Study of the response to antifungal and fungal-host interaction of T.rubrum dermatophyte using different models of infection

Abstract

Trichophyton rubrum is the most frequent causative agent of superficial dermatomycoses in Brazil and worldwide. Dermatophytes are keratinolytic fungi, which have the ability to utilize various host proteins (mainly keratin) as a source of nutrients in the skin, nails and hair. In addition, these infections also affect immunocompromised patients, being able to behave in an invasive way causing serious infections. Despite the clinical importance of infections caused by T. rubrum, the molecular processes of the fungus-host relationship were not fully understood. The T.rubrum dermatophyte is able to modulate the innate immune response of the host cell causing the non-recognition of the pathogen by the cellular defense system, reducing the human immune response, facilitating the infectious process. MicroRNAs are small non-coding regulatory RNAs that have been identified as an important part of the immune response to a variety of pathogens, modulating primarily the intensity of the inflammatory response, and may be a potent therapeutic target. In order to better understand the complex fungus-host relationship, it is necessary to use appropriate models of in vitro infection, among which the use of keratinocytes of the stratum corneum of the skin, macrophages, the use of fragments of nails, explants of skin derived from plastic surgery, in addition to models that consist of the addition of proteins such as elastin and keratin in culture medium. Additionally, knowledge about fungal virulence factors involved in host infection can be used as targets for the development of new antifungal agents. Currently, there are few drugs on the market and their targets are limited because of the shared similarities between fungal and mammalian cells. The demand for new antifungals of natural origin with new specific targets is increasing, due to an increase in the frequency of infectious diseases, as well as the emergence of strains resistants to the current treatment. The objective of this project is to analyze the cellular and molecular events of the antifungal response and the fungus-host interaction in the T. rubrum dermatophyte using different infection models (culture medium added with protein substrates, human keratinocyte cell line and human macrophages cell line). The results can be contribute to the discovery of new molecular targets that can be explored by antifungal agents, in order to develop more effective and specific compounds for the treatment of dermatophytoses. (AU)