Role of autophagy genetic variants for the risk of Candida infections.
Candida albicans can cause candidemia in neutropenic and critically ill patients and oropharyngeal candidiasis in human immunodeficiency virus (HIV)-positive patients with low CD4(+) counts. Because all patients at risk do not develop Candida infections, it is possible that a patient's genetic background might play a role in his or her susceptibility to infection. Autophagy mediates pathogen clearance and modulation of inflammation. Our aim was to assess the effect of genetic variations in the ATG16L1 and IRGM autophagy genes on the susceptibility of patients with candidemia and oropharyngeal candidiasis. We assessed genetic variations in the ATG16L1 and IRGM genes in a cohort of candidemia patients of both African and European origin. In addition, we evaluated the effect of these polymorphisms on the susceptibility to oropharyngeal candidiasis of an HIV-positive cohort from Tanzania. Functional studies have been performed to assess the effect of the ATG16L1 and IRGM genetic variants on both in vitro and in vivo cytokine production. The results indicate that ATG16L1 variants modulate production of tumor necrosis factor-alpha, but not other cytokines, while no effects were seen in the presence of IRGM polymorphisms. In addition, no significant associations between the single-nucleotide polymorphisms in the ATG16L1 and IRGM genetic variants and the incidence of candidemia or oropharyngeal candidiasis were identified. Despite moderate effects on the modulation of proinflammatory cytokine production, genetic variation in the autophagy genes ATG16L1 and IRGM has a minor impact on the susceptibility to both mucosal and systemic Candida infections.
Rosentul, DC; Plantinga, TS; Farcas, M; Oosting, M; Hamza, OJM; Scott, WK; Alexander, BD; Yang, JC; Laird, GM; Joosten, LAB; van der Meer, JWM; Perfect, JR; Kullberg, B-J; van der Ven, AJAM; Johnson, MD; Netea, MG
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