<i>C</i><i>oxiella burnetii</i>: turning hostility into a home

Moffatt, Jennifer H.; Newton, Patrice; Newton, Hayley J

doi:10.1111/cmi.12432

Cited by 63 publications

(49 citation statements)

References 73 publications

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“…Successful colonization of mammalian cells by C. burnetii requires the formation of a single CCV that is actively controlled by the bacterial T4SS and its secreted factors (46)(47)(48). Consequently, the T4SS and its secreted factors have been described as a novel virulence factor of Coxiella in mammals (16,17,49).…”

Section: Resultsmentioning

confidence: 99%

Host and Bacterial Factors Control Susceptibility of Drosophila melanogaster to Coxiella burnetii Infection

et al. 2017

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Coxiella burnetii is the causative agent of Q fever, a zoonotic disease that threatens both human and animal health. Due to the paucity of experimental animal models, little is known about how host factors interface with bacterial components and affect pathogenesis. Here, we used Drosophila melanogaster, in conjunction with the biosafety level 2 (BSL2) Nine Mile phase II (NMII) clone 4 strain of C. burnetii, as a model to investigate host and bacterial components implicated in infection. We demonstrate that adult Drosophila flies are susceptible to C. burnetii NMII infection and that this bacterial strain, which activates the immune deficiency (IMD) pathway, is able to replicate and cause mortality in the animals. We show that in the absence of Eiger, the only known tumor necrosis factor (TNF) superfamily homolog in Drosophila, Coxiella-infected flies exhibit reduced mortality from infection. We also demonstrate that the Coxiella type 4 secretion system (T4SS) is critical for the formation of the Coxiella-containing vacuole and establishment of infection in Drosophila. Altogether, our data reveal that the Drosophila TNF homolog Eiger and the Coxiella T4SS are implicated in the pathogenesis of C. burnetii in flies. The Drosophila/NMII model mimics relevant aspects of the infection in mammals, such as a critical role of host TNF and the bacterial T4SS in pathogenesis. Our work also demonstrates the usefulness of this BSL2 model to investigate both host and Coxiella components implicated in infection.KEYWORDS Q fever, innate immunity, IMD, TNF, Eiger, NMII, pathogenesis, T4SS, tumor necrosis factor C oxiella burnetii is an obligate intracellular Gram-negative bacterium and the causative agent of the zoonosis Q fever (1). Acute C. burnetii infection in humans is characterized primarily by influenza-like symptoms and pneumonia. Domestic ruminants act as reservoir hosts of C. burnetii and have been implicated in several outbreaks of Q fever worldwide (1-3). Based on morbidity, low infectious dose, and the environmental stability of the organism, the U.S. Centers for Disease Control and Prevention (CDC) has designated C. burnetii a category B biological weapon agent (4). C. burnetii presents two antigenic forms: a pathogenic phase I variant and an attenuated phase II variant that has a truncated O chain in its lipopolysaccharide (5, 6). C. burnetii phase I is associated with Q fever, whereas phase II does not cause disease in immunocompetent hosts (7-9). The Nine Mile phase II (NMII) clone 4/RSA439 is an attenuated strain of C. burnetii derived from the virulent Nine Mile phase I (NMI) strain through repeated passages in embryonated eggs (5). Although attenuated in immunocompetent hosts, the NMII strain has been shown to be virulent to SCID mice (10) and to cause fever in gamma interferon knockout (IFN-␥ Ϫ/Ϫ ) and Toll-like receptor 2 knockout (TLR2 Ϫ/Ϫ ) mice (11). Because C. burnetii NMI and NMII strains present similar replication kinetics in tissue culture models, the NMII strain has been used as a safer o...

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Section: Resultsmentioning

confidence: 99%

Host and Bacterial Factors Control Susceptibility of Drosophila melanogaster to Coxiella burnetii Infection

et al. 2017

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“…On the contrary, Salmonella enterica serovar Typhimurium uses the SPI-1 substrate SopB to maintain elevated levels of PI(3)P at the surface of Salmonella-containing vacuoles, favoring their biogenesis (39)(40)(41). Based on previous reports, the main source of PI(3)P-positive membranes for CCVs are early endosomes and autophagosomes (4). However, PI(3)P at late endosomes/lysosomes is expected to be further phosphorylated to PI(3,5)P 2 , by the activity of the PI 5-kinase PIKfyve.…”

Section: Discussionmentioning

confidence: 99%

“…Cells were fixed in 3% (wt/vol) paraformaldehyde in PBS solution at room temperature for 30 min or in methanol/acetone (1:1) at −20°C for 5 min. Samples were then rinsed in PBS solution and incubated in blocking solution (0.5% BSA, 50 mM NH 4 Cl in PBS solution, pH 7.4). When appropriate, 0.05% saponin was added to the blocking solution for cell permeabilization.…”

