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Modulation of regulatory T cell response in therapy and prevention of sporotrichosis. Use of antisense oligonucleotides as molecular adjuvants in recombinant anti-Sporothrix vaccine

Grant number: 21/05494-8
Support type:Regular Research Grants
Duration: September 01, 2022 - August 31, 2024
Field of knowledge:Health Sciences - Pharmacy
Principal researcher:Iracilda Zeppone Carlos
Grantee:Iracilda Zeppone Carlos
Home Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
Assoc. researchers:Alexander Batista Duharte ; Damiana Téllez Martínez ; Deivys Leandro Portuondo Fuentes ; Fanny Guzmán Quimbayo ; Rafael Solana ; Salvador Francisco Aliño Pellicer

Abstract

Sporotrichosis is an important fungal disease with worldwide distribution that affects humans and animals. Among the species in the complex, S. schenckii sensu stricto is the causal agent present in all countries, while S. brasiliensis is especially found in Brazil, where this infection is already considered an important zoonosis. Many cases of sporotrichosis caused by cat scratches and contact with contaminated wounds have been reported in several cities in Brazil, mainly in the city of Rio de Janeiro, where the disease has gained epidemic proportions. More recently, in the state of São Paulo, there are increasing reports of the incidence of disease and is currently an important concern for health authorities. One of the risk factors that determines the susceptibility and severity of the disease is the host's immune status. Studies carried out in our laboratory and by other groups, have already demonstrated the role of innate immunity and different populations of T lymphocytes including Th1, Th2 and Th17 in the immune response against S. schenckii in infection models and during the response to a specific vaccine candidate. Studies of the function of regulatory T cells (Tregs) are an attractive topic due to their importance in controlling the immune response against tumors and infectious diseases and because their mechanisms are still poorly understood. Tregs cells are a population of lymphocytes that are fundamental in controlling immunity and excessive tissue damage caused in response to different infections, including those by fungi. In previous studies, we have evaluated the role of CD4 + CD25 + Foxp3 + Treg cells in infection by S. schenckii, from their frequency during infection with this pathogen to the determination of their activity and importance for the post-infection and post-infection immune response vaccination in transgenic DEREG mice (from English: "DEpletion of REGulatory T cells") with depletion or not of these cells. The effect of Tregs on the efficacy of a vaccine candidate against sporotrichosis was also evaluated in this model, and we observed that Tregs depletion was associated with an increase in the Th1 response and in the production of specific antibodies. In a pilot study carried out in partnership with the University of Valencia Spain, it was confirmed that the administration of an antisense oligonucleotide (ASO) silencing Foxp3, the transcription factor of Tregs cells, improved the immunogenicity of a recombinant vaccine against S. schenckii. Yet, in another previous proof-of-concept (PoC) study, we demonstrated that a vaccine formulation composed of 6 Sporothrix spp enolase peptides and Freund's adjuvant induced specific antigen antibody titers in BALB/c mice, which showed protective properties when passively transferred to mice challenged with S. brasiliensis. Because Freund's adjuvant is toxic for clinical use and is designed to optimize the vaccine formulation for a future industrial scale, we propose in the present study to evaluate this technology for the development of new generation vaccines for sporotrichosis using the adjuvant effect of oligonucleotides antisense anti-Foxp3 and anti-CTL-4 in a multi-epitope recombinant protein based on the amino acid sequences of the six enolase peptides' Sporothrix spp. (AU)

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