Nanoparticle-delivered TLR4 and RIG-I agonists enhance immune response to SARS-CoV-2 subunit vaccine

Atalis, Alexandra; Keenum, M. Cole; Pandey, Bhawana; Beach, Alexander; Pradhan, Pallab; Vantucci, Casey E.; O’Farrell, Laura; Richard, Noël; Jain, Ritika; Hosten, Justin; Smith, Clinton; Kramer, Liana; Jiménez, Ángela Conchillo; Ochoa, Miguel Armenta; Frey, David; Roy, Krishnendu

doi:10.1016/j.jconrel.2022.05.023

Cited by 25 publications

(22 citation statements)

References 64 publications

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“…Using Venn diagram mapping, we further identified five core ferulic acid targets against OS and COVID-19 via autophagy, including MAPK1, TLR4, PIK3R1, STAT3, and PARP1. Among these core target genes, TLR4, STAT3, and PARP1 are associated with the development of COVID-19 ( 29 – 31 ). Moreover, the GO and KEGG enrichment assays revealed that biological processes were distinctly enriched in the positive regulation of tumor necrosis factor production, particularly the positive regulation of tumor necrosis factor superfamily cytokine production.…”

Section: Discussionmentioning

confidence: 99%

Preclinical findings: The pharmacological targets and molecular mechanisms of ferulic acid treatment for COVID-19 and osteosarcoma via targeting autophagy

Pang

Yi²,

Luo³

et al. 2022

Front. Endocrinol.

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The variant virus-based 2019 coronavirus disease (COVID-19) pandemic has reportedly impacted almost all populations globally, characterized by a huge number of infected individuals. Clinical evidence proves that patients with cancer are more easily infected with severe acute respiratory disease coronavirus 2 (SARS-CoV-2) because of immunologic deficiency. Thus, there is an urgent need to develop candidate medications to treat patients with cancer plus COVID-19, including those with osteosarcoma (OS). Ferulic acid, a latent theriacal compound that has anti-tumor and antivirus activities, is discovered to have potential pharmacological use. Thus, in this study, we aimed to screen and determine the potential therapeutic targets of ferulic acid in treating patients with OS plus COVID-19 as well as the pharmacological mechanisms. We applied a well-established integrated methodology, including network pharmacology and molecular docking technique, to detail target prediction, network construction, gene ontology, and pathway enrichment in core targets. The network pharmacology results show that all candidate genes, by targeting autophagy, were the core targets of ferulic acid in treating OS and COVID-19. Through molecular docking analysis, the signal transducer and activator of transcription 3 (STAT3), mitogen-activated protein kinase 1 (MAPK1), and phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) were identified as the pharmacological targets of ferulic acid in treating OS. These preclinical findings from bioinformatics analysis altogether effectively determined the pharmacological molecules and mechanisms via targeting autophagy, demonstrating the therapeutic effectiveness of ferulic acid against COVID-19 and OS.

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Section: Discussionmentioning

confidence: 99%

Preclinical findings: The pharmacological targets and molecular mechanisms of ferulic acid treatment for COVID-19 and osteosarcoma via targeting autophagy

Pang

Yi²,

Luo³

et al. 2022

Front. Endocrinol.

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“…PLGA-PEI NPs were synthesized as previously described. 27 Briefly, PLGA (50 lactate:50 glycolate, MW: 7000–17,000, Resomer RG 502H, Sigma-Aldrich, #719897) was dissolved in dichloromethane (DCM, Sigma-Aldrich, #270997) and endotoxin-free water in a 1:20:5 w/v/v ratio to form a primary emulsion that was sonicated at 65% power for 2 min. For particles with encapsulated TLR4 agonist, MPLA PHAD® (1 μg/mg PLGA, Avanti Polar Lipids, #699800P) was dissolved in DCM prior to emulsification.…”

Section: Methodsmentioning

confidence: 99%

“…The RIG-I agonist PUUC was synthesized according to previously described methods using custom PAGE-purified Ultramer oligonucleotide templates (Integrated DNA Technologies) with the MEGAshortscript TM T7 Transcription Kit (Invitrogen, #AM1354). 27 PUUC was mixed with PLGA-PEI NPs in 10 mM sodium phosphate buffer (prior treated with diethyl pyrocarbonate (DEPC), pH 6.5) in hydrophobic, low-adhesion tubes under continuous rotation at 4˚C for 24 h. After rotation, PUUC loading was confirmed by centrifuging NPs at 10,000 x g for 20 min and measuring RNA absorbance in supernatants with the Nucleic Acid Quantification program (Gen 5) using a Synergy HT plate reader and BioTek Take3 microvolume plate. Particle size and surface potential were evaluated with a Zetasizer Nano ZS (Malvern).…”

Section: Puuc and Mpla+puuc Plp Synthesismentioning

confidence: 99%

“…We have previously reported a PUUC loading efficiency of 100% (5 µg/mg NP) with particle sizes ~250 nm in diameter with an average surface zeta potential of 31.7 mV and 25.0 mV for PUUC and MPLA+PUUC particles, respectively. 27…”

