Effect of Foxp3 silencing on immunogenicity of vaccines against Sporothrix schenckii

• Grant number: 18/15187-2
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: April 20, 2019
• End date: April 19, 2020
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Iracilda Zeppone Carlos
• Grantee: Alexander Batista Duharte
• Supervisor: Salvador Francisco Aliño Pellicer
• Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Institution abroad: Universitat de València, Spain
• Associated to the scholarship: 16/04250-0 - Role of CD4+CD25+FoxP3+ Regulatory T cells in the post-infection and post-vaccination immune response to Sporothrix schenckii, BP.PD

Abstract

The present project proposes to use the Foxp3 gene silencing technology to evaluate the influence of T regulatory cells (Tregs) on the immune response against a vaccine of wall proteins and a recombinant enolase-based vaccine against S. schenckii. The effect of Tregs depletion on the primary and secondary response will be evaluated separately and simultaneously. The use of the DEREG transgenic mouse model, that is being used in the depletion project for Tregs depletion, despite its multiple advantages in relation to other models, due to its specificity and the possibility of depleting Tregs cells at any point of infection. or vaccination, has as a disadvantage that does not allow the prolonged depletion of these cells, being difficult to obtain reliable results to characterize the effect of Tregs in multi-dose vaccination schemes. The silencing of the Foxp3 gene is an alternative that overcomes this difficulty, so it can be used repeatedly in the same animal to evaluate the effect of maintained and controlled depletion of Tregs, as has been demonstrated in antitumour vaccines by Salvador Aliño´s group (Valencia University, Spain), without evidence of induction of autoimmune effects. The use of this methodology would allow to evaluate the simultaneous effect in multiple doses, which is not possible with the transgenic mouse DEREG. In parallel, with this methodology the possibility of using Foxp3 gene silencers for the first time as molecular adjuvants in an antifungal vaccine will be evaluated. The project will be developped of three stages: 1) Obtaining vaccine preparations and the Foxp3 silencing oligonucleotide (ASOfoxp3). 2) Evaluating the effect of the silencing of the FoxP3 gene on the immunogenicity of the vaccines under study and the response of Tregs cells. 3) Evaluating the effect of the silencing of the FoxP3 gene on the protective efficacy of the vaccines under study in challenge models with S. schenckii.

Scientific publications

(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)

BATISTA-DUHARTE, ALEXANDER; SENDRA, LUIS; HERRERO, MARIA JOSE; PORTUONDO, DEIVYS LEANDRO; TELLEZ-MARTINEZ, DAMIANA; OLIVERA, GLADYS; FERNANDEZ-DELGADO, MANUEL; JAVEGA, BEATRIZ; HERRERA, GUADALUPE; MARTINEZ, ALICIA; et al. Foxp3 Silencing with Antisense Oligonucleotide Improves Immunogenicity of an Adjuvanted Recombinant Vaccine against Sporothrix schenckii. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 22, n. 7, APR 2021. (18/15187-2)

BATISTA-DUHARTE, ALEXANDER; PERA, ALEJANDRA; ALINO, SALVADOR F.; SOLANA, RAFAEL. Regulatory T cells and vaccine effectiveness in older adults. Challenges and prospects. International Immunopharmacology, v. 96, JUL 2021. (18/15187-2)

BATISTA-DUHARTE, ALEXANDER; SENDRA, LUIS; HERRERO, MARIA JOSE; TELLEZ-MARTINEZ, DAMIANA; CARLOS, IRACILDA ZEPPONE; ALINO, SALVADOR FRANCISCO. Progress in the Use of Antisense Oligonucleotides for Vaccine Improvement. BIOMOLECULES, v. 10, n. 2, FEB 2020. (18/15187-2)