There is an urgent need to develop new host-targeted therapeutics that safely limit the severity of respiratory viral infections. Severe and fatal influenza virus (IAV) infections are associated with significant viral replication and damaging hyperinflammatory responses which can lead to morbidity, mortality and long-term multi-system organ damage. LAT8881 is synthetic form of the naturally occurring C-terminal fragment of human growth hormone (GH), acting independently of the GH receptor to reduce inflammation-induced damage and promote tissue repair in an animal model of osteoarthritis. Additionally, LAT8881 has been investigated in several clinical trials in healthy volunteers and for the treatment of obesity and has an established safety profile.
In light of its effects in improving inflammatory damage in animal models, we investigated the potential for LAT8881 and related compounds to treat severe HKx31 H3N2 IAV infection. Daily, intranasal delivery of LAT8881 or its metabolite LAT9991F from 1 day following infection significantly reduced disease susceptibility and resulted in a dose-dependent reduction in infectious viral loads and pro-inflammatory cytokines in the lungs, as well as an increased abundance of protective alveolar macrophages. LAT8881 had similar activity with that of the antiviral oseltamivir phosphate and when combined, therapeutic effects were improved. In vitro LAT8881 treatment enhanced the viability of multiple cell types, particularly in the presence of cytotoxic stress, which was countered by siRNA inhibition of host lanthionine synthetase C-like (LANCL) proteins.
These studies provide the first evidence identifying LAT8881 and LAT9991F as novel host-protective therapies that improve survival, limit viral replication, and reduce local inflammation during severe IAV infection.