Pulmonary surfactant–biomimetic nanoparticles potentiate heterosubtypic influenza immunity

Vulnerability of respiratory mucosa to invasions of airborne pathogens, such as SARS-CoV, MERS-CoV and avian viruses which sometimes cause a life-threatening epidemic and even pandemic, underscores significance of developing a pulmonary vaccine adjuvant-delivery system (VADS). Herein, 30-nm aluminum nanoparticles (ANs), unlike the mostly used adjuvant alum which is unsuitable for delivering pulmonary vaccines due to side effects, proved able to act as a VADS fitting inhalation immunization to elicit wide-spread anti-antigen immunity. In vitro ANs facilitated cellular uptake of their cargos and, after pulmonary vaccination, induced mouse production of high levels of anti-antigen IgG in serum and IgA in saliva, nasal, bronchoalveolar and also vaginal fluids. Besides, IFN-γ and anti-antigen IgG2a enriched in immunized mice which meanwhile showed no obvious lung inflammation indicated balanced Th1/Th2 responses were safely induced. These outcomes suggest ANs may be an efficient pulmonary VADS for defending against pathogens, especially, the ones invading hosts via respiratory system. Graphic AbstractAluminum nanoparticles can safely induce humoral and cellular immunity at systemic and mucosal level through pulmonary vaccination to contrast the conventional adjuvant alum.

Extracellular 2'3'-cyclic-GMP-AMP (cGAMP) is an immunotransmitter secreted by cancer cells and taken up by host cells to activate the anti-cancer STING pathway. No cGAMP exporter has been identified, and SLC19A1, a recently identified cGAMP importer, does not account for the import activity in most cell types. Here, we identify the LRRC8A:C heteromeric channel, a volume-regulated anion channel (VRAC), as a cGAMP transporter. This channel mediates cGAMP import or export depending on the cGAMP chemical gradient, and channel activation or inhibition modulates cGAMP transport. Other 2'3'-cyclic dinucleotides are also transported by LRRC8A:C channels, including the investigational cancer therapeutic ADU-S100. Furthermore, we demonstrate that the LRRC8A-containing channel is the dominant cGAMP importer in primary human vasculature cells. Given tumor vasculature's regulation of immune infiltration and its disruption in response to STING agonists, we have uncovered a leading molecular mechanism for extracellular cGAMP signaling in this important anticancer target.

Fig. 1 Current vaccines (inactivated flu vaccines) help by boosting immunity against one subtype of influenza virus. However, this approach means seasonal and regular vaccines are required to combat the constant mutations caused by antigenic drift. Wang et al. showed augmenting current vaccines with a new nanoparticle (PS-GAMP) that can activate long-term immunity against different subtypes of influenza viruses (heterosubtypic influenza immunity). The results also hold promise to use this type of technology for universal vaccines against other respiratory viruses Protecting against different subtypes of influenza viruses: a.. . Yi et al.