Link between Impaired Maturation of Phagosomes and Defective<i>Coxiella burnetii</i>Killing in Patients with Chronic Q Fever

Ghigo, Éric; Honstettre, Amélie; Capo, Christian; Gorvel, Jean‐Pierre; Raoult, Didier; Mège, Jean‐Louis

doi:10.1086/425041

Cited by 63 publications

(67 citation statements)

References 27 publications

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“…In Coxiella infection of mammalian cells, following internalization, the nascent CCV proceeds through the default endocytic pathway and ultimately fuses with the lysosomal compartment (61). The mature CCV is then decorated with late vacuolar markers, such as Rab7, LAMP1, LAMP2, and LAMP3, and autophagosome markers, such as LC3 and Rab24 (61)(62)(63)(64)(65). We show that, similar to mammalian cells, LAMP1 surrounds the CCV at 4 days postinfection, suggesting that the default endocytic pathway of infected Drosophila S2 cells was not disturbed by infection.…”

Section: Discussionmentioning

confidence: 74%

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: Discussionmentioning

confidence: 74%

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

et al. 2017

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“…The inflammatory-cytokine changes in immunocompetent mice in this study were similar to those in humans with acute Q fever (10): TNF-␣ and IL-6 were upregulated, but IL-1␤ was not. IFN-␥ increased in CB-17 mice infected with group I isolates, and it is associated with the control of bacterial growth, stimulates phagosome-lysosome fusion, and may enable monocytes/macrophages to kill C. burnetii (13,14). A difference in vacuole formation between isolates has also been shown, with NM and S developing within single large vacuoles while Priscilla occupied several smaller vacuoles per cell (18).…”

Section: Vol 77 2009mentioning

confidence: 99%

“…For example, human immunodeficiency virus infection is a risk factor for the development of chronic Q fever endocarditis (9,29). Deficiencies in the hostspecific cell-mediated immune response in Q fever patients have been associated with the suppression of monocyte and macrophage activities (25), and monocytes from chronic-Q fever patients have been shown to be defective in phagosome maturation and to have impaired C. burnetii-killing potential, regulated in part by elevated interleukin-10 (IL-10) expression (14). There is strong clinical evidence to support the role of increased host production of IL-10 in the development of both Q fever endocarditis and chronic fatigue syndrome (11,12,21,39).…”

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confidence: 99%

Coxiella burnetiiIsolates Cause Genogroup-Specific Virulence in Mouse and Guinea Pig Models of Acute Q Fever

et al. 2009

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Q fever is a zoonotic disease of worldwide significance caused by the obligate intracellular bacterium Coxiella burnetii. Humans with Q fever may experience an acute flu-like illness and pneumonia and/or chronic hepatitis or endocarditis. Various markers demonstrate significant phylogenetic separation between and clustering among isolates from acute and chronic human disease. The clinical and pathological responses to infection with phase I C. burnetii isolates from the following four genomic groups were evaluated in immunocompetent and immunocompromised mice and in guinea pig infection models: group I (Nine Mile, African, and Ohio), group IV (Priscilla and P), group V (G and S), and group VI (Dugway). Isolates from all of the groups produced disease in the SCID mouse model, and genogroup-consistent trends were noted in cytokine production in response to infection in the immunocompetent-mouse model. Guinea pigs developed severe acute disease when aerosol challenged with group I isolates, mild to moderate acute disease in response to group V isolates, and no acute disease when infected with group IV and VI isolates. C. burnetii isolates have a range of disease potentials; isolates within the same genomic group cause similar pathological responses, and there is a clear distinction in strain virulence between these genomic groups.

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“…Production of the anti-inflammatory mediator interleukin 10 (IL-10), which downmodulates TNF-␣, reverses this effect (16). Whereas TNF-␣ and IL-6 are innate cytokines produced early, expression of IL-10 appears to occur later in infection and has largely been associated with development of chronic Q fever in human patients (14,17,18). IFN-␥, produced by T cells and natural killer cells, is critical for protection of mice from C. burnetii infection and eventual clearance of the bacteria (18)(19)(20)(21).…”

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Type I Interferon Counters or Promotes Coxiella burnetii Replication Dependent on Tissue

et al. 2016

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Coxiella burnetii is an intracellular pathogen and the cause of Q fever. Gamma interferon (IFN-␥) is critical for host protection from infection, but a role for type I IFN in C. burnetii infection has not been determined. Type I IFN supports host protection from a related pathogen, Legionella pneumophila, and we hypothesized that it would be similarly protective in C. burnetii infection. In contrast to our prediction, IFN-␣ receptor-deficient (IFNAR ؊/؊ ) mice were protected from C. burnetii-induced infection. Therefore, the role of type I IFN in C. burnetii infection was distinct from that in L. pneumophila. Mice treated with a double-stranded-RNA mimetic were protected from C. burnetii-induced weight loss through an IFNAR-independent pathway. We next treated mice with recombinant IFN-␣ (rIFN-␣). When rIFN-␣ was injected by the intraperitoneal route during infection, disease-induced weight loss was exacerbated. Mice that received rIFN-␣ by this route had dampened interleukin 1␤ (IL-1␤) expression in bronchoalveolar lavage fluids. However, when rIFN-␣ was delivered to the lung, bacterial replication was decreased in all tissues. Thus, the presence of type I IFN in the lung protected from infection, but when delivered to the periphery, type I IFN enhanced disease, potentially by dampening inflammatory cytokines. To better characterize the capacity for type I IFN induction by C. burnetii, we assessed expression of IFN-␤ transcripts by human macrophages following stimulation with lipopolysaccharide (LPS) from C. burnetii. Understanding innate responses in C. burnetii infection will support the discovery of novel therapies that may be alternative or complementary to the current antibiotic treatment.

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Link between Impaired Maturation of Phagosomes and DefectiveCoxiella burnetiiKilling in Patients with Chronic Q Fever

Cited by 63 publications

References 27 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 burnetiiIsolates Cause Genogroup-Specific Virulence in Mouse and Guinea Pig Models of Acute Q Fever

Type I Interferon Counters or Promotes Coxiella burnetii Replication Dependent on Tissue

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