Screening of new antifungal molecules and characterization of pathogenicity process of the dermatophyte Trichophyton rubrum

• Grant number: 19/10514-8
• Support Opportunities: Regular Research Grants
• Start date: March 01, 2020
• End date: October 31, 2022
• Field of knowledge: Biological Sciences - Genetics - Molecular Genetics and Genetics of Microorganisms
• Principal Investigator: Ana Lucia Fachin Saltoratto
• Grantee: Ana Lucia Fachin Saltoratto
• Host Institution: Universidade de Ribeirão Preto (UNAERP). Campus Ribeirão Preto. Ribeirão Preto , SP, Brazil
• Associated scholarship(s): 22/01456-7 - Screening for new antifungal molecules and characterization the pathogenicity process in the dermatophyte Trichophyton rubrum, BP.TT; 21/11593-9 - Screening for new antifungal molecules and characterization the pathogenicity process in the dermatophyte Trichophyton rubrum, BP.TT; 21/04115-3 - Screening for new antifungal molecules and characterization the pathogenicity process in the dermatophyte Trichophyton rubrum, BP.TT; 20/06155-0 - Screening for new antifungal molecules and characterization the pathogenicity process in the dermatophyte Trichophyton rubrum, BP.TT

Abstract

Trichophyton rubrum is the main causative agent of superficial mycoses in the skin and nails in Brazil and in the world. This dermatophyte uses keratinized substrates as the primary nutrient during infection. Nowadays, there is an increase in dermatophytoses in immunocompromised patients, in which these lesions present a more penetrating and invasive character, making treatment difficult. Chalcones and curcumin have pronounced antifungal and anti-inflammatory activity. Modifying the chemical structure of these molecules of natural origin may open up a new perspective of more effective antifungal therapy. The pathogenicity process of T.rubrum is initiated by the process of adherence of the fungus and the penetration of keratinized tissue, followed by the activation of inflammation and production of reactive oxygen species by macrophages, which are essential for the host defense mechanism of infection. However, there are currently few cellular and molecular strategies available that allow better understanding of the fungus-host relationship due to the limitations of the models that mimic this interaction. The culture medium added with protein substrates and the co-culture of T.rubrum in human keratinocyte lineage can be used to simulate surface infection and coculture in macrophages cells can mimic the systemic infection. Our research group demonstrated that the analysis of Dual RNA seq of the human keratinocyte cell line and T. rubrum co-culture revealed the modulation of genes involved in the fungal infection mechanism, cytokine production, defense and maintenance of keratinocyte cellular homeostasis. In addition, the microRNA-seq of human macrophages co-cultured with T.rubrum was performed. In silico analysis of the target genes of the modulated microRNAs was related to inflammatory response, oxidative stress, apoptosis, drug resistance and cell proliferation. The objective of this project is to evaluate new antifungal molecules (chalconoides and curcuminoids) and to characterize the pathogenic process of T. rubrum using different infection models. To achieve this aim, we intend to identify the modulated proteins in culture medium with keratin, to evaluate the expression of fungal genes and selected human keratinocytes in Dual RNA seq in different co-culture situations; in order to characterize the effect of pathways modulated by micro RNAs of macrophages such as oxidative stress, inflammatory process (release of interleukins), apoptosis and phagocytosis during infection. Through the obtained results, it is expected to show new molecular targets related to the pathogenic process of the dermatophyte, as well as to identify new antifungal molecules. (AU)

Scientific publications

(7)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

PETRUCELLI, MONISE FAZOLIN; DE ABREU, MARIANA HEINZEN; MICHELOTTO CANTELLI, BRUNA ALINE; SEGURA, GABRIELA GONZALEZ; NISHIMURA, FELIPE GARCIA; BITENCOURT, TAMIRES APARECIDA; MARINS, MOZART; FACHIN, ANA LUCIA. Epidemiology and Diagnostic Perspectives of Dermatophytoses. JOURNAL OF FUNGI, v. 6, n. 4, DEC 2020. (19/10514-8)

