THE ROLE OF LAMP1 SWITCHING DURING CELL-ENTRY OF LASSA VIRUS

Cell entry of many enveloped viruses occurs by engagement with cellular receptors, followed by internalization into endocytic compartments and pH-induced membrane fusion. A previously unnoticed step of receptor switching was found to be critical during cell entry of two devastating human pathogens: Ebola and Lassa viruses. Our recent studies revealed the functional role of receptor switching by Lassa virus. We have demonstrated that receptor switching from alpha-dystroglycan, the major cellular receptor of Lassa to LAMP1 is serving as the triggering cue for the spike-mediated membrane fusion. The molecular mechanism of this triggering involves a highly conserved triad of histidine residues, suggesting that other viruses from this family may also utilize such a switching mechanism. We thus investigated some viruses that are genetically close to Lassa and discovered that they do not switch to LAMP1. Using a crystal structure of the receptor-binding module from Morogoro virus, a virus that is genetically close to Lassa, we revealed structural differences that allowed us to map the LAMP1 binding site on the receptor-binding domain of the Lassa-spike complex. This mapping suggests that switching to LAMP1 is a unique mechanism that Lassa has evolved to use, perhaps contributing to its remarkable pathogenicity.