Section: Methodsmentioning

confidence: 99%

“…Key to the successful colonization of host cells is the acidification of CCVs, which activates bacterial metabolism and effectors translocation by a Dot/Icm type IV secretion system (3). Bioinformatics analysis identified more than 300 Coxiella candidate effectors, a third of which have been validated for secretion (1,4). Many Coxiella effectors remain poorly understood or completely uncharacterized, but it is clear that several of these manipulate host vesicular trafficking, allowing CCVs to intercept and recruit membranes, proteins, and lipids from the endocytic, autophagy, and recycling pathways (4).…”

mentioning

confidence: 99%

“…Bioinformatics analysis identified more than 300 Coxiella candidate effectors, a third of which have been validated for secretion (1,4). Many Coxiella effectors remain poorly understood or completely uncharacterized, but it is clear that several of these manipulate host vesicular trafficking, allowing CCVs to intercept and recruit membranes, proteins, and lipids from the endocytic, autophagy, and recycling pathways (4). SNAREs such as VAMP7 and Syntaxin-17 play a key role in this process, mediating the fusion events that lead to the biogenesis of large CCVs that occupy the majority of the host cell cytoplasm (5,6).…”

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confidence: 99%

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Coxiella burnetii effector CvpB modulates phosphoinositide metabolism for optimal vacuole development

Martínez

Allombert

Cantet

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

129

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The Q fever bacterium Coxiella burnetii replicates inside host cells within a large Coxiella-containing vacuole (CCV) whose biogenesis relies on the Dot/Icm-dependent secretion of bacterial effectors. Several membrane trafficking pathways contribute membranes, proteins, and lipids for CCV biogenesis. These include the endocytic and autophagy pathways, which are characterized by phosphatidylinositol 3-phosphate [PI(3)P]-positive membranes. Here we show that the C. burnetii secreted effector Coxiella vacuolar protein B (CvpB) binds PI(3)P and phosphatidylserine (PS) on CCVs and early endosomal compartments and perturbs the activity of the phosphatidylinositol 5-kinase PIKfyve to manipulate PI(3)P metabolism. CvpB association to early endosome triggers vacuolation and clustering, leading to the channeling of large PI(3)P-positive membranes to CCVs for vacuole expansion. At CCVs, CvpB binding to early endosome-and autophagy-derived PI(3)P and the concomitant inhibition of PIKfyve favor the association of the autophagosomal machinery to CCVs for optimal homotypic fusion of the Coxiella-containing compartments. The importance of manipulating PI(3)P metabolism is highlighted by mutations in cvpB resulting in a multivacuolar phenotype, rescuable by gene complementation, indicative of a defect in CCV biogenesis. Using the insect model Galleria mellonella, we demonstrate the in vivo relevance of defective CCV biogenesis by highlighting an attenuated virulence phenotype associated with cvpB mutations.Coxiella burnetii | host-pathogen interactions | phosphoinositides

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Microbial Inhibitors of Apoptosis

Häcker

2016

Encyclopedia of Life Sciences

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Infection with microbial agents (bacteria, fungi, viruses and parasites) is a challenge to a host cell. The host cell's response to infection is complex and entails changes in the activity of a number of intracellular signalling pathways, commonly including the apoptotic machinery. Microbes, if they have evolved the capacity to infect mammals or other complex hosts, have to be able to deal with such defence systems. The lifestyle of microbes varies substantially – viruses, for instance, depend on an intact cell, whereas many bacteria grow on surfaces and are not sensitive to host cell apoptosis. What we know about microbial interference with host cell apoptosis is in accordance with these lifestyles. Viruses often directly target and inhibit the apoptosis machinery with specific proteins, whereas other microbes frequently also interfere with host apoptosis, but this interaction is more frequently indirect. Key Concepts Microbes (bacteria, fungi, viruses and parasites) can vary widely in terms of growth requirements and intimacy of association with host cells. Apoptosis may be induced in cells infected with microbes as a defence mechanism. A number of viruses carry genes whose products can directly interfere with the host cell's apoptosis apparatus. Activation of host cells by microbes may enhance survival of the host cell or a responding immune cell. Activation of antiapoptotic pathways in immune cells by microbial components is a regulatory mechanism of the immune response.

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Coxiella burnetii: turning hostility into a home

Cited by 63 publications

References 73 publications

Host and Bacterial Factors Control Susceptibility of Drosophila melanogaster to Coxiella burnetii Infection

Host and Bacterial Factors Control Susceptibility of Drosophila melanogaster to Coxiella burnetii Infection

Coxiella burnetii effector CvpB modulates phosphoinositide metabolism for optimal vacuole development

Microbial Inhibitors of Apoptosis

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