SEGURA, GABRIELA GONZALEZ; CANTELLI, BRUNA ALINE; PERONNI, KAMILA; SANCHES, PABLO RODRIGO; KOMOTO, TATIANA TAKAHASI; RIZZI, ELEN; BELEBONI, RENE OLIVEIRA; DA SILVA JUNIOR, WILSON ARAUJO; MARTINEZ-ROSSI, NILCE MARIA; MARINS, MOZART; et al. Cellular and Molecular Response of Macrophages THP-1 during Co-Culture with Inactive Trichophyton rubrum Conidia. JOURNAL OF FUNGI, v. 6, n. 4, DEC 2020. (19/10514-8, 16/22701-9)

KOMOTO, TATIANA TAKAHASI; NISHIMURA, FELIPE GARCIA; EVANGELISTA, ADRIANE FEIJO; DE FREITAS, ANA JULIA AGUIAR; DA SILVA, GABRIEL; SILVA, WILSON ARAUJO; PERONNI, KAMILA; MARQUES, MARCIA MARIA CHIQUITELLI; MARINS, MOZART; FACHIN, ANA LUCIA. Exploring the Therapeutic Potential of trans-Chalcone: Modulation of MicroRNAs Linked to Breast Cancer Progression in MCF-7 Cells. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 24, n. 13, p. 14-pg., 2023-07-01. (19/10514-8)

PETRUCELLI, MONISE FAZOLIN; CANTELLI, BRUNA ALINE M.; MARINS, MOZART; FACHIN, ANA LUCIA. The Transcriptional Regulation of Genes Involved in the Immune Innate Response of Keratinocytes Co-Cultured with Trichophyton rubrum Reveals Important Roles of Cytokine GM-CSF. JOURNAL OF FUNGI, v. 8, n. 11, p. 15-pg., 2022-11-01. (19/10514-8)

DE ABREU, MARIANA HEINZEN; BITENCOURT, TAMIRES APARECIDA; FRANCO, MATHEUS ELOY; MORELI, IGOR SAWASAKI; MICHELOTTO CANTELLI, BRUNA ALINE; KOMOTO, TATIANA TAKAHASI; MARINS, MOZART; FACHIN, ANA LUCIA. Expression of genes containing tandem repeat patterns involved in the fungal-host interaction and in the response to antifungals in Trichophyton rubrum. MYCOSES, v. 63, n. 6, APR 2020. (15/23435-8, 16/22701-9, 19/10514-8)

CANTELLI, BRUNA ALINE; SEGURA, GABRIELA GONZALEZ; BITENCOURT, TAMIRES APARECIDA; DE ABREU, MARIANA HEINZEN; PETRUCELLI, MONISE FAZOLIN; PERONNI, KAMILA; SANCHES, PABLO RODRIGO; BELEBONI, RENE OLIVEIRA; DA SILVA JUNIOR, WILSON ARAUJO; MARTINEZ-ROSSI, NILCE MARIA; et al. Transcriptome Analysis of Co-Cultures of THP-1 Human Macrophages with Inactivated Germinated Trichophyton rubrum Conidia. JOURNAL OF FUNGI, v. 9, n. 5, p. 14-pg., 2023-05-12. (19/10514-8, 16/22701-9)

NISHIMURA, FELIPE GARCIA; SAMPAIO, BEATRIZ BORSANI; DO COUTO, GABRIELLY OLIVEIRA; DA SILVA, ARYANE DIAS; DA SILVA, WANESSA JULIA; PERONNI, KAMILA CHAGAS; EVANGELISTA, ADRIANE FEIJO; HOSSAIN, MOHAMMAD; DIMMOCK, JONATHAN R.; BANDY, BRIAN; et al. The Transcriptome of BT-20 Breast Cancer Cells Exposed to Curcumin Analog NC2603 Reveals a Relationship between EGR3 Gene Modulation and Cell Migration Inhibition. Molecules, v. 29, n. 6, p. 13-pg., 2024-03-01. (19/10514-8)