Variation in immune response genes and chronic Q fever. Concepts: preliminary test with post-Q fever fatigue syndrome

Helbig, Karla J.; Heatley, Sue L.; Harris, R. J.; Mullighan, Charles G.; Bardy, Peter; Marmion, B. P.

doi:10.1038/sj.gene.6363912

Cited by 27 publications

(26 citation statements)

References 23 publications

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“…Our results do not discount a protective role for Nramp1 during animal infection. Indeed, patients with post-Q fever fatigue syndrome show an increased frequency of allelic variants of Nramp1 [63]. Conversely, there is no correlation between the expression of Nramp1 and the sensitivity of various inbred mouse strains to C .…”

Section: Discussionmentioning

confidence: 99%

Robust growth of avirulent phase II Coxiella burnetii in bone marrow-derived murine macrophages

et al. 2017

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Published data show that murine bone marrow-derived macrophages (BMDM) restrict growth of avirulent phase II, but not virulent phase I, Coxiella burnetii. Growth restriction of phase II bacteria is thought to result from potentiated recognition of pathogen-associated molecular patterns, which leads to production of inhibitory effector molecules. Past studies have used conditioned medium from L-929 murine fibroblasts as a source of macrophage-colony stimulating factor (M-CSF) to promote differentiation of bone marrow-derived myeloid precursors into macrophages. However, uncharacterized components of conditioned medium, such as variable amounts of type I interferons, can affect macrophage activation status and their permissiveness for infection. In the current study, we show that the C. burnetii Nine Mile phase II (NMII) strain grows robustly in primary macrophages from C57BL/6J mice when bone marrow cells are differentiated with recombinant murine M-CSF (rmM-CSF). Bacteria were readily internalized by BMDM, and replicated within degradative, LAMP1-positive vacuoles to achieve roughly 3 logs of growth over 6 days. Uninfected BMDM did not appreciably express CD38 or Egr2, markers of classically (M1) and alternatively (M2) activated macrophages, respectively, nor did infection change the lack of polarization. In accordance with an M0 phenotype, infected BMDM produced moderate amounts of TNF and nitric oxide. Similar NMII growth results were obtained using C57BL/6J myeloid progenitors immortalized with an estrogen-regulated Hoxb8 (ER-Hoxb8) oncogene. To demonstrate the utility of the ER-Hoxb8 system, myeloid progenitors from natural resistance-associated macrophage protein 1 (Nramp1) C57BL/6J knock-in mice were transduced with ER-Hoxb8, and macrophages were derived from immortalized progenitors using rmM-CSF and infected with NMII. No difference in growth was observed when compared to macrophages from wild type mice, indicating depletion of metal ions by the Nramp1 transporter does not negatively impact NMII growth. Results with NMII were recapitulated in primary macrophages where C57BL/6J Nramp1+ BMDM efficiently killed Salmonella enterica serovar Typhimurium. M-CSF differentiated murine macrophages from bone marrow and conditional ER-Hoxb8 myeloid progenitors will be useful ex vivo models for studying Coxiella-macrophage interactions.

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Section: Discussionmentioning

confidence: 99%

Robust growth of avirulent phase II Coxiella burnetii in bone marrow-derived murine macrophages

et al. 2017

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“…Although predisposing host factors are clearly important in the development of human acute or chronic Q fever (32,51), C. burnetii isolates also exhibit distinct phenotypes in terms of infectivity of cell culture (53), cytopathic effects on host cells (53,66), and pathogenicity in animal models of Q fever (43,64,68). The general consensus of these studies is that the NMI reference isolate (genomic group I), biologically representative of human acute disease isolates, is more infectious, grows faster in cell culture, and is more virulent in animal models of infection than chronic disease isolates of genomic groups IV and V. Evidence of C. burnetii pathotype-specific ORFs was recently provided by Glazunova et al (24), who found by multispacer sequence typing analysis that both plasmid type and genotype correlate with disease outcome.…”

Section: Discussionmentioning

confidence: 99%

Genetic Diversity of the Q Fever Agent,Coxiella burnetii, Assessed by Microarray-Based Whole-Genome Comparisons

