Bacterial Outer Membrane Vesicles Provide Broad-Spectrum Protection against Influenza Virus Infection via Recruitment and Activation of Macrophages

Abstract

Influenza A virus (IAV) poses a constant worldwide threat to human health. Although conventional vaccines are available, their protective efficacy is type or strain specific, and their production is time-consuming. For the control of an influenza pandemic in particular, agents that are immediately effective against a wide range of virus variants should be developed. Although pretreatment of various Toll-like receptor (TLR) ligands have already been reported to be effective in the defense against subsequent IAV infection, the efficacy was limited to specific subtypes, and safety concerns were also raised. In this study, we investigated the protective effect of an attenuated bacterial outer membrane vesicle ­harboring modified lipid A moiety of lipopolysaccharide (fmOMV) against IAV infection and the underlying mechanisms. Administration of fmOMV conferred significant protection against a lethal dose of pandemic H1N1, PR8, H5N2, and highly pathogenic H5N1 viruses; this broad antiviral activity was dependent on macrophages but independent of neutrophils. fmOMV induced recruitment and activation of macrophages and elicited type I IFNs. Intriguingly, fmOMV showed a more significant protective effect than other TLR ligands tested in previous reports, without exhibiting any adverse effect. These results show the potential of fmOMV as a prophylactic agent for the defense against influenza virus infection.

TLR Agonists as Mediators of Trained Immunity: Mechanistic Insight and Immunotherapeutic Potential to Combat Infection

“…Further, fmOMV confers protection against a lethal dose of pandemic viruses (H1N1, PR8, H5N2, and highly pathogenic H5N1) which is dependent on macrophages but independent of neutrophils. Treatment with fmOMV increased macrophage recruitment and production of type I IFNs without observance of adverse effects ( 81 ).…”

Bacterial Outer Membrane Vesicles (OMVs)-Based Dual Vaccine for Influenza A H1N1 Virus and MERS-CoV

“…LPS in the outer surface of OMVs acts as a self-adjuvant that induces humoral and cellular immunity. Therefore, OMVs vaccines may be used without extra adjuvant to increase the immunogenicity and produce antiviral innate immune responses against various influenza virus infections via activation of macrophages [42,43,44]. Despite that the exact role of LPS in the context of OMVs vaccines requires further investigations, high amounts of LPS could be a drawback due to its known endotoxicity and ability to induce excessive secretions of pro-inflammatory cytokines [45].…”

Innate Receptor Activation Patterns Involving TLR and NLR Synergisms in COVID-19, ALI/ARDS and Sepsis Cytokine Storms: A Review and Model Making Novel Predictions and Therapeutic Suggestions

“…The antagonistic actions of NOD2 on TLR2 and TLR4 may also work in reverse given sufficient time for the system of interactions to equilibrate. For example, bacterial outer membrane protein vesicles protect against H1N1, H5N2 and H5N1 and MERS fatal infections in mice [ 193 , 194 , 195 ] and antagonizing TLR4 blocks the cytokine storm associated with influenza virus infection and improves survival in mice [ 196 ]. Given the paucity of research that has so far been published on the activation (or lack thereof) of NLR in severe COVID-19, it is also possible that additional studies will find that NOD1 and/or NOD2 are actually activated or their expression increased during the development of cytokine storms.…”

“…Figure 9 represents the initiation of TLR/NLR activation, while Figure 3 B represents the established pattern after antagonistic feedback; antibiotic treatments undoubtedly modulate bacterial PAMP presentation to TLR and NOD, and there are likely to be as-yet-uncharacterized negative feedback effects of TLR2, TLR4, etc. on NOD1/NOD2 [ 193 , 194 , 195 , 196 ] and, especially, in this case, RIG1, which would otherwise be predicted to be upregulated by the influenza virus ( Table 2 ).…”