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Host cell-free growth of the Q fever bacterium Coxiella burnetii

ABSTRACT: The inability to propagate obligate intracellular pathogens under axenic (host cell-free) culture conditions imposes severe experimental constraints that have negatively impacted progress in understanding pathogen virulence and disease mechanisms. Coxiella burnetii, the causative agent of human Q (Query) fever, is an obligate intracellular bacterial pathogen that replicates exclusively in an acidified, lysosome-like vacuole. To define conditions that support C. burnetii growth, we systematically evaluated the organism’s metabolic requirements using expression microarrays, genomic reconstruction, and metabolite typing. This led to development of a complex nutrient medium that supported substantial growth (~ 3 log10) of C. burnetii in a 2.5% oxygen environment. Importantly, axenically grown C. burnetii were highly infectious for Vero cells and exhibited developmental forms characteristic of in vivo grown organisms. Axenic cultivation of C. burnetii will facilitate studies of the organism’s pathogenesis and genetics, and aid development of Q fever preventatives such as an effective subunit vaccine. Furthermore, the systematic approach used here may be broadly applicable to development of axenic media that support growth of other medically important obligate intracellular pathogens.

ORGANISM(S): Coxiella burnetii Chlamydia trachomatis Yersinia pestis Streptococcus pyogenes Borreliella burgdorferi Staphylococcus aureus

PROVIDER: GSE13338 | GEO | 2009/10/21

SECONDARY ACCESSION(S): PRJNA109859

REPOSITORIES: GEO

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Host cell-free growth of the Q fever bacterium Coxiella burnetii

Project description:The inability to propagate obligate intracellular pathogens under axenic (host cell-free) culture conditions imposes severe experimental constraints that have negatively impacted progress in understanding pathogen virulence and disease mechanisms. Coxiella burnetii, the causative agent of human Q (Query) fever, is an obligate intracellular bacterial pathogen that replicates exclusively in an acidified, lysosome-like vacuole. To define conditions that support C. burnetii growth, we systematically evaluated the organismâ??s metabolic requirements using expression microarrays, genomic reconstruction, and metabolite typing. This led to development of a complex nutrient medium that supported substantial growth (~ 3 log10) of C. burnetii in a 2.5% oxygen environment. Importantly, axenically grown C. burnetii were highly infectious for Vero cells and exhibited developmental forms characteristic of in vivo grown organisms. Axenic cultivation of C. burnetii will facilitate studies of the organismâ??s pathogenesis and genetics, and aid development of Q fever preventatives such as an effective subunit vaccine. Furthermore, the systematic approach used here may be broadly applicable to development of axenic media that support growth of other medically important obligate intracellular pathogens. Host cell-free growth, Vero cell growth and carryover baseline of Coxiella burnetii

2010-06-20 | E-GEOD-13338 | biostudies-arrayexpress

Quantitative proteome profiling of Coxiella burnetii reveals major metabolic and stress differences under axenic and cell culture cultivation – proteome dataset

Project description:Coxiella burnetii, a category B select agent, is endemic worldwide, except New Zealand. It causes annually several outbreaks of the zoonotic disease Q fever predominantly in small ruminants. To date, the lipopolysaccharide (LPS), besides a type IV secretion system (T4SS), is the only defined and characterized virulence determinant of C. burnetii. This surface molecule is used to distinguish between virulent (Ph I) and low-virulent (Ph II) organisms, the latter emerge only after frequent passaging in the laboratory. As an obligate intracellular pathogen, targeted genetic modification is still not a routine and labour intensive procedure. The deeper study of novel determinants is complicated and demands not only advanced techniques for axenic and for cell culture-based cultivation but also novel approaches in the high-resolution mass spectrometry. This work is the first proteomic study comparing. C. burnetii Ph I and Ph II propagated in different axenic media and in cell culture.

2019-10-24 | PXD013224 | Pride

Transcription profiling of human monocytes and monocyte-derived macrophages infected with Coxiella burnetii and incubated with apoptotic or necrotic lymphocytes

Project description:Q fever is due to Coxiella burnetii, an obligate intracellular bacterium. We investigated the mechanism of establishment of chronic form of the Q fever that mainlym anifested by endocarditis. We showed that patients with acute Q fever and valvulopathy, who have the higher risk to develop an endocarditis, exhibited high levels of circulating apoptotic cells. We further investigated the effect of the uptake of dead cells on the intracellular fate of the bacterium and the immune response of monocytes and macrophages.

