Genetic aspects of the pathogenesis and control strategies of recurrent candidiasis and dermatophytosis caused by Trichophyton rubrum

Abstract

Trichophyton rubrum is the main causative agent of superficial mycoses in Brazil and worldwide. There is currently an increase in dermatophytosis in immunocompromised patients without known immunodeficiency, in which these lesions are more penetrating and invasive, making treatment difficult. Vulvovaginal candidiasis is an infection caused by Candida, which causes intense vulvar itching, pain, rash and vaginal discharge. Around 5-8% of women suffer from recurrent vulvovaginal candidiasis, defined as at least three episodes of infections per year. The innate immune system acts as the first line of defense against infection by Candida and dermatophytes, it is regulated by pattern recognition receptors (PRRs). These include Toll-like receptors (TLRs), DECTIN-1 and C-type lectin receptors (CLRs), which detect mannans present in the fungal cell wall. The CARD9 gene is involved in signaling and activating the innate immune response to fungi via PRRs, regulating inflammation through the release of cytokines. Host genetic factors such as mutations in the genes encoding PRRs and the CARD9 gene may be related to fungal infections caused by T.rubrum and Candida. Genotyping of patients with recurrent fungal infections showed deficiency of the CARD9 gene. Furthermore, they showed a decrease in circulating cytokines such as IL-17 and granulocyte/macrophage colony-stimulating factor (GM-CSF) after fungal stimulation. These cases of deep and recurrent fungal infections have increased the search for new, more effective antifungal therapies. Results from the previous Fapesp project (2019/10514-8) showed that curcumin analogues showed pronounced antifungal and anti-inflammatory activity against T.rubrum. Currently, there are few cellular and molecular strategies available that allow us to better understand the fungus-host relationship. Co-cultivation of T.rubrum in human keratinocyte and macrophage lines can be used to simulate superficial and systemic infection, respectively.Our research group performed dual RNAseq analysis of keratinocyte co-culture with T. rubrum and revealed pronounced expression of the CF2 gene and release of the cytokine GM-CSF. Studies have indicated the use of the cytokine GM-CSF (Sargramostin) in patients with CARD9 deficiency with candidiasis and dermatophytosis due to its antifungal and immunomodulatory effect. The objective of this project is to evaluate the genetic susceptibility to fungal infections of patients with recurrent candidiasis and dermatophytosis caused by T.rubrum through genotyping of CARD9 and PRRs. In addition to isolating and characterizing clinical samples of Candida and T.rubrum, in order to understand the mechanisms of fungus-host interaction and test new antifungal chemotherapies, such as curcumin analogues and the cytokine GM-CSF. (AU)