作者: Sato, Sachiko ; Rabezanahary, Henintsoa ; Carignan, Damien ; Baz, Mariana ; Gilbert, Mégan ; Breton, Yann ; Bolduc, Marilène ; Saint-Louis, Philippe ; Dubuc, Isabelle ; Rancourt, Anne ; Pelletier, Martin ; Satoh, Masahiko S ; Leclerc, Denis ; Garneau, Caroline ; Flamand, Louis

Toll-like receptor (TLR) 7/8 agonists, such as imidazoquinoline derivatives (IMDs), hold great potential as immune modulators that can boost innate antiviral and anticancer immunity. However, significant challenges persist in achieving sufficient efficacy while minimizing toxic side effects. To date, only imiquimod (IMQ) has received FDA approval, and its use is restricted to topical applications. Therefore, there is a significant need for novel and safe TLR 7/8 agonists. In response to this, we developed a new generation of TLR7/8 agonist, the PapMV nanoparticle (PapMV nano). IMDs and PapMV nano are both innate immune system-activating drugs that have demonstrated antiviral and anticancer activities, but they differ significantly in three key aspects: (1) composition (proteins and ssRNA for PapMV nano vs. synthetic molecules for IMDs), (2) structure (large nanoparticles vs. small molecules), and (3) the mechanism of cell entry (internalization for PapMV nano vs. cell diffusion for IMDs). To compare how immune cells react to these two types of drug products, we studied cell motility, cell metabolism, and the induction of apoptosis in human monocyte-derived macrophages (hMDMs). Our data reveal that PapMV nano enhances motility and mitochondrial respiration while decreasing glycolysis, whereas IMDs have no impact on motility and mitochondrial respiration but increase glycolysis. PapMV nano is also the only agonist that does not induce apoptosis. Although the cellular responses to these two types of agonists differ strikingly, both are capable of eliciting antiviral immunity. We confirmed this potential for PapMV nano by demonstrating its capacity to prevent SARS-CoV-2 infection, supporting its utilization as a safe and effective immune modulator, capable of providing broad protection against respiratory viruses.

2025-02-01·IMMUNOLOGY LETTERS

Rescuing pathogen-specific memory B-cell from PBMC of prior Zika virus-infected individuals

Article

作者: Gonçalves Fonseca, Simone ; Fontinele, Hitallo Guilherme Costa ; Silva, Jacyelle Medeiros ; França, Renato Kaylan Alves de Oliveira ; Fonseca, Simone Gonçalves ; Barros, Pedro Henrique ; Brigido, Marcelo Macedo ; Maranhão, Andrea Queiroz

Immunological memory, a fundamental immune system mechanism, is instrumental in long-term protection. Successful vaccines can elicit and sustain immunological memory against pathogens for the long term. Memory B cells (MBC) are key players in secondary responses due to their longevity and rapid differentiation into high-affinity antibody-secreting cells upon second antigen exposure. However, the availability of circulating MBCs is limited. Here we describe a protocol, which presents a straightforward and practical method for activating and expanding Zika virus (ZIKV) specific MBC. PBMCs collected from individuals who had been infected with ZIKV two years prior were cultured by supplementing with IL-2 and R848, a TLR-7/8 agonist, and then pulsed with inactivated virus. After seven days, this stimulation led to a notable rise in virus-specific functional MBC, as evidenced by a significant increase in the production of anti-ZIKV IgG. Importantly, the ZIKV pulse did not induce changes in the PBMC culture of individuals without a history of ZIKV infection. These findings demonstrate that virus-specific MBC can be expanded in vitro, even using PBMC cultures from individuals infected years before. Therefore, our protocol is a practical and effective tool for studies that require a larger number of human MBCs from previously infected individuals that are functional and specific to the pathogen under investigation.

2024-07-12·ACS Pharmacology & Translational Science

Design and Synthesis of Polyphenolic Imidazo[4,5-c]quinoline Derivatives to Modulate Toll Like Receptor-7 Agonistic Activity and Adjuvanticity

Article

作者: Sakala, Isaac G. ; Patil, Madhuri T. ; Sihag, Binita ; Petrovsky, Nikolai ; Salunke, Deepak B. ; Singh, Rahul ; Kumar, Kushvinder ; Singh, Kamal Nain ; Honda-Okubo, Yoshikazu

TLR-7/8 agonists are a well-known class of vaccine adjuvants, with a leading example now included in Covaxin, a licensed human COVID-19 vaccine. This thereby provides the opportunity to develop newer, more potent adjuvants based on structure-function studies of these classes of compounds. Imidazoquinoline-based TLR7/8 agonists are the most potent, but when used as a vaccine adjuvant side effects can arise due to diffusion from the injection site into a systemic circulation. In this work, we sought to address this issue through structural modifications in the agonists to enhance their adsorption capacity to the classic adjuvant alum. We selected a potent TLR7-selective agonist, BBIQ (EC₅₀ = 0.85 μM), and synthesized polyphenolic derivatives to assess their TLR7 agonistic activity and adjuvant potential alone or in combination with alum. Most of the phenolic derivatives were more active than BBIQ and, except for 12b, all were TLR7 specific. Although the synthesized compounds were less active than resiquimod, the immunization data on combination with alum, specifically the IgG1, IgG2b and IgG2c responses, were superior in comparison to BBIQ as well as the reference standard resiquimod. Compound 12b was 5-fold more potent (EC₅₀ = 0.15 μM in TLR7) than BBIQ and induced double the IgG response to SARS-CoV-2 and hepatitis antigens. Similarly, compound 12c (EC₅₀ = 0.31 μM in TLR7) was about 3-fold more potent than BBIQ and doubled the IgG levels. Even though compound 12d exhibited low TLR7 activity (EC₅₀ = 5.13 μM in TLR7), it demonstrated superior adjuvant results, which may be attributed to its enhanced alum adsorption capability as compared with BBIQ and resiquimod. Alum-adsorbed polyphenolic TLR7 agonists thereby represent promising combination adjuvants resulting in a balanced Th1/Th2 immune response.

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