Section: Puuc and Mpla+puuc Plp Synthesismentioning

confidence: 99%

“…We have previously reported that these PLGA-PEI pathogen-like particles (PLPs) can simultaneously activate multiple PRRs, 25,26 including intracellular RIG-I and extracellular TLR4 in vitro and in vivo . 27 After intranasal administration with PUUC NPs or MPLA+PUUC NPs, we employed PCR microarray analysis to survey the general transcriptional landscape of the lung at 4 and 24 h. We then used Cellular Indexing of Transcriptomes and Epitopes (CITE-Seq) to define cell types according to surface protein and mRNA expression, 28 perform differentially expressed gene (DEG) analysis, gene set enrichment analysis (GSEA), RNA velocity analysis of neutrophils, and cell-cell signaling analysis at the same time points. Analyses were conducted comparing each treatment against naïve lungs and for the MPLA+PUUC-treated lungs against PUUC-treated lungs.…”

Section: Introductionmentioning

confidence: 99%

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Single-Cell Epitope-Transcriptomics Reveal Lung Stromal and Immune Cell Response Kinetics to Nanoparticle delivered RIG-I and TLR4 Agonists

Keenum

Chatterjee

Atalis

et al. 2022

Preprint

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Lung-resident and circulatory lymphoid, myeloid, and stromal cells, expressing various pattern recognition receptors (PRRs), detect pathogen and danger-associated molecular patterns (PAMPs/DAMPs), and defend against respiratory pathogens and injuries. Here, we report the early responses of murine lungs to nanoparticle-delivered PAMPs, specifically the RIG-I agonist poly-U/UC (PUUC), with or without the TLR4 agonist monophosphoryl lipid A (MPLA). Using cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq), we characterized the responses at 4 and 24 hours after intranasal administration. Within 4 hours, ribosome-associated transcripts decreased in both stromal and immune cells, followed by widespread interferon-stimulated gene (ISG) expression. Using RNA velocity, we show that lung-neutrophils dynamically regulate the synthesis of cytokines like CXCL-10, IL-1α, and IL-1β. Co-delivery of MPLA and PUUC increased chemokine synthesis and upregulated antimicrobial binding proteins targeting iron, manganese, and zinc in many cell types, including fibroblasts, endothelial cells, and epithelial cells. Overall, our results elucidate the early PAMP-induced cellular responses in the lung and demonstrate that stimulation of the RIG-I pathway, with or without TLR4 agonists, induces a ubiquitous microbial defense state in lung stromal and immune cells. Nanoparticle-delivered combination PAMPs may have applications in intranasal antiviral and antimicrobial therapies and prophylaxis.

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A Dual‐Adjuvanted Parenteral‐Intranasal Subunit Nanovaccine generates Robust Systemic and Mucosal Immunity Against SARS‐CoV‐2 in Mice

Pandey,

Wang,

Jimenez

et al. 2024

Advanced Science

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Existing parenteral SARS‐CoV‐2 vaccines produce only limited mucosal responses, essential for reducing transmission and achieving sterilizing immunity. Appropriately designed mucosal boosters can overcome the shortcomings of parenteral vaccines and enhance pre‐existing systemic immunity. Here, a new protein subunit nanovaccine is developed by utilizing dual‐adjuvanted (RIG‐I: PUUC RNA and TLR‐9: CpG DNA) polysaccharide‐amino acid‐lipid nanoparticles (PAL‐NPs) along with SARS‐CoV‐2 S1 trimer protein, that can be delivered both intramuscularly (IM) and intranasally (IN) to generate balanced mucosal‐systemic SARS‐CoV‐2 immunity. Mice receiving IM‐Prime PUUC+CpG PAL subunit nanovaccine, followed by an IN‐Boost, developed high levels of IgA, IgG, and cellular immunity in the lungs and showed robust systemic humoral immunity. Interestingly, as a purely intranasal subunit vaccine (IN‐Prime/IN‐Boost), PUUC+CpG PAL‐NPs induced stronger lung‐specific T cell immunity than IM‐Prime/IN‐Boost, and a comparable IgA and neutralizing antibodies, although with a lower systemic antibody response, indicating that a fully mucosal delivery route for SARS‐CoV‐2 vaccination may also be feasible. The data suggest that PUUC+CpG PAL subunit nanovaccine is a promising candidate for generating SARS‐CoV‐2 specific mucosal immunity.

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Nanoparticle-delivered TLR4 and RIG-I agonists enhance immune response to SARS-CoV-2 subunit vaccine

Cited by 25 publications

References 64 publications

Preclinical findings: The pharmacological targets and molecular mechanisms of ferulic acid treatment for COVID-19 and osteosarcoma via targeting autophagy

Preclinical findings: The pharmacological targets and molecular mechanisms of ferulic acid treatment for COVID-19 and osteosarcoma via targeting autophagy

Single-Cell Epitope-Transcriptomics Reveal Lung Stromal and Immune Cell Response Kinetics to Nanoparticle delivered RIG-I and TLR4 Agonists

A Dual‐Adjuvanted Parenteral‐Intranasal Subunit Nanovaccine generates Robust Systemic and Mucosal Immunity Against SARS‐CoV‐2 in Mice

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