The network interplay of type 1 interferon and toll-like receptor signaling cascades hallmarks the immune response against Candida spp. infections

Abstract

\n Here we employed a stepwise, integrative, and systems immunology approach to unravel the human immune responses to C. albicans and C. auris by analyzing publicly available human transcriptome data. Modular gene co-expression analysis revealed an interplay between Toll-like Receptors (TLR) and Interferon (IFN) networks. Enrichment analyses and hierarchical clustering revealed that this relationship is consistently triggered in peripheral white blood cells, peripheral blood mononuclear cells, and dendritic cell transcriptomes, involving IFN-γ, IFN-α/β- (e.g., ISGs, IRFs, SOCS, and GBPs) and TLR-associated molecules (TLR3,4,7/8,9, and TRAF-mediated NF-κB). These TLR- and IFN-associated genes cluster and increase their correlation levels after Candida stimulation, forming a highly interconnected interferome network, which contains an immune overlap with the anti-viral responses. Notably, our analysis shed new lights on the molecular basis of several genes associated with inborn errors of immunity that cause host susceptibility to fungal infections such as Candida spp., which reinforce our transcriptomic findings.