Intact interferon-γ response against Coxiella burnetii by peripheral blood mononuclear cells in chronic Q fever

Schoffelen, Teske; Textoris, Julien; Bleeker‐Rovers, Chantal P.; Amara, Amira Ben; Meer, J.W.M. van der; Netea, Mihai G.; Mège, Jean Louis; Deuren, Marcel van; Vosse, Esther van de

doi:10.1016/j.cmi.2016.11.008

Cited by 19 publications

(23 citation statements)

References 32 publications

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“…On the other hand, measurements of the adaptive cytokine production, such as that with an IFN-␥ assay (17), reflect the response to viable bacteria appropriately. Consistent with previous studies performed by our research group (6,7,16), heat-killed C. burnetii induced higher IFN-␥ and CXCL9 production in chronic Q fever patients than in controls, which could now also be confirmed for viable C. burnetii. Multiple theories may explain the attenuated cytokine production after incubation with viable bacteria compared to that of heat-killed bacteria.…”

Section: Discussionsupporting

confidence: 91%

“…IFN-␥ is crucial in the defense against intracellular pathogens and known to be highly produced upon stimulation with heat-killed C. burnetii by chronic Q fever patients, in contrast to healthy controls (6,7). In contrast to the mostly innate cytokines, IFN-␥ production was not influenced by C. burnetii viability in chronic Q fever patients.…”

Section: Fig 2 (A To D)mentioning

confidence: 92%

“…To evaluate the systemic immune response in chronic Q fever patients, various studies examined the cytokine and chemokine response to heat-killed C. burnetii. Nearly all of these studies showed a robust innate cytokine response in chronic Q fever patients, with a strikingly more profound production of interferon gamma (IFN-␥) than in Q fever seronegative controls who lacked IFN-␥ response (6)(7)(8)(9). Various studies also showed a higher production of anti-inflammatory interleukin-10 (IL-10) in chronic Q fever patients (10)(11)(12)(13).…”

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confidence: 99%

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Viable Coxiella burnetii Induces Differential Cytokine Responses in Chronic Q Fever Patients Compared to Heat-Killed Coxiella burnetii

Jansen¹,

Dinkla

Roest

et al. 2018

Infect Immun

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Cytokine responses of chronic Q fever patients to the intracellular bacterium have mostly been studied using stimulation of immune cells with heat-killed due to the extensive measures needed to work with viable biosafety level 3 agents. Whether research with heat-killed can be translated to immune responses to viable is imperative for the interpretation of previous and future studies with heat-killed Peripheral blood mononuclear cells (PBMCs) of chronic Q fever patients ( = 10) and healthy controls ( = 10) were stimulated with heat-killed or viable of two strains, Nine Mile and the Dutch outbreak strain 3262, for 24 h, 48 h, and 7 days in the absence or presence of serum containing anti- antibodies. When stimulated with viable , PBMCs of chronic Q fever patients and controls produced fewer proinflammatory cytokines (interleukin-6 [IL-6], tumor necrosis factor alpha, and IL-1β) after 24 h than after stimulation with heat-killed In the presence of Q fever seronegative serum, IL-10 production was higher after stimulation with viable rather than heat-killed ; however, when incubating with anti- antibody serum, the effect on IL-10 production was reduced. Levels of adaptive, merely T-cell-derived cytokine (gamma interferon, IL-17, and IL-22) and CXCL9 production were not different between heat-killed and viable stimulatory conditions. Results from previous and future research with heat-killed should be interpreted with caution for innate cytokines, but heat-killed -induced adaptive cytokine production is representative of stimulation with viable bacteria.

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Section: Discussionsupporting

confidence: 91%

Section: Fig 2 (A To D)mentioning

confidence: 92%

mentioning

confidence: 99%

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Viable Coxiella burnetii Induces Differential Cytokine Responses in Chronic Q Fever Patients Compared to Heat-Killed Coxiella burnetii

Jansen¹,

Dinkla

Roest

et al. 2018

Infect Immun

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“…Evidently, the IFNγ re-call response of circulating T-cells in individuals with chronic Q fever is fully functional – both in response to individual epitopes and whole-cell C. burnetii . This is in line with previous studies using IFNγ ELISA following whole blood stimulation (14, 15) and ELISpot using freshly isolated PBMCs (16). If this strong IFNγ response is insufficient to promote clearance of infection foci by activating C. burnetii -infected monocytes/macrophages then the defect could be downstream of IFNγ signaling as proposed previously (14).…”

