Surface immunogenic protein from Streptococcus agalactiae and Fissurella latimarginata hemocyanin are TLR4 ligands and activate MyD88- and TRIF dependent signaling pathways
The development of vaccine adjuvants is of interest for the management of chronic diseases, cancer, and future pandemics. Therefore, the role of Toll-like receptors (TLRs) in the effects of vaccine adjuvants has been investigated. TLR4 ligand-based adjuvants are the most frequently used adjuvants fo...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-09-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1186188/full |
| _version_ | 1797681834505535488 |
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| author | Diego A. Díaz-Dinamarca Diego A. Díaz-Dinamarca Diego A. Díaz-Dinamarca Michelle L. Salazar Daniel F. Escobar Byron N. Castillo Bastián Valdebenito Pablo Díaz Augusto Manubens Fabián Salazar Fabián Salazar Fabián Salazar Mayarling F. Troncoso Sergio Lavandero Sergio Lavandero Janepsy Díaz María Inés Becker María Inés Becker Abel E. Vásquez Abel E. Vásquez |
| author_facet | Diego A. Díaz-Dinamarca Diego A. Díaz-Dinamarca Diego A. Díaz-Dinamarca Michelle L. Salazar Daniel F. Escobar Byron N. Castillo Bastián Valdebenito Pablo Díaz Augusto Manubens Fabián Salazar Fabián Salazar Fabián Salazar Mayarling F. Troncoso Sergio Lavandero Sergio Lavandero Janepsy Díaz María Inés Becker María Inés Becker Abel E. Vásquez Abel E. Vásquez |
| author_sort | Diego A. Díaz-Dinamarca |
| collection | DOAJ |
| description | The development of vaccine adjuvants is of interest for the management of chronic diseases, cancer, and future pandemics. Therefore, the role of Toll-like receptors (TLRs) in the effects of vaccine adjuvants has been investigated. TLR4 ligand-based adjuvants are the most frequently used adjuvants for human vaccines. Among TLR family members, TLR4 has unique dual signaling capabilities due to the recruitment of two adapter proteins, myeloid differentiation marker 88 (MyD88) and interferon-β adapter inducer containing the toll-interleukin-1 receptor (TIR) domain (TRIF). MyD88-mediated signaling triggers a proinflammatory innate immune response, while TRIF-mediated signaling leads to an adaptive immune response. Most studies have used lipopolysaccharide-based ligands as TLR4 ligand-based adjuvants; however, although protein-based ligands have been proven advantageous as adjuvants, their mechanisms of action, including their ability to undergo structural modifications to achieve optimal immunogenicity, have been explored less thoroughly. In this work, we characterized the effects of two protein-based adjuvants (PBAs) on TLR4 signaling via the recruitment of MyD88 and TRIF. As models of TLR4-PBAs, we used hemocyanin from Fissurella latimarginata (FLH) and a recombinant surface immunogenic protein (rSIP) from Streptococcus agalactiae. We determined that rSIP and FLH are partial TLR4 agonists, and depending on the protein agonist used, TLR4 has a unique bias toward the TRIF or MyD88 pathway. Furthermore, when characterizing gene products with MyD88 and TRIF pathway-dependent expression, differences in TLR4-associated signaling were observed. rSIP and FLH require MyD88 and TRIF to activate nuclear factor kappa beta (NF-κB) and interferon regulatory factor (IRF). However, rSIP and FLH have a specific pattern of interleukin 6 (IL-6) and interferon gamma-induced protein 10 (IP-10) secretion associated with MyD88 and TRIF recruitment. Functionally, rSIP and FLH promote antigen cross-presentation in a manner dependent on TLR4, MyD88 and TRIF signaling. However, FLH activates a specific TRIF-dependent signaling pathway associated with cytokine expression and a pathway dependent on MyD88 and TRIF recruitment for antigen cross-presentation. Finally, this work supports the use of these TLR4-PBAs as clinically useful vaccine adjuvants that selectively activate TRIF- and MyD88-dependent signaling to drive safe innate immune responses and vigorous Th1 adaptive immune responses. |
