High-Dose Mannose-Binding Lectin Therapy for Ebola Virus Infection

摘要

Mannose-binding lectin (MBL) targets diverse microorganisms for phagocytosis and complement-mediated lysis by binding specific surface glycans. Although recombinant human MBL (rhMBL) trials have focused on reconstitution therapy, safety studies have identified no barriers to its use at higher levels. Ebola viruses cause fatal hemorrhagic fevers for which no treatment exists and that are feared as potential biothreat agents. We found that mice whose rhMBL serum concentrations were increased >7- fold above average human levels survived otherwise fatal Ebola virus infections and became immune to virus rechallenge. Because Ebola glycoproteins potentially model other glycosylated viruses, rhMBL may offer a novel broadspectrum antiviral approach. Circulating mannose-binding lectin (MBL) is a first-line host defense against a wide range of viral and other pathogens. MBL is a C-type lectin that recognizes hexose sugars including mannose, glucose, fucose, and N-acetylglucosamine on the surface of many pathogens. It does not recognize the terminal carbohydrates galactose and sialic acid on normal host cells. Therefore, MBL preferentially recognizes glycosylated viruses including influenza virus, human immunodeficiency virus, severe acute respiratory syndrome coronovirus (SARS- CoV), Ebola virus, and Marburg virus. It also recognizes many glycosylated grampositive and gram-negative bacteria. As a result of common genetic variants, MBL serum levels in humans range from 0 to 10,000 ng/mL. Thirty percent of the human population has levels ,500 ng/mL, which are associated with increased susceptibility to infections in children and immunocompromised individuals.