Stopping Lassa in its tracks
A study published recently in Science sheds new light on how Lassa virus infections are blocked or ‘neutralised’ by host antibodies. Researchers from Scripps Institute, California used X-ray crystallography to obtain a high-resolution structure of Lassa virus glycoprotein complex (GPC) bound to a neutralising antibody from a human survivor. As the only viral protein that is exposed to the human immune system, GPC is the Achilles’ heel of Lassa virus and a major focus of vaccine development.
First discovered in 1969 in Nigeria, Lassa virus mainly spreads by contact with infected rats or their droppings. Direct patient-to-patient transmission is also possible but much less common than with Ebola. In West Africa, where it is endemic, Lassa virus infects 300,000-500,000 people annually. Most patients infected with Lassa virus do not develop clinical symptoms; however, in a minority of cases in can lead to life-threatening haemorrhagic fever. The overall mortality rate associated with Lassa virus is estimated to be ~1% but during a recent epidemic in Nigeria this rate rose alarmingly to ~50%, placing Lassa virus on par with its distant cousin Ebola in terms of mortality. There is, as yet, no licensed vaccine for Lassa virus and the number of treatment options remains limited.
Lassa viral GPC is a trimer with each monomer comprising two subunits, GP1 and GP2. GP1 interacts with host cell receptors whereas GP2 mediates fusion between viral and host cell membranes. Binding of GP1 to the extracellular receptor a-dystroglycan promotes the uptake of the virus into host cells where it enters intracellular compartments called endosomes. The acidic (low pH) environment encountered by the virus in endosomes facilitates the release of a-dystroglycan and promotes interaction of GPC with another receptor, LAMP1. Binding to LAMP1 is thought to trigger membrane fusion and release of the viral genome into the host cell cytoplasm.
The crystal structure of the GPC-antibody complex presents some key insights into GPC function as well as the molecular mechanism of antibody-mediated virus neutralisation. The GPC trimer was arranged as a tight tripod in the crystal with its exposed surface predominantly covered in sugars or ‘glycans’ which prevent access to antibodies. The neutralising antibody used by the researchers, named 37.7H, bound simultaneously to two GP2 subunits of adjacent GPC monomers suggesting that it acts by stabilising the GPC trimer and blocking pH-induced conformational changes. Indeed, the study went on to show that the presence of this antibody strongly inhibited both LAMP1 binding of GPC and viral membrane fusion.
The molecular insights provided by this study into Lassa virus neutralisation will likely be important for future efforts in developing more effective vaccines and therapeutics.
Hastie, K. M., et al. (2017). “Structural basis for antibody-mediated neutralization of Lassa virus.” Science 356(6341):
923-928. DOI: 10.1126/science.aam7260