A combination of interferon-gamma and interleukin-2 production by Coxiella burnetii-stimulated circulating cells discriminates between chronic Q fever and past Q fever

Schoffelen, Teske; Sprong, Tom; Bleeker‐Rovers, Chantal P.; Wegdam-Blans, Marjolijn C A; Ammerdorffer, Anne; Pronk, M. J. H.; Soethoudt, Y.E.P.; Kasteren, M.E.E. van; Herremans, Tineke; Bijlmer, H. A.; Netea, Mihai G.; Meer, J.W.M. van der; Joosten, Leo A. B.; Deuren, Marcel van

doi:10.1111/1469-0691.12423

Cited by 30 publications

(51 citation statements)

References 30 publications

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“…Previously, our group showed that antigen-specific IFNγ production was significantly higher in QFS patients ( n = 28; 319.4 pg/mL) than in Q fever seropositive controls ( n = 135; 120 pg/mL) [8]. It was also shown that antigen-specific IFNγ production is a useful tool for diagnosing a previous Q fever infection [13], and adding antigen-specific IL-2 production helped discriminate chronic Q fever patients from Q fever seropositive controls and QFS patients [8, 17]. In this study, antigen-specific IFNγ production was not significantly higher in QFS patients than in asymptomatic Q fever seropositive controls.…”

Section: Discussionmentioning

confidence: 99%

Interferon-γ and CXCL10 responses related to complaints in patients with Q fever fatigue syndrome

Raijmakers

Jansen

Keijmel

et al. 2018

Eur J Clin Microbiol Infect Dis

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Approximately 20% of patients with acute Q fever develop Q fever fatigue syndrome (QFS), a debilitating fatigue syndrome. This study further investigates the role of C. burnetii-specific IFNγ, but also IL-2, CXCL9, CXCL10, and CXLC11 production in QFS patients. C. burnetii-specific IFNy, IL-2, CXCL9, CXCL10, and CXCL11 production were tested in ex vivo stimulated whole blood of QFS patients who recovered from their complaints (n = 8), QFS patients with persisting complaints (n = 27), and asymptomatic Q fever seropositive controls (n = 10). With the exclusion of one outlier, stimulation with C. burnetii revealed significantly higher IFNy and CXCL10 production in QFS patients with persisting complaints (medians 288.0 and 176.0 pg/mL, respectively) than in QFS patients who recovered from their complaints (medians 93.0 and 85.5 pg/mL, respectively) (p = 0.041 and 0.045, respectively). No significant differences between groups were found for C. burnetii-specific IL-2, CXCL9, and CXCL11 production. These findings point towards a difference in cell-mediated immunity in QFS patients with persisting complaints compared to those who recovered from their complaints. Such a difference may aid to eventually diagnose QFS more objectively and might serve as an indicator of its underlying etiology.

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Section: Discussionmentioning

confidence: 99%

Interferon-γ and CXCL10 responses related to complaints in patients with Q fever fatigue syndrome

Raijmakers

Jansen

Keijmel

et al. 2018

Eur J Clin Microbiol Infect Dis

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“…Previous studies in humans have looked at the in vitro IFN-γ response in people vaccinated against Q fever, people that have had a previous Q fever infection, and chronic Q fever patients (23–28). However, the testing of in vitro IFN-γ responses in acute human Q fever has not been reported.…”

Section: Discussionmentioning

confidence: 99%

“…These data from human patients infected with an obligate intracellular pathogen are in line with our observations in mice infected with C. burnetii . However, Ruhwald et al (28) showed that IP-10 levels after antigen stimulation are higher compared with IFN-γ levels in human peripheral blood. In our study, we found that IP-10 was induced in antigen-stimulated splenocytes, but levels of IP-10 (1400 pg/mL) were lower than levels of IFN-γ (5000 pg/mL).…”

Section: Discussionmentioning

confidence: 99%

Early cytokine and antibody responses against Coxiella burnetii in aerosol infection of BALB/c mice

