Mechanism of Lassa Virus Entry and Identification of Low Molecular Weight Drugs with Potential to Inhibit both Lassa and Ebola Virus Entry
Hulseberg, Christine, Microbiology - School of Medicine, University of Virginia
White, Judith, Microbiology, University of Virginia
The arenavirus family has seven members that are considered Category A pathogens capable of causing severe hemorrhagic fever in humans. Lassa virus is by far the most clinically relevant virus in this family, causing tens or hundreds of thousands of infections in West Africa each year. Despite this tremendous public health burden, there are no specific licensed antiviral therapies for Lassa hemorrhagic fever, nor are there effective and approved vaccines. To develop the best possible drugs against Lassa virus, particularly those that intervene at an early stage of the viral infectious cycle, a detailed knowledge of its entry mechanism, particularly where and how host cell factors are involved, is required. The discovery that Lassa uses an endosomal receptor, Lamp1, during entry has opened a new field of inquiry about its role in facilitating viral entry. We show multiple lines of cell-based evidence that Lamp1 promotes entry of Lassa virus from compartments within the endocytic pathway by shifting the pH at which it fuses with the endosomal membrane. Our model for Lamp1’s role proposes that, in its absence, pH-sensitive fusion proteins on the surface of Lassa virions are not activated, which prevents the viruses from escaping from endosomal compartments before inactivation. Noting many similar features between Lassa and Ebola virus entry, including that both viruses use a different endosomal receptor, we then asked whether a number of Ebola entry inhibitors also inhibit Lassa virus entry. After showing that six out of nine of these drugs were equally effective at blocking Lassa entry, one compound in particular, the anti-influenza drug, arbidol, was selected for further mechanistic studies. Our results are consistent with the proposal that arbidol impairs fusion of Lassa virus with host cells endosomes.
PHD (Doctor of Philosophy)
Lassa virus, Lamp1, Ebola virus, Viral membrane fusion, Endocytic pathway, Arbidol, Entry inhibitors