Coexpression network analysis of human candida infection reveals key modules and hub genes responsible for host-pathogen interactions

Abstract

Invasive fungal infections are a significant reason for morbidity and mortality among organ transplant recipients. Therefore, it is critical to investigate the host and candida niches to understand the epidemiology of fungal infections in transplantation. Candida albicans is an opportunistic fungal pathogen that causes fatal invasive mucosal infections, particularly in solid organ transplant patients. Therefore, identifying and characterizing these genes would play a vital role in understanding the complex regulation of host-pathogen interactions. Using 32 RNA-sequencing samples of human cells infected with C. albicans, we developed WGCNA coexpression networks and performed DESeq2 differential gene expression analysis to identify the genes that positively correlate with human candida infection. Using hierarchical clustering, we identified 5 distinct modules. We studied the inter- and intramodular gene network properties in the context of sample status traits and identified the highly enriched genes in the correlated modules. We identified 52 genes that were common in the most significant WGCNA turquoise module and differentially expressed genes in human endothelial cells (HUVEC) infection vs. control samples. As a validation step, we identified the differentially expressed genes from the independent Candida-infected human oral keratinocytes (OKF6) samples and validated 30 of the 52 common genes. We then performed the functional enrichment analysis using KEGG and GO. Finally, we performed protein-protein interaction (PPI) analysis using STRING and CytoHubba from 30 validated genes. We identified 8 hub genes (JUN, ATF3, VEGFA, SLC2A1, HK2, PTGS2, PFKFB3, and KLF6) that were enriched in response to hypoxia, angiogenesis, vasculogenesis, hypoxia-induced signaling, cancer, diabetes, and transplant-related disease pathways. The discovery of genes and functional pathways related to the immune system and gene coexpression and differential gene expression analyses may serve as novel diagnostic markers and potential therapeutic targets.