Schoffelen¹,

Self²,

Fitzpatrick³

et al. 2015

Diagnostic Microbiology and Infectious Disease

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Coxiella burnetii, a Gram-negative intracellular bacterium, can give rise to Q fever in humans and is transmitted mainly by inhalation of infected aerosols from animal reservoirs. Serology is commonly used to diagnose Q fever, but the early cellular immune response –i.e. C. burnetii-specific interferon(IFN)-γ production in response to antigen challenge– might be an additional diagnostic. Detection of IFN-γ responses has been used to identify past and chronic Q fever infections, but the IFN-γ response in acute Q fever has not been described. By challenging immunocompetent BALB/c mice with aerosols containing phase I C. burnetii, the timing and extent of IFN-γ recall responses was evaluated in an acute C. burnetii infection. Other cytokines were also measured in an effort to identify other potential diagnostic markers. The data show that after initial expansion of bacteria first in lungs and then in other tissues, the infection was cleared from day 10 onwards as reflected by the decreasing number of bacteria. The antigen-induced IFN-γ production by splenocytes coincided with emergence of IgM phase II-antibodies at day 10 post-infection, and preceded appearance of IgG-antibodies. This was accompanied by the production of pro-inflammatory cytokines including IL-6, KC and IP-10, followed by MCP-1, but not by IL-1β and TNF-α, and only very low production of the anti-inflammatory cytokine IL-10. These data suggest that analysis of antigen-specific IFN-γ responses could be a useful tool for diagnosis of acute Q-fever. Moreover, the current model of C.burnetii infection could be used to give new insights into immunological factors that predispose to development of persistent infection.

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“…M2 cells typically have an IL-12 low , IL-23 low , IL-10 high phenotype with a variable capacity to produce inflammatory chemotactic cytokines (Benoit et al, 2008). Other prominent NF-κB-dependent cytokines induced by C. burnetii include TNF-α, IL-1β, IFN-γ, RANTES, MCP-1, SCYA3, SCYA4, and IL-8 (Raoult and Marrie, 1995; Ren et al, 2003; Meghari et al, 2005, 2006, 2008; Soraya Meghari et al, 2006; Benoit et al, 2008; Mahapatra et al, 2010; Amara et al, 2012; Schoffelen et al, 2014; Graham et al, 2016). In addition, C. burnetii regulates host apoptosis at the transcriptional level by altering expression of NF-κB-mediated cell survival-related genes ( cIAP2 and a1/bfl-1 ) (Voth et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Coxiella burnetii Employs the Dot/Icm Type IV Secretion System to Modulate Host NF-κB/RelA Activation

Mahapatra

Gallaher

Smith

et al. 2016

Front. Cell. Infect. Microbiol.

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Coxiella burnetii is the causative agent of Q fever and an obligate intracellular pathogen in nature that survives and grows in a parasitophorous vacuole (PV) within eukaryotic host cells. C. burnetii promotes intracellular survival by subverting apoptotic and pro-inflammatory signaling pathways that are typically regulated by nuclear transcription factor-κB (NF-κB). We and others have demonstrated that C. burnetii NMII proteins inhibit expression of pro-inflammatory cytokines and induce expression of anti-apoptotic genes during infection. Here, we demonstrate that C. burnetii promotes intracellular survival by modulating NF-κB subunit p65 (RelA) phosphorylation, and thus activation, in a Type Four B Secretion System (T4BSS)-dependent manner. Immunoblot analysis of RelA phosphorylated at serine-536 demonstrated that C. burnetii increases NF-κB activation via the canonical pathway. However, RelA phosphorylation levels were even higher in infected cells where bacterial protein or mRNA synthesis was inhibited. Importantly, we demonstrate that inhibition of RelA phosphorylation impairs PV formation and C. burnetii growth. We found that a T4BSS-defective mutant (CbΔdotA) elicited phosphorylated RelA levels similar to those of wild type C. burnetii infection treated with Chloramphenicol. Moreover, cells infected with CbΔdotA or wild type C. burnetii treated with Chloramphenicol showed similar levels of GFP-RelA nuclear localization, and significantly increased localization compared to wild type C. burnetii infection. These data indicate that without de novo protein synthesis and a functional T4BSS, C. burnetii is unable to modulate NF-κB activation, which is crucial for optimal intracellular growth.

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A combination of interferon-gamma and interleukin-2 production by Coxiella burnetii-stimulated circulating cells discriminates between chronic Q fever and past Q fever

Cited by 30 publications

References 30 publications

Interferon-γ and CXCL10 responses related to complaints in patients with Q fever fatigue syndrome

Interferon-γ and CXCL10 responses related to complaints in patients with Q fever fatigue syndrome

Early cytokine and antibody responses against Coxiella burnetii in aerosol infection of BALB/c mice

Coxiella burnetii Employs the Dot/Icm Type IV Secretion System to Modulate Host NF-κB/RelA Activation

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