Poly(I:C)-Encapsulating Nanoparticles Enhance Innate Immune Responses to the Tuberculosis Vaccine Bacille Calmette–Guérin (BCG) via Synergistic Activation of Innate Immune Receptors

• DOI: 10.1021/acs.molpharmaceut.7b00795
• Publication Date: 2017-10-04T03:29:03Z
• Authors: Martin T. Speth; Urska Repnik; Elisabeth Müller; Julia Spanier; Ulrich Kalinke; Alexandre Corthay; Gareth Griffiths
• Keywords: Tuberculosis vaccines

The attenuated live vaccine strain bacille Calmette–Guérin (BCG) is currently the only available against tuberculosis (TB), but largely ineffective adult pulmonary TB, most common disease form. This in part due to BCG’s ability interfere with host innate immune response, a feature that might be targeted enhance potency of this vaccine. Here, we investigated chitosan-based nanoparticles (pIC-NPs) containing polyinosinic–polycytidylic acid (poly(I:C)), an inducer immunity via Toll-like receptor 3 (TLR3), immunogenicity BCG mouse bone marrow derived macrophages (BMDM) vitro. Incorporation poly(I:C) into NPs protected it degradation by ribonucleases and increased its uptake BMDM. Whereas soluble was ineffective, pIC-NPs strongly enhanced proinflammatory response BCG-infected synergistic fashion, as evident production cytokines induction nitric oxide synthesis. Using from mice deficient key signaling molecules involved pathogen recognition identified combined activation MyD88- TRIF-dependent TLR pathways essential for effect between NP. Moreover, synergy dependent on order two stimuli, functioning priming event subsequent pIC-NP stimulus, which acted through auto-/paracrine type I interferon (IFN) feedback loop. Our results provide foundation promising new approach BCG-vaccine costimulation NPs. They also contribute molecular understanding observed interaction