Project Summary
The Mammarenavirus genus of the Arenavirus family contains multiple zoonotic pathogens with the potential to
cause hemorrhagic fever. These include the South American viruses Junin virus (JUNV; Argentinian
hemorrhagic fever) and Machupo virus (MACV; Bolivian hemorrhagic fever), and Lassa virus (LASV), which
causes thousands of cases of Lassa Fever in West Africa each year. The case fatality rate for these viruses is
20-70%. Lujo virus (LUJV) is the most recently identified African arenavirus. This virus was responsible for five
infections, of which four were fatal. Notably, this outbreak was characterized by human-to-human transmission
rather than transmission between rodent and human, as is most common for other arenaviruses. Arenaviruses
are genetically and geographically divided into New World (e.g. JUNV and MACV) and Old World (e.g. LASV)
groups. Its African location placed LUJV into the OW group. However, LUJV is genetically divergent from other
African arenaviruses and is phylogenetically equidistant between the NW and OW groups. Further, its
glycoprotein GPC recognizes a different receptor and is antigenically distinct from the other arenaviruses. As
the only protein expressed on the viral surface, GPC is responsible for receptor engagement, cell tropism and
entry, and is the primary target of antibodies. Understanding the unique structure and surface chemistry of
LUJV GPC in its native conformation is key to understanding receptor recognition in the native trimer context,
what antibody targets might be on this divergent virus, and how we might design vaccines and therapeutics
should the virus re-emerge. The premise of this proposal is that structures of the medically relevant LUJV GP
alone and in complex with its cell surface receptor will reveal reasons for its unique cell entry requirements and
any differences in its epitope landscape. We will use state-of-the-art biophysical techniques such as cryo
electron microscopy, surface plasmon resonance and composition-gradient multiangle light scattering, to
characterize the interaction of the prefusion-stabilized LUJV GP trimer (pfGP-TD) with its receptor NRP2. In
Aim 2, we will identify antibodies from mice immunized with LUJV pfGP-TD using the Berkeley Lights Beacon
platform. Results from the innovative research proposed here will launch multiple lines of inquiry for future
studies and will help guide development of vaccines against a diverse range of arenaviruses.
