Induction of protective immune responses at respiratory mucosal sites.

Many pathogens enter the host through mucosal sites. Thus, interfering with pathogen entry through local neutralization at mucosal sites therefore is an effective strategy for preventing disease. Mucosally administered vaccines have the potential to induce protective immune responses at mucosal sites.

Enhanced mucosal B- and T-cell responses against SARS-CoV-2 after heterologous intramuscular mRNA prime/intranasal protein boost vaccination with a combination adjuvant.

Current COVID-19 mRNA vaccines delivered intramuscularly (IM) induce effective systemic immunity, but with suboptimal immunity at mucosal sites, limiting their ability to impart sterilizing immunity. There is strong interest in rerouting immune responses induced in the periphery by parenteral vaccination to the portal entry site of respiratory viruses, such as SARS-CoV-2, by mucosal vaccination. We previously demonstrated the combination adjuvant, NE/IVT, consisting of a nanoemulsion (NE) and an RNA-based RIG-I agonist (IVT) induces potent systemic and mucosal immune responses in protein-based SARS-CoV-2 vaccines administered intranasally (IN).

Endosomal trafficking inhibitor EGA can control TLR7-mediated IFNα expression by human plasmacytoid dendritic cells.

Plasmacytoid dendritic cells (pDC) are the major producer of type 1 IFN in response to TLR7 agonists. Aberrant TLR7 activation and type 1 IFN expression by pDCs are linked to the pathogenesis of certain types of autoimmune diseases, including systemic lupus erythematosus (SLE). This study investigated the underlying mechanisms for TLR7-mediated cytokine expression by pDCs using a late endosome trafficking inhibitor, EGA (4-bromobenzaldehyde -(2,6-dimethylphenyl) semicarbazone).

Disruption of endosomal trafficking with EGA alters TLR9 cytokine response in human plasmacytoid dendritic cells.

Plasmacytoid dendritic cells (pDCs) exhibit bifurcated cytokine responses to TLR9 agonists, an IRF7-mediated type 1 IFN response or a pro-inflammatory cytokine response the activation of NF-κB. This bifurcated response has been hypothesized to result from either distinct signaling endosomes or endo-lysosomal trafficking delay of TLR9 agonists allowing for autocrine signaling to affect outcomes. Utilizing the late endosome trafficking inhibitor, EGA, we assessed the bifurcated cytokine responses of pDCs to TLR9 stimulation.