Section: Discussionsupporting

confidence: 92%

Coxiella burnetii epitope-specific T-cell responses in chronic Q fever patients

Scholzen¹,

Richard

Moise

et al. 2019

Preprint

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24Infection with Coxiella burnetii, the causative agent of Q fever, can result in life-threatening 25 persistent infection. Reactogenicity hinders worldwide implementation of the only licensed 26 human Q fever vaccine. We previously demonstrated long-lived immunoreactivity in individuals 27 with past symptomatic and asymptomatic Coxiella infection (convalescents) to promiscuous 28 HLA-class II C. burnetii epitopes, providing the basis for a novel T-cell-targeted subunit 29 vaccine. Here we investigated in a cohort of 22 individuals with persistent infection (chronic Q 30 fever) whether they recognize the same set of epitopes, or distinct epitopes that could be 31 candidates for a therapeutic vaccine or aid in the diagnosis of persistent infection. 32Individuals with chronic Q fever showed strong class II epitope-specific cultured ELISpot 33 responses largely overlapping with the peptide repertoire identified previously for convalescents. 34Five additional peptides were recognized more frequently by chronic subjects, but there was no 35 combination of epitopes uniquely recognized by or non-reactive in chronic Q fever subjects. 36Consistent with more recent/prolonged exposure, we found, however, stronger direct ex vivo 37 responses to whole-cell C. burnetii and individual peptides in direct ELISpot than in 38 convalescents. 39In conclusion, we have validated and expanded a previously published set candidate epitopes for 40 a novel T-cell targeted subunit Q fever vaccine in the context of chronic Q fever patients and 41 demonstrated that they successfully mounted a T-cell response comparable to that of 42 convalescents. Finally, we demonstrate that individuals treated for chronic Q fever mount a 43 broader ex vivo response to class II epitopes than convalescents, which could be explored for 44 diagnostic purposes. 45 46 Q fever is a zoonotic disease that is endemic in many countries worldwide. It is caused by the 47 environmentally highly stable small Gram-negative coccobacillus Coxiella burnetii, which is 48 transmitted to humans predominantly by aerosol from infected ruminants such as goats, sheep 49 and cattle (1). Outbreaks usually occur in the occupational setting including the livestock 50 industry and deployed military personnel (1). Coxiella outbreaks can also occur in the general 51 population, the largest to date being the outbreak in the Netherlands from 2007-2010 with an 52 estimated 40,000 infections at the center of the epidemic area alone (2). While infection remains 53 asymptomatic in an estimated 50-60% of individuals and acute symptomatic infection is readily 54 treatable with antibiotics, a large proportion (10-20%) of individual with acute Q fever later 55 develop Q fever fatigue syndrome. Further, 1-5% of (often asymptomatically) infected 56 individuals progress to persistent infection also known as chronic Q fever. Chronic Q fever has a 57 poor prognosis and manifests as endocarditis, infected aneurysms or vascular prosthesis infection 58 in individuals with specific risk factors (1, 3).5...

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“…Evidently, the IFN-␥ recall response of circulating T cells in individuals with chronic Q fever is fully functional, both in response to individual epitopes and in response to whole-cell C. burnetii. This is in line with previous studies using IFN-␥ enzyme-linked immunosorbent assay (ELISA) following whole-blood stimulation (14,15) and ELISpot using freshly isolated PBMCs (16). If this strong IFN-␥ response is insufficient to promote clearance of infection foci by activating C. burnetii-infected monocytes/macrophages, then the defect could be downstream of IFN-␥ signaling, as proposed previously (14).…”

Section: Discussionsupporting

confidence: 89%

Coxiella burnetii Epitope-Specific T-Cell Responses in Patients with Chronic Q Fever

Scholzen¹,

Richard

Moise

et al. 2019

Infect Immun

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Infection with Coxiella burnetii, the causative agent of Q fever, can result in life-threatening persistent infection. Reactogenicity hinders worldwide implementation of the only licensed human Q fever vaccine. We previously demonstrated long-lived immunoreactivity in individuals with past symptomatic and asymptomatic Coxiella infection (convalescents) to promiscuous HLA class II C. burnetii epitopes, providing the basis for a novel T-cell targeted subunit vaccine. In this study, we investigated in a cohort of 22 individuals treated for persistent infection (chronic Q fever) whether they recognize the same set of epitopes or distinct epitopes that could be candidates for a therapeutic vaccine or aid in the diagnosis of persistent infection. In cultured enzyme-linked immunosorbent spot (ELISpot) assays, individuals with chronic Q fever showed strong class II epitope-specific responses that were largely overlapping with the peptide repertoire identified previously for convalescents. Five additional peptides were recognized more frequently by chronic subjects, but there was no combination of epitopes uniquely recognized by or nonreactive in subjects with chronic Q fever. Consistent with more recent/prolonged exposure, we found, however, stronger ex vivo responses by direct ELISpot to both whole-cell C. burnetii and individual peptides in chronic patients than in convalescents. In conclusion, we have validated and expanded a previously published set of candidate epitopes for a novel T-cell targeted subunit Q fever vaccine in treated patients with chronic Q fever and demonstrated that they successfully mounted a T-cell response comparable to that of convalescents. Finally, we demonstrated that individuals treated for chronic Q fever mount a broader ex vivo response to class II epitopes than convalescents, which could be explored for diagnostic purposes.

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Intact interferon-γ response against Coxiella burnetii by peripheral blood mononuclear cells in chronic Q fever

Cited by 19 publications

References 32 publications

Viable Coxiella burnetii Induces Differential Cytokine Responses in Chronic Q Fever Patients Compared to Heat-Killed Coxiella burnetii

Viable Coxiella burnetii Induces Differential Cytokine Responses in Chronic Q Fever Patients Compared to Heat-Killed Coxiella burnetii

Coxiella burnetii epitope-specific T-cell responses in chronic Q fever patients

Coxiella burnetii Epitope-Specific T-Cell Responses in Patients with Chronic Q Fever

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