| first_indexed | 2024-03-11T23:50:45Z |
| format | Article |
| id | doaj.art-fe040994137a4fb786bc7c6c6b76ff8d |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-11T23:50:45Z |
| publishDate | 2023-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-fe040994137a4fb786bc7c6c6b76ff8d2023-09-19T07:38:27ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-09-011410.3389/fimmu.2023.11861881186188Surface immunogenic protein from Streptococcus agalactiae and Fissurella latimarginata hemocyanin are TLR4 ligands and activate MyD88- and TRIF dependent signaling pathwaysDiego A. Díaz-Dinamarca0Diego A. Díaz-Dinamarca1Diego A. Díaz-Dinamarca2Michelle L. Salazar3Daniel F. Escobar4Byron N. Castillo5Bastián Valdebenito6Pablo Díaz7Augusto Manubens8Fabián Salazar9Fabián Salazar10Fabián Salazar11Mayarling F. Troncoso12Sergio Lavandero13Sergio Lavandero14Janepsy Díaz15María Inés Becker16María Inés Becker17Abel E. Vásquez18Abel E. Vásquez19Sección de Biotecnología, Subdepartamento, Innovación, Desarrollo, Transferencia Tecnológica (I+D+T) y Evaluación de Tecnologías Sanitarias (ETESA), Instituto de Salud Pública, Santiago, ChileLaboratorio de Inmunología, Fundación Ciencia y Tecnología para el Desarrollo (FUCITED), Santiago, ChileFacultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, ChileLaboratorio de Inmunología, Fundación Ciencia y Tecnología para el Desarrollo (FUCITED), Santiago, ChileSección de Biotecnología, Subdepartamento, Innovación, Desarrollo, Transferencia Tecnológica (I+D+T) y Evaluación de Tecnologías Sanitarias (ETESA), Instituto de Salud Pública, Santiago, ChileLaboratorio de Inmunología, Fundación Ciencia y Tecnología para el Desarrollo (FUCITED), Santiago, ChileSección de Biotecnología, Subdepartamento, Innovación, Desarrollo, Transferencia Tecnológica (I+D+T) y Evaluación de Tecnologías Sanitarias (ETESA), Instituto de Salud Pública, Santiago, ChileSección de Biotecnología, Subdepartamento, Innovación, Desarrollo, Transferencia Tecnológica (I+D+T) y Evaluación de Tecnologías Sanitarias (ETESA), Instituto de Salud Pública, Santiago, ChileInvestigación y Desarrollo, BIOSONDA S.A., Santiago, ChileLaboratorio de Inmunología, Fundación Ciencia y Tecnología para el Desarrollo (FUCITED), Santiago, ChileInvestigación y Desarrollo, BIOSONDA S.A., Santiago, ChileMedical Research Council Centre for Medical Mycology, University of Exeter, Exeter, United KingdomAdvanced Center for Chronic Diseases (ACCDiS), Facultad Ciencias Químicas y Farmacéuticas and Facultad de Medicina, Universidad de Chile, Santiago, ChileAdvanced Center for Chronic Diseases (ACCDiS), Facultad Ciencias Químicas y Farmacéuticas and Facultad de Medicina, Universidad de Chile, Santiago, ChileDepartment of Internal Medicine (Cardiology Division), University of Texas Southwestern Medical Center, Dallas, TX, United StatesDepartamento Agencia Nacional de Dispositivos Médicos, Innovación y Desarrollo, Instituto de Salud Pública de Chile, Santiago, ChileLaboratorio de Inmunología, Fundación Ciencia y Tecnología para el Desarrollo (FUCITED), Santiago, ChileInvestigación y Desarrollo, BIOSONDA S.A., Santiago, ChileSección de Biotecnología, Subdepartamento, Innovación, Desarrollo, Transferencia Tecnológica (I+D+T) y Evaluación de Tecnologías Sanitarias (ETESA), Instituto de Salud Pública, Santiago, ChileFacultad de Ciencias de la Salud, Escuela de Medicina, Universidad del Alba, Santiago, ChileThe development of vaccine adjuvants is of interest for the management of chronic diseases, cancer, and future pandemics. Therefore, the role of Toll-like receptors (TLRs) in the effects of vaccine adjuvants has been investigated. TLR4 ligand-based adjuvants are the most frequently used adjuvants for human vaccines. Among TLR family members, TLR4 has unique dual signaling capabilities due to the recruitment of two adapter proteins, myeloid differentiation marker 88 (MyD88) and interferon-β adapter inducer containing the toll-interleukin-1 receptor (TIR) domain (TRIF). MyD88-mediated signaling triggers a proinflammatory innate immune