2008-10-09 | E-MEXP-1289 | biostudies-arrayexpress

RpoS regulates genes associated with development of the small cell variant developmental form of Coxiella burnetii

Project description:Coxiella burnetii, the etiological agent of Q fever, undergoes a unique biphasic developmental cycle where bacteria transition from replicating (exponential phase) large cell variant (LCV) forms to a non-replicating, (stationary phase) small cell variant (SCV) forms. The alternative sigma factor RpoS is an essential regulator of stress responses and stationary phase growth in several bacterial species, including Legionella pneumophila, which has a developmental cycle superficially similar to C. burnetii. To characterize RpoS function during C. burnetii growth and developmental, we constructed a C. burnetii ∆rpoS mutant to define the effects on intracellular and axenic growth, as well as, gene regulation during SCV development. C. burnetii ∆rpoS exhibited intracellular growth defects in J774 mouse macrophage-like cells, but not in Vero epithelial cells. RNA sequencing of C. burnetii ∆rpoS revealed that a substantial portion of the C. burnetii genome is regulated by RpoS during SCV development. Genes previously shown to have increased expression during SCV generation, including the expression of the SCV-specific protein ScvA and pathways involved in oxidative stress, arginine transport, and peptidoglycan remodeling pathways, were dysregulated in the rpoS mutant. These genes were enriched for a predicted RpoS-binding site. These data were corroborated with independent assays demonstrating that the C. burnetii rpoS mutant had increased sensitivity to hydrogen peroxide and carbenicillin. Collectively, these results demonstrate that RpoS is essential for the regulation of genes involved in SCV development and growth inside macrophage-like cells.

2019-02-08 | GSE110091 | GEO

Coxiella burnetii infects JEG trophoblastic cell line, a model of placenta infection

Project description:Q fever is a zoonosis caused by Coxiella burnetii, an obligate intracellular bacterium usually found in myeloid cells. The infection is a source of severe obstetrical complications in humans and cattle, and of chronic evolution in pregnant women. As C. burnetii is found in the placenta of aborted foetuses in humans and ruminants, we wondered if it may infect trophoblasts. In this work, we showed that C. burnetii, infected JEG trophoblastic cells without replication and was localized within phagolysosomes. We analyzed gene expression programs induced by C. burnetii in JEG trophoblastic cell line and compared it with transcriptomic program of BeWo trophoblasts in which C. burnetii replicates. These transcriptomic programs induced by C. burnetii in JEG trophoblasts was poor and markedly different from that induced by C. burnetii in BeWo trophoblasts. Hence, the differences in transcriptomic programs may explain the different intracellular fate of C. burnetii in JEG and BeWo cells. Our results suggest that C. burnetii may use trophoblastic cells as a reservoir by interfering with gene expression. Comparaison between unstimulated JEG cell line and Coxiella burnetii stimulated JEG cell line (bacterial ratio 200:1) for 6 hours

2012-12-07 | E-GEOD-30330 | biostudies-arrayexpress

Coxiella burnetii infects JEG trophoblastic cell line, a model of placenta infection

2012-12-07 | GSE30330 | GEO

Macrophage infectivity potentiator protein, a peptidyl prolyl cis/trans isomerase, essential for Coxiella burnetii growth and pathogenesis

