Immune Response Pathways to Candida albicans in IL-12p40 Deficient Mice

Objectives: Oro-pharyngeal candidiasis is one of the clinical manifestations seen in patients with defects in innate and cell mediated immunity. We have previously reported on the establishment of a chronic oro-pharyngeal infection in IL-12p40 knockout mice. Methods: In this study, oral tissues and draining lymph nodes were isolated from infected and naïve IL-12p40 knockout and wildtype C57/BL6 mice, and analysed using Affymetrix Mouse Genechips. Quality control of the samples was carried out using hierarchical clustering, and analysis was done using MAS5, RMA, GCRMA and PLIER algorithms. The aim was to generate a reliable and manageable gene list for each of the oral tissues and lymph nodes, and of highly expressed genes. Results: There were significant differences between the results generated from the different algorithms. Statistical (t-test and ANOVA) and non-statistical (fold change >2) tools were used to identify differentially expressed genes. In draining lymph nodes and oral tissues, the number of differentially expressed genes was substantially greater in the knockout mice with respect to strain and/or disease. Groups of genes were selected that represent markers for strain and/or disease in oral tissues and draining lymph nodes. Within the draining lymph nodes, genes involved in early events of T cell receptor signaling (CD37), and T cell proliferation and differentiation (IL-2 inducible T cell kinase) were highly expressed in the knockout mice after infection. None of these genes were expressed in the wildtype. Similarly, in the oral tissues, type II cytokeratins specifically expressed in the epidermis (keratin complex and keratin associated proteins), genes involved in cell junctions (claudin proteins), neutrophil protein (defensin 4) and IL-1 family members were only expressed in the knockout mice. Conclusions: These results suggest a possible disruption to the early signaling of the innate immune response at the local infection site. This research was supported by ADRF.