SILVERFLU

Influenza (the flu) affects annually 10% of the worldwide population and is associated with high mortality in at risk populations due partially to an exacerbated inflammatory host response. When influenza virus enters in the host, it replicates in epithelial cells of both the upper and lower respiratory tract. Alveolar epithelial cells produce anti-viral molecules like pulmonary surfactant. Pulmonary surfactant is a lipid-protein complex that covers the alveolar surface and contributes to maintain the alveolar space open (mechanical function) and sterile (host-defence function). The preferential distribution of surfactant at the air-liquid interface of the alveolar lining fluid, implies that inhaled environmental contaminants (e.g. manufactured nanoparticles) and pathogens encounter this lipid-protein complex before contact with the alveolar epithelium. Host-defence functions of surfactant are due in one hand, to the capacity of surfactant proteins and lipids to modulate immune cellular responses and on the other hand to their anti-microbial properties (including anti-viral). Despite of host anti-viral responses are efficient to fight influenza infection, during severe influenza or in at risk populations, additional therapeutic treatments are needed for a successful recover of the patient. Present treatments (anti-virals and vaccination) are not efficient enough and economical costs associated to flu are still highly elevated. Thus, there is an urge to find new suitable and efficient treatments able to fight both viral replication and uncontrolled host responses. Silver nanoparticles (Ag NPs) have been shown to possess anti-microbial properties (including anti-viral) by undetermined mechanisms. The use of Ag NPs in human therapy is controversial because immune-toxicological studies of these NPs are lacking and mechanisms of action are unknown. Recent published data and our preliminary experiments demonstrate that, at non-toxic doses, Ag NPs are able to reduce viral replication in lung epithelial cells (the primary cells along with macrophages to support influenza infection). Further, treatment with Ag NPs post-infection reduced viral loads in the lungs of infected mice. The objective of SILVERFLU project will be to design non-toxic preparations based on Ag NPs able to control influenza infection. Our strategy to increase the dose and reduce toxic effects of Ag NPs will be to associate Ag NPs to synthetic liposomes made of DPPC and POPG, the two main phospholipids present in natural lung surfactant. The biocompatibility of lung surfactant lipids (which are naturally present) and their own anti-inflammatory and anti-viral properties will help to: i) potentiate anti-viral properties of Ag NPs, ii) deliver Ag NPs to the lungs reducing their toxicity, iii) down-regulate influenza-induced inflammatory responses. SILVERFLU will provide mixtures of Ag NPs associated to DPPC and POPG, well characterized from a physicochemical and toxicological point of view. The capacity of NP/lipid complexes to modulate influenza replication and influenza induced host responses will be assayed in cell cultures (lung epithelial cells and alveolar macrophages) and in vivo models. Our goal is to produce Ag NPs preparations able to reduce viral replication and control inflammatory responses without disturbing the establishment of lasting immunity (specific cytotoxic cells and antibody production)