Project description:Coxiella burnetii is a Gram-negative intracellular pathogen that causes the debilitating disease Q fever, which affects both animals and humans. The only available vaccine, Q-Vax, is effective but has a high risk of severe adverse reactions, limiting its use as a countermeasure to contain outbreaks. Therefore, it is essential to identify new drug targets to treat this infection. Macrophage infectivity potentiator (Mip) proteins catalyze the folding of proline-containing proteins through their peptidyl prolyl cis-trans isomerase (PPIase) activity and have been shown to play an important role in the virulence of several pathogenic bacteria but to date its role in C. burnetii pathogenesis has not been investigated. This study demonstrates that CbMip is likely to be an essential protein in C. burnetii. Pipecolic acid derived compounds, SF235 and AN296 demonstrate inhibitory activities against CbMip and these compounds were found to significantly inhibit intracellular replication of C. burnetii in both HeLa and THP-1 cells. Furthermore, SF235 and AN296 were also found to exhibit antibiotic properties against both the virulent (Phase I) and avirulent (Phase II) forms of C. burnetii Nine Mile Strain RSA439 in axenic culture with comparative proteomic demonstrating selective alterations in response to these agents. This study also showed that exposure of C. burnetii to Mip inhibitors resulted in increased sensitivity to oxidative stress. Furthermore, compounds SF235 and AN296 demonstrated protective activity in vivo and significantly improved the survival of Galleria mellonella infected with C. burnetii. These results suggest that unlike in other bacteria, Mip in C. burnetii is required for growth and replication and that inhibitors against CbMip offer potential as novel therapeutics against C. burnetii.

2023-06-15 | PXD036679 | Pride

Interferon-Î³ response against C. burnetii of peripheral blood mononuclear cells in the development of chronic Q fever

Project description:Background: Q fever is caused by the Coxiella burnetii, an intracellular bacterium that infects mononuclear cells. In some individuals, it causes a persistent cardiovascular infection (chronic Q fever). The aim of present study was to investigate the C. burnetii-induced IFN-Î³ response in chronic Q fever patients. Methods: IFN-Î³ was measured in supernatants of C. burnetii-stimulated peripheral blood mononuclear cells (PBMCs) of patients. Gene-expression profiles of the IFN-Î³ pathway in PBMCs after incubation with C. burnetii were compared between chronic Q fever patients and control individuals. Results: IFN-Î³ production by PBMCs of chronic Q fever patients incubated with C. burnetii in vitro, was significantly higher compared to controls. In transcriptome analysis, genes downstream of IFN-Î³ were strongly upregulated in patients. Conclusion: Present study showed that IFN-Î³ production and the response to IFN-Î³ seems to be intact in chronic Q fever patients. PBMC were purified from Q fever patients (n=6) or healthy volunteers (n=4), and then stimulated by Coxiella burnetii, LPS or left untreated (NS)

2016-03-13 | E-GEOD-66476 | biostudies-arrayexpress

Interferon-γ response against C. burnetii of peripheral blood mononuclear cells in the development of chronic Q fever

Project description:Background: Q fever is caused by the Coxiella burnetii, an intracellular bacterium that infects mononuclear cells. In some individuals, it causes a persistent cardiovascular infection (chronic Q fever). The aim of present study was to investigate the C. burnetii-induced IFN-γ response in chronic Q fever patients. Methods: IFN-γ was measured in supernatants of C. burnetii-stimulated peripheral blood mononuclear cells (PBMCs) of patients. Gene-expression profiles of the IFN-γ pathway in PBMCs after incubation with C. burnetii were compared between chronic Q fever patients and control individuals. Results: IFN-γ production by PBMCs of chronic Q fever patients incubated with C. burnetii in vitro, was significantly higher compared to controls. In transcriptome analysis, genes downstream of IFN-γ were strongly upregulated in patients. Conclusion: Present study showed that IFN-γ production and the response to IFN-γ seems to be intact in chronic Q fever patients.

2016-03-13 | GSE66476 | GEO

Mast cell cytonemes as a defense mechanism against Coxiella burnetii

Project description:Mast cells (MCs) are critical mediators of inflammation; however, their microbicidal activity against invading pathogens remains largely unknown. Here, we describe a nonpreviously reported antibacterial mechanism used by MCs against Coxiella burnetii, the agent of Q fever. We show that C. burnetii interaction with MCs does not result in bacterial uptake but rather induces the formation of extracellular actin filaments named cytonemes. MC cytonemes express cathelicidin and neutrophil elastase and mediate the capture and destruction of entrapped bacteria. We provide evidence that MC cytoneme formation and microbicidal activity are dependent on the cooperation of the scavenger receptor CD36 and Toll-like receptor 4. Taken together, our results suggest that MCs use an extracellular sophisticated mechanism of defense to eliminate intracellular pathogens, such as C. burnetii, before their entry into host cells.

2019-03-13 | GSE111971 | GEO

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