response, while TRIF-mediated signaling leads to an adaptive immune response. Most studies have used lipopolysaccharide-based ligands as TLR4 ligand-based adjuvants; however, although protein-based ligands have been proven advantageous as adjuvants, their mechanisms of action, including their ability to undergo structural modifications to achieve optimal immunogenicity, have been explored less thoroughly. In this work, we characterized the effects of two protein-based adjuvants (PBAs) on TLR4 signaling via the recruitment of MyD88 and TRIF. As models of TLR4-PBAs, we used hemocyanin from Fissurella latimarginata (FLH) and a recombinant surface immunogenic protein (rSIP) from Streptococcus agalactiae. We determined that rSIP and FLH are partial TLR4 agonists, and depending on the protein agonist used, TLR4 has a unique bias toward the TRIF or MyD88 pathway. Furthermore, when characterizing gene products with MyD88 and TRIF pathway-dependent expression, differences in TLR4-associated signaling were observed. rSIP and FLH require MyD88 and TRIF to activate nuclear factor kappa beta (NF-κB) and interferon regulatory factor (IRF). However, rSIP and FLH have a specific pattern of interleukin 6 (IL-6) and interferon gamma-induced protein 10 (IP-10) secretion associated with MyD88 and TRIF recruitment. Functionally, rSIP and FLH promote antigen cross-presentation in a manner dependent on TLR4, MyD88 and TRIF signaling. However, FLH activates a specific TRIF-dependent signaling pathway associated with cytokine expression and a pathway dependent on MyD88 and TRIF recruitment for antigen cross-presentation. Finally, this work supports the use of these TLR4-PBAs as clinically useful vaccine adjuvants that selectively activate TRIF- and MyD88-dependent signaling to drive safe innate immune responses and vigorous Th1 adaptive immune responses.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1186188/fullprotein-based adjuvants (PBAs)TLR4 agonistMyD88TRIFantigen-presenting cellsvaccines |
| spellingShingle | Diego A. Díaz-Dinamarca Diego A. Díaz-Dinamarca Diego A. Díaz-Dinamarca Michelle L. Salazar Daniel F. Escobar Byron N. Castillo Bastián Valdebenito Pablo Díaz Augusto Manubens Fabián Salazar Fabián Salazar Fabián Salazar Mayarling F. Troncoso Sergio Lavandero Sergio Lavandero Janepsy Díaz María Inés Becker María Inés Becker Abel E. Vásquez Abel E. Vásquez Surface immunogenic protein from Streptococcus agalactiae and Fissurella latimarginata hemocyanin are TLR4 ligands and activate MyD88- and TRIF dependent signaling pathways Frontiers in Immunology protein-based adjuvants (PBAs) TLR4 agonist MyD88 TRIF antigen-presenting cells vaccines |
| title | Surface immunogenic protein from Streptococcus agalactiae and Fissurella latimarginata hemocyanin are TLR4 ligands and activate MyD88- and TRIF dependent signaling pathways |
| title_full | Surface immunogenic protein from Streptococcus agalactiae and Fissurella latimarginata hemocyanin are TLR4 ligands and activate MyD88- and TRIF dependent signaling pathways |
| title_fullStr | Surface immunogenic protein from Streptococcus agalactiae and Fissurella latimarginata hemocyanin are TLR4 ligands and activate MyD88- and TRIF dependent signaling pathways |
| title_full_unstemmed | Surface immunogenic protein from Streptococcus agalactiae and Fissurella latimarginata hemocyanin are TLR4 ligands and activate MyD88- and TRIF dependent signaling pathways |
| title_short | Surface immunogenic protein from Streptococcus agalactiae and Fissurella latimarginata hemocyanin are TLR4 ligands and activate MyD88- and TRIF dependent signaling pathways |
| title_sort | surface immunogenic protein from streptococcus agalactiae and fissurella latimarginata hemocyanin are tlr4 ligands and activate myd88 and trif dependent signaling pathways |
| topic | protein-based adjuvants (PBAs) TLR4 agonist MyD88 TRIF antigen-presenting cells vaccines |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1186188/full |
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