matrix components such as fibronectin and vitronectin through arginine-glycine-aspartic acid (RGD) domains.
- BL2 containment
A level of biocontainment that involves the use of standard laboratory space in which work using an infectious agent is carried out within a biosafety cabinet.
- SRC tyrosine kinases
A family of kinases that was originally identified through homology to Rous sarcoma virus oncogene v-src and is involved in signal transduction from cellular receptors.
Loss of weight, fatigue and weakness that are associated with severe inflammatory disease and cannot be reversed by nutritional supplementation.
- Himar1-based transposon system
A eukaryotic horn fly element that is extensively used to create mutations in bacteria and relies on only an AT dinucleotide for insertion.
- C. burnetii str. Nine Mile I
The original Coxiella burnetii strain isolated from ticks in 1935. This strain was later serially passaged in embryonated hen eggs and guinea pigs to obtain the avirulent isolate C. burnetii str. Nine Mile II.
- Two-component regulatory system
A bacterial signal transduction system involving a sensor kinase that responds to an environmental stimulus by phosphorylating a response regulator, which controls the transcription of downstream genes.
- Insertion sequences
Mobile genetic elements consisting of short inverted repeats flanking one or more ORFs.
- Ankyrin repeats
Eukaryotic protein domains consisting of repeating segments of 33 amino acids that form a helix–turn–helix motif and mediate protein–protein interactions. These domains are some of the most commonly found domains in eukaryotic proteins.
- Coiled-coil domains
Structural motifs that are found in proteins and consist of 2–5 α-helices wrapped around each other in a left-handed manner to form a superhelix.
- Tetratricopeptide repeats
Structural motifs that mediate protein–protein interactions and are composed of a degenerate ∼34 amino acid sequence that is often arranged in a tandem array.
- F-box domains
Structural motifs composed of approximately 50 amino acids and that contain tryptophan-aspartic acid repeats. These domains function as protein–protein interaction domains. F-box proteins were first characterized as components of ubiquitin ligase complexes.
- Fic domains
(Filamentation induced by cyclic AMP domains). Protein domains that mediate ampylation of proteins and regulate protein function.
About this article
Cite this article
van Schaik, E., Chen, C., Mertens, K. et al. Molecular pathogenesis of the obligate intracellular bacterium Coxiella burnetii. Nat Rev Microbiol 11, 561–573 (2013). https://doi.org/10.1038/nrmicro3049
This article is cited by
Parasites & Vectors (2020)
Novel multiparameter correlates of Coxiella burnetii infection and vaccination identified by longitudinal deep immune profiling
Scientific Reports (2020)
Scientific Reports (2020)
Archives of Public Health (2018)
Permissiveness of bovine epithelial cells from lung, intestine, placenta and udder for infection with Coxiella burnetii
Veterinary Research (2017)