CXCL9, a promising biomarker in the diagnosis of chronic Q fever

Contains fulltext : 177306.pdf (publisher's version ) (Open Access)BACKGROUND: In the aftermath of the largest Q fever outbreak in the world, diagnosing the potentially lethal complication chronic Q fever remains challenging. PCR, Coxiella burnetii IgG phase I antibodies, CRP and 18F-FDG-PET/CT scan are used for diagnosis and monitoring in clinical practice. We aimed to identify and test biomarkers in order to improve discriminative power of the diagnostic tests and monitoring of chronic Q fever. METHODS: We performed a transcriptome analysis on C. burnetii stimulated PBMCs of 4 healthy controls and 6 chronic Q fever patients and identified genes that were most differentially expressed. The gene products were determined using Luminex technology in whole blood samples stimulated with heat-killed C. burnetii and serum samples from chronic Q fever patients and control subjects. RESULTS: Gene expression of the chemokines CXCL9, CXCL10, CXCL11 and CCL8 was strongly up-regulated in C. burnetii stimulated PBMCs of chronic Q fever patients, in contrast to healthy controls. In whole blood cultures of chronic Q fever patients, production of all four chemokines was increased upon C. burnetii stimulation, but also healthy controls and past Q fever individuals showed increased production of CXCL9, CXCL10 and CCL8. However, CXCL9 and CXCL11 production was significantly higher for chronic Q fever patients compared to past Q fever individuals. In addition, CXCL9 serum concentrations in chronic Q fever patients were higher than in past Q fever individuals. CONCLUSION: CXCL9 protein, measured in serum or as C. burnetii stimulated production, is a promising biomarker for the diagnosis of chronic Q fever

Effects of Coxiella burnetii on MAPKinases phosphorylation

Q fever is a disease caused by Coxiella burnetii, an obligate intracellular bacterium. Acute Q fever is characterized by efficient immune response, whereas chronic Q fever is characterized by dysregulated immune response as demonstrated by the lack of granulomas, the failure of C. burnetii to induce lymphoproliferation, and interferon-γ production. The mitogen-activated protein kinase (MAPK) signaling pathway plays crucial roles in innate immune responses and control of bacterial infections. However, its role in Q fever has not been addressed. First, we investigated the activation of MAPKs p38, c-jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) 1/2 in murine macrophages stimulated with C. burnetii. Coxiella burnetii NM phase I (virulent) and NM phase II (avirulent) induced the activation of JNK and ERK1/2. Avirulent C. burnetii activate p38, whereas C. burnetii did not induce the phosphorylation of p38. Second, the level of p38 activation was studied in Q fever patients. We found that p38 was activated in monocyte-derived macrophages from healthy donors and patients with acute Q fever in response to a potent agonist such as lipopolysaccharide. Interestingly, p38 was not activated in patients with active chronic Q fever and was activated in patients with cured chronic Q fever. These results suggest that the determination of p38 activation may serve as a tool for measuring Q fever activity

The ligands of Numb proteins X1 and X2 are specific markersfor chronic Q fever

Q fever is a disease caused by Coxiella burnetii, an obligate intracellular bacterium. Acute Q fever is spontaneously resolutive and is characterized by an efficient immune response. In contrast, chronic Q fever is characterized by dysregulated immune response, as demonstrated by the failure of C. burnetii to induce lymphoproliferation and the lack of granulomas. Recently, it has been demonstrated that when co-expressed in heterologous mammalian cell lines, the ligands of Numb proteins X1 and X2 (LNX1 and LNX2) regulate the level of the T-cell co-receptor CD8, which plays an essential role in T-cell-mediated immune response. We decided to investigate the expression of LNX1 and LNX2 genes in patients with acute or chronic Q fever. Interestingly, we found a high level of LNX1 and LNX2 mRNAs in endocarditis, the principal manifestation of chronic Q fever, but not in acute Q fever. Our data suggest that LNXs may be used as complementary biomarkers to follow the prognosis of chronic Q fever

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

OBJECTIVES: Q fever is caused by Coxiella burnetii, an intracellular bacterium that infects phagocytes. The aim of the present study was to investigate whether the C. burnetii-induced IFN-gamma response is defective in chronic Q fever patients. METHODS: IFN-gamma was measured in supernatants of C. burnetii-stimulated peripheral blood mononuclear cells (PBMCs) of 17 chronic Q fever patients and 17 healthy individuals. To assess IFN-gamma responses, expression profiles of IFN-gamma-induced genes in C. burnetii-stimulated PBMCs were studied in six patients and four healthy individuals. Neopterin was measured in PBMC supernatants (of eight patients and four healthy individuals) and in sera (of 21 patients and 11 healthy individuals). In a genetic association study, polymorphisms in genes involved in the Th1-cytokine response were analysed in a cohort of 139 chronic Q fever patients and a cohort of 220 control individuals with previous exposition to C. burnetii. RESULTS: IFN-gamma production by C. burnetii-stimulated PBMCs from chronic Q fever patients was significantly higher than in healthy controls. Many IFN-gamma response genes were strongly upregulated in PBMCs of patients. Neopterin levels were significantly higher in PBMC supernatants and sera of patients. The IL12B polymorphisms rs3212227 and rs2853694 were associated with chronic Q fever. CONCLUSIONS: IFN-gamma production, as well as the response to IFN-gamma, is intact in chronic Q fever patients, and even higher than in healthy individuals. Polymorphisms in the IL-12p40 gene are associated with chronic Q fever. Thus, a deficiency in IFN-gamma responses does not explain the failure to clear the infection. The genetic data suggest, however, that the IL-12/IFN-gamma pathway does play a role