Functional genomics identifies type I interferon pathway as central for host defense against Candida albicans

Abstract

Candida albicans is the most common human fungal pathogen causing mucosal and systemic infections. However, human antifungal immunity remains poorly defined. Here, by integrating transcriptional analysis and functional genomics, we identified Candida-specific host defense mechanisms in humans. Candida induced significant expression of genes from the type I interferon (IFN) pathway in human peripheral blood mononuclear cells. This unexpectedly prominent role of type I IFN pathway in anti-Candida host defense was supported by additional evidence. Polymorphisms in type I IFN genes modulated Candida-induced cytokine production and were correlated with susceptibility to systemic candidiasis. In in-vitro experiments, type I IFNs skewed Candida-induced inflammation from a Th17-response toward a Th1-response. Patients with chronic mucocutaneaous candidiasis displayed defective expression of genes in the type I IFN pathway. These findings indicate that the type I IFN pathway is a main signature of Candida-induced inflammation and plays a crucial role in anti-Candida host defense in humans.

Sepsis-induced immune dysfunction: can immune therapies reduce mortality?

“…The Th17 cytokine response is diminished in sepsis and may negatively impact mortality (87). Given the fundamental role of Th17 in the eradication of fungal infections, reduced Th17 cytokine production in sepsis may be responsible for the increased susceptibility to fungal infections frequently encountered in critically ill patient populations (88). Moreover, IL-7 treatment has been demonstrated to increase Th17 cell responsiveness and reduce mortality from secondary fungal infections, making IL-17 a potential therapeutic agent (89).…”

Host response toCandida albicansbloodstream infection and sepsis

“…They confirmed these analyses by showing that polymorphisms in type I interferon genes modulated Candida-induced cytokine production and were correlated with susceptibility to systemic candidiasis. 55 Genetic analyses of patients at risk for non-Candida fungal infections have also identified other important regulators of anti-fungal immunity. 3,21,56 Together, these model systems have generated important insight into mechanisms governing immune responses against Candida and established a repertoire of receptors and signaling cascades relevant for fungal recognition.…”

Host genetics of invasive Aspergillus and Candida infections

“…By analyzing the transcriptional profile of human PBMCs in response to different pathogens, Smeekens et al identified the type I IFN pathway as specific transcriptional signature for Candida infection. By performing a genetic analysis of 11 candidate genes from this pathway, they identified SNPs in four genes to be associated with candidemia, including a SNP in the signal transducer and activator of transcription 1 (STAT1), a SNP nearby the chemokine (C-C motif) ligand 8 (CCL8), a SNP in the nuclear body protein SP110 (known also as IFN-induced protein 41), and a SNP in the proteasome (prosome, macropain) subunit beta type 8 (PSMB8) [83]. These novel observations suggest pivotal role of type 1 IFN signaling also in anti-Candida immunity, but biologically, the plausibility of these associations needs be further elucidated.…”