Abstract
ObjectivesChronic Q fever is a persistent infection with the intracellular bacterium Coxiella burnetii. Development of chronic Q fever is associated with single nucleotide polymorphisms (SNPs) in genes encoding for pattern recognition receptors, for phagolysosomal pathway components and for matrix metalloproteinases (MMPs). We evaluated the association of SNPs in these innate-immunity and MMP genes with clinical outcomes. MethodsSNPs were selected from previous association studies and analysed in a cohort of patients with chronic Q fever. The primary outcome was all-cause mortality; secondary outcomes were therapy failure and chronic Q fever–related complications. Subdistribution hazard ratios (SHR) were calculated. ResultsNineteen SNPs were analysed in 134 patients with proven and 29 with probable chronic Q fever. In multivariable analysis, none of the selected SNPs was associated with all-cause mortality. However, SNP rs3751143 located in P2RX7 appeared to be associated with therapy failure (SHR 2.42; 95% confidence interval, 1.16–5.05; p 0.02), which is in line with other reports, showing that a loss of function of the P2X7 receptor leads to inefficient killing of intracellular organisms. In addition, SNP rs7125062 located in MMP1, involved in the cleavage of extracellular matrix, was associated with fewer chronic Q fever–related complications such as acute aneurysms (SHR 0.49; 95% confidence interval, 0.29–0.83; p 0.008). ConclusionsA polymorphism in P2RX7, known to lead to loss of function of the receptor and inefficient killing of intracellular organisms, and a polymorphism in MMP1 were respectively associated with more therapy failures and fewer complications such as acute aneurysms in patients with chronic Q fever.
Highlights
The immune response to C. burnetii is initiated after pattern recognition receptors such as Toll-like receptors (TLRs) and nucleotide-binding oligomerization domains (NOD) recognize the bacterium [8]
The occurrence of complications in chronic Q fever patients may be linked to genetic variation in matrix metalloproteinases (MMPs) genes. In this retrospective cohort study involving patients with chronic Q fever, we investigated whether genetic variations in innate immunity and MMP genes play a role in mortality, therapy failure or chronic Q fevererelated complications
Reasons for withholding therapy were chronic Q fever not recognized by clinician (n 1⁄4 3) and unknown (n 1⁄4 2)
Summary
Known risk factors for the development of chronic Q fever, associated with the focus of the infection, are vascular prosthesis, aneurysms, and valvulopathy [6]. Genetic factors associated with the immune response to C. burnetii have recently been shown to contribute to the progression to chronic Q fever in individuals with these focalizing risk factors [7]. Despite the bacteriolytic properties of the phagolysosome that is being formed as part of the cellular response of macrophages, C. burnetii manages to survive and replicate itself in the Coxiella-containing vacuole. Proteins involved in this phagolysosomal pathway are Rab, Rab and autophagy proteins, among others [9,10]. Eradication of C. burnetii is aided by reactive oxygen species, nitric oxide and innate immune receptor P2X7 [11]
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