Application of immunomoduladors, by carbohydrate recognition, as therapeutic agents: mechanism of action to immunotherapy

• Grant number: 18/21708-5
• Support Opportunities: Research Projects - Thematic Grants
• Duration: May 01, 2019 - April 30, 2024
• Field of knowledge: Biological Sciences - Immunology - Immunochemistry
• Principal Investigator: Maria Cristina Roque Antunes Barreira
• Grantee: Maria Cristina Roque Antunes Barreira
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Bruno Rafael Barboza ; Constance Oliver ; Flávia Costa Mendonça Natividade ; Maria Célia Jamur ; Nayla de Souza Pitangui ; Patrícia Kellen Martins Oliveira Brito ; Rafael Ricci de Azevedo ; Relber Aguiar Gonçales ; Thiago Aparecido da Silva
• Associated scholarship(s): 20/16548-9 - Chitin of Paracoccidioides brasiliensis: role in the host-pathogen interaction, BP.PD; 19/26876-6 - Capacity of ArtinM to induce the repolarization of M2 macrophages to M1 in in vitro Paracoccidioides brasiliensis infection, BP.IC

Abstract

The studies about carbohydrate recognition and its biological activities is evaluated by Immunochemistry and Glycobiology Lab, which has the ArtinM lectin, and two lectins from Toxoplasma gondii (TgMIC1 and TgMIC4; TgMICs) and one lectin from Paracoccidioides brasiliensis (Paracoccin, PCN) as major lectins for investigation. The native form of ArtinM, PCN, and TgMICs has been evaluated and the relevance of the biological activity of these lectins instigated us to express them, and the recombinant form of these lectins maintained the biological activities of native forms. ArtinM, obtained from the Artocarpus heterophyllus seeds, has specificity for mannotriose Man± 1-3 [Man± 1-6] Man, and PCN found on P. brasiliensis yeast surface has specificity for N-acetylglucosamine and chitin. TgMICs are found on apical region of T. gondii, and TgMIC1 and TgMIC4 bind, respectively, to ±2-3-sialil lactosamine and ²1-3- or ²1-4-galactosamine. The effect of the ArtinM, PCN, and TgMICs in innate immune cells depend of its interaction with glycoproteins on cell surface, as Toll-like receptors (TLR) 2 and/or TLR4. These innate immune receptors are glycosylated and the recognition by these lectins induce the production of inflammatory mediators, mainly IL-12 and IFN-g, which drive the adaptive immunity to Th1 profile. These mechanisms are related to the immunomodulatory activity promoted by ArtinM, PCN, and TgMICs, and the administration of these lectins favor the protection against intracellular pathogens. Our group also investigated the role of PCN and TgMICs in biology of the P. brasiliensis and T. gondii, respectively, and in the host-pathogen interaction. Then, our current proposal intends to extent the description of mechanisms involved in the immunomodulatory activity of ArtinM, PCN, and TgMICs, and its application as immunotherapeutic agents. For that, we planned eight proposals that will be useful for understanding the main points as follows: (I) stablish that ArtinM can be a study model to evaluate the immunomodulatory activity through carbohydrate recognition, and also demonstrate the application of ArtinM as immunomodulator agent against systemic fungal infection; (II) stablish that PCN is a virulence factor of P. brasiliensis to explore its function as therapeutic target against paracoccidioidomycosis; (III) report the cell signaling triggered by TgMICs through interaction with TLR2 and TLR4 on innate immune cells, and also to describe the role of TgMICs during the T. gondii infection. (AU)

Scientific publications

(5)

(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)

GONCALES, RELBER AGUIAR; RICCI-AZEVEDO, RAFAEL; VIEIRA, VANESSA C. S.; FERNANDES, FABRICIO F.; THOMAZ, SANDRA M. DE O.; CARVALHO, AGOSTINHO; VENDRUSCOLO, PATRICIA E.; CUNHA, CRISTINA; ROQUE-BARREIRA, MARIA CRISTINA; RODRIGUES, FERNANDO. Paracoccin Overexpression in Paracoccidioides brasiliensis Enhances Fungal Virulence by Remodeling Chitin Properties of the Cell Wall. Journal of Infectious Diseases, v. 224, n. 1, p. 164-174, JUL 1 2021. (14/22561-7, 17/02998-0, 13/04088-0, 18/21708-5, 16/00629-4)

MIGUEL, CAMILA BOTELHO; DA SILVA, THIAGO APARECIDO; RODRIGUES, WELLINGTON FRANCISCO; MARTINS OLIVEIRA-BRITO, PATRICIA KELLEN; ROQUE-BARREIRA, MARIA CRISTINA; LAZO-CHICA, JAVIER EMILIO. Administration of artinm lectin reduces the severity of the acute phase infection with Trypanosoma cruzi. FASEB BIOADVANCES, v. 3, n. 5, p. 295-304, MAY 2021. (18/21708-5)

DE CAMPOS, GABRIELA YAMAZAKI; OLIVEIRA, RAQUEL AMORIM; MARTINS OLIVEIRA-BRITO, PATRICIA KELLEN; ROQUE-BARREIRA, MARIA CRISTINA; DA SILVA, THIAGO APARECIDO. Pro-inflammatory response ensured by LPS and Pam3CSK4 in RAW 264.7 cells did not improve a fungistatic effect on Cryptococcus gattii infection. PeerJ, v. 8, NOV 25 2020. (16/17037-2, 18/21708-5, 18/18538-0, 18/19949-4)

PITANGUI, NAYLA DE SOUZA; FERNANDES, FABRICIO FREITAS; GONCALES, RELBER AGUIAR; ROQUE-BARREIRA, MARIA CRISTINA. Virulence Vs. Immunomodulation: Roles of the Paracoccin Chitinase and Carbohydrate-Binding Sites in Paracoccidioides brasiliensis Infection. FRONTIERS IN MOLECULAR BIOSCIENCES, v. 8, AUG 31 2021. (18/21708-5, 17/06251-6, 20/16548-9)

RICCI-AZEVEDO, RAFAEL; COSTA MENDONCA-NATIVIDADE, FLAVIA; CAROLINA SANTANA, ANA; ALCOFORADO DINIZ, JULIANA; CRISTINA ROQUE-BARREIRA, MARIA. Microneme Proteins 1 and 4 From Toxoplasma gondii Induce IL-10 Production by Macrophages Through TLR4 Endocytosis. FRONTIERS IN IMMUNOLOGY, v. 12, APR 12 2021. (16/10446-4, 17/02998-0, 18/21708-5, 16/14657-0, 14/13324-1, 13/04088-0)