Beare¹,

Samuel

Howe³

et al. 2006

J Bacteriol

125

132

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Coxiella burnetii, a gram-negative obligate intracellular bacterium, causes human Q fever and is considered a potential agent of bioterrorism. Distinct genomic groups of C. burnetii are revealed by restriction fragmentlength polymorphisms (RFLP). Here we comprehensively define the genetic diversity of C. burnetii by hybridizing the genomes of 20 RFLP-grouped and four ungrouped isolates from disparate sources to a high-density custom Affymetrix GeneChip containing all open reading frames (ORFs) of the Nine Mile phase I (NMI) reference isolate. We confirmed the relatedness of RFLP-grouped isolates and showed that two ungrouped isolates represent distinct genomic groups. Isolates contained up to 20 genomic polymorphisms consisting of 1 to 18 ORFs each. These were mostly complete ORF deletions, although partial deletions, point mutations, and insertions were also identified. A total of 139 chromosomal and plasmid ORFs were polymorphic among all C. burnetii isolates, representing ca. 7% of the NMI coding capacity. Approximately 67% of all deleted ORFs were hypothetical, while 9% were annotated in NMI as nonfunctional (e.g., frameshifted). The remaining deleted ORFs were associated with diverse cellular functions. The only deletions associated with isogenic NMI variants of attenuated virulence were previously described large deletions containing genes involved in lipopolysaccharide (LPS) biosynthesis, suggesting that these polymorphisms alone are responsible for the lower virulence of these variants. Interestingly, a variant of the Australia QD isolate producing truncated LPS had no detectable deletions, indicating LPS truncation can occur via small genetic changes. Our results provide new insight into the genetic diversity and virulence potential of Coxiella species.

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“…Studies on the immune reaction in naturally or experimentally infected individuals have suggested that cellular immunity and the synthesis of IFN γ are essential for control of Coxiella burnetii infection [68–70]. Helbig et al [69] demonstrated the predominant role of IFN γ , its level of production determining the outcome of infection. Indeed, IFN γ has been successfully tested to treat Q fever in patients not responding to antibiotic treatment [71, 72].…”

Section: Pathogenesismentioning

confidence: 99%

Q Fever: Current State of Knowledge and Perspectives of Research of a Neglected Zoonosis

Porter

Czaplicki²,

Mainil

et al. 2011

International Journal of Microbiology

195

201

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Q fever is an ubiquitous zoonosis caused by an resistant intracellular bacterium, Coxiella burnetii. In certain areas, Q fever can be a severe public health problem, and awareness of the disease must be promoted worldwide. Nevertheless, knowledge of Coxiella burnetii remains limited to this day. Its resistant (intracellular and environmental) and infectious properties have been poorly investigated. Further understanding of the interactions between the infected host and the bacteria is necessary. Domestic ruminants are considered as the main reservoir of bacteria. Infected animals shed highly infectious organisms in milk, feces, urine, vaginal mucus, and, very importantly, birth products. Inhalation is the main route of infection. Frequently asymptomatic in humans and animals, Q fever can cause acute or chronic infections. Financial consequences of infection can be dramatic at herd level. Vaccination with inactive whole-cell bacteria has been performed and proved effective in humans and animals. However, inactive whole-cell vaccines present several defects. Recombinant vaccines have been developed in experimental conditions and have great potential for the future. Q fever is a challenging disease for scientists as significant further investigations are necessary. Great research opportunities are available to reach a better understanding and thus a better prevention and control of the infection.

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Variation in immune response genes and chronic Q fever. Concepts: preliminary test with post-Q fever fatigue syndrome

Cited by 27 publications

References 23 publications

Robust growth of avirulent phase II Coxiella burnetii in bone marrow-derived murine macrophages

Robust growth of avirulent phase II Coxiella burnetii in bone marrow-derived murine macrophages

Genetic Diversity of the Q Fever Agent,Coxiella burnetii, Assessed by Microarray-Based Whole-Genome Comparisons

Q Fever: Current State of Knowledge and Perspectives of Research of a Neglected Zoonosis

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