Receptor Heterodimerization and Co-Receptor Engagement in TLR2 Activation Induced by MIC1 and MIC4 from Toxoplasma gondii

Author(s):Show less -

Mendonca-Natividade, Flavia Costa ^[1] ; Lopes, Carla Duque ^[1] ; Ricci-Azevedo, Rafael ^[1] ; Sardinha-Silva, Aline ^[1] ; Pinzan, Camila Figueiredo ^[1] ; Paiva Alegre-Maller, Ana Claudia ^[1] ; Nohara, Lilian L. ^[2] ; Carneiro, Alan B. ^{[2, 3]} ; Panunto-Castelo, Ademilson ^[4] ; Almeida, Igor C. ^[2] ; Roque-Barreira, Maria Cristina ^[1]

Affiliation

^[1] Univ Sao Paulo FMRP USP, Ribeirao Preto Med Sch, Dept Cell & Mol Biol & Pathogen Bioagents, Lab Immunochem & Glycobiol, BR-14049900 Ribeirao Preto, SP - Brazil

^[2] Univ Texas El Paso, Dept Biol Sci, BBRC, El Paso, TX 79968 - USA

^[3] Fed Univ Rio de Janeiro UFRJ, Inst Med Biochem, Program Mol Biol & Biotechnol, BR-21941599 Rio De Janeiro, RJ - Brazil

^[4] Univ Sao Paulo USP FFCLRP USP, Dept Biol, Fac Philosophy Sci & Letters Ribeirao Preto, BR-14040900 Ribeirao Preto, SP - Brazil

• Document type: Journal article
• Source: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 20, n. 20 OCT 2 2019.
• Web of Science Citations: 0

Abstract

The microneme organelles of Toxoplasma gondii tachyzoites release protein complexes (MICs), including one composed of the transmembrane protein MIC6 plus MIC1 and MIC4. In this complex, carbohydrate recognition domains of MIC1 and MIC4 are exposed and interact with terminal sialic acid and galactose residues, respectively, of host cell glycans. Recently, we demonstrated that MIC1 and MIC4 binding to the N-glycans of Toll-like receptor (TLR) 2 and TLR4 on phagocytes triggers cell activation and pro-inflammatory cytokine production. Herein, we investigated the requirement for TLR2 heterodimerization and co-receptors in MIC-induced responses, as well as the signaling molecules involved. We used MICs to stimulate macrophages and HEK293T cells transfected with TLR2 and TLR1 or TLR6, both with or without the co-receptors CD14 and CD36. Then, the cell responses were analyzed, including nuclear factor-kappa B (NF-kappa B) activation and cytokine production, which showed that (1) only TLR2, among the studied factors, is crucial for MIC-induced cell activation; (2) TLR2 heterodimerization augments, but is not critical for, activation; (3) CD14 and CD36 enhance the response to MIC stimulus; and (4) MICs activate cells through a transforming growth factor beta-activated kinase 1 (TAK1)-, mammalian p38 mitogen-activated protein kinase (p38)-, and NF-kappa B-dependent pathway. Remarkably, among the studied factors, the interaction of MIC1 and MIC4 with TLR2 N-glycans is sufficient to induce cell activation, which promotes host protection against T. gondii infection. (AU)

• FAPESP's process: 13/04088-0 - Lectin from pathogens
• Grantee: Maria Cristina Roque Antunes Barreira
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 17/02998-0 - Effects of Toxoplasma gondii and Paracoccidioides brasiliensis, exerted through their respective lectins on intracellular pathways activated by the recognition of N-linked glycans to toll like receptors on neutrophils
• Grantee: Rafael Ricci de Azevedo
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 14/13324-1 - Interaction of microneme proteins of Toxoplasma gondii with N-linked glycans of TLR4: effects on innate immunity
• Grantee: Flávia Costa Mendonça Natividade
• Support Opportunities: Scholarships in Brazil - Doctorate