Phosphatidylserine (PS) receptors contribute to two crucial biological processes: apoptotic clearance and entry of many enveloped viruses. In both cases, they recognize PS exposed on the plasma membrane. Here we demonstrate that phosphatidylethanolamine (PE) is also a ligand for PS receptors and that this phospholipid mediates phagocytosis and viral entry. We show that a subset of PS receptors, including T-cell immunoglobulin (Ig) mucin domain protein 1 (TIM1), efficiently bind PE. We further show that PE is present in the virions of flaviviruses and filoviruses, and that the PE-specific cyclic peptide lantibiotic agent Duramycin efficiently inhibits the entry of West Nile, dengue, and Ebola viruses. The inhibitory effect of Duramycin is specific: it inhibits TIM1-mediated, but not L-SIGNmediated, virus infection, and it does so by blocking virus attachment to TIM1. We further demonstrate that PE is exposed on the surface of apoptotic cells, and promotes their phagocytic uptake by TIM1-expressing cells. Together, our data show that PE plays a key role in TIM1-mediated virus entry, suggest that disrupting PE association with PS receptors is a promising broad-spectrum antiviral strategy, and deepen our understanding of the process by which apoptotic cells are cleared. M embers of the filovirus and flavivirus families are the causative agents of life-threatening diseases. Ebola virus (EBOV), a filovirus, causes hemorrhagic fever with an average case fatality rate as high as 65% (1). Although there are EBOV vaccine candidates (2, 3), there is currently no licensed vaccine or treatment. Dengue virus (DENV) and West Nile virus (WNV) belong to the flavivirus family. Both are transmitted to humans through mosquito bites and can cause lethal hemorrhagic fever (in the case of DENV) or severe neurological diseases (in the case of WNV) (4, 5). Flaviviruses are emerging as major health concerns in tropical and subtropical areas worldwide. More than one third of the world's population is estimated to be at risk for DENV infection, with approximately 400 million people infected yearly (6). There are currently no approved vaccines or therapeutic agents against DENV or WNV.Virus entry into host cells typically initiates with the interaction between viral entry glycoproteins (GPs) and a receptor or coreceptor expressed at the surface of the target cell. Viruses also use less specific mechanisms to localize to target cell membranes, for example through GP association with various attachment factors (7). During the past few years, it has been increasingly recognized that many viruses also use a strategy known as apoptotic mimicry to promote their association with, and internalization into their target cells (8). Receptors for phospholipids, specifically phosphatidylserine (PS), normally involved in the clearance of apoptotic cells, markedly enhance the infection of a number of enveloped viruses. These PS receptors are presumed to engage PS on the virion membrane rather than the viral entry protein (9, 10). Enveloped viruses acquire...
At least five New World (NW) arenaviruses cause hemorrhagic fevers in South America. These pathogenic clade B viruses, as well as nonpathogenic arenaviruses of the same clade, use transferrin receptor 1 (TfR1) of their host species to enter cells. Pathogenic viruses are distinguished from closely related nonpathogenic ones by their additional ability to utilize human TfR1 (hTfR1). Here, we investigate the receptor usage of North American arenaviruses, whose entry proteins share greatest similarity with those of the clade B viruses. We show that all six North American arenaviruses investigated utilize host species TfR1 orthologs and present evidence consistent with arenavirus-mediated selection pressure on the TfR1 of the North American arenavirus host species. Notably, one of these viruses, AV96010151, closely related to the prototype Whitewater Arroyo virus (WWAV), entered cells using hTfR1, consistent with a role for a WWAV-like virus in three fatal human infections whose causative agent has not been identified. In addition, modest changes were sufficient to convert hTfR1 into a functional receptor for most of these viruses, suggesting that a minor alteration in virus entry protein may allow these viruses to use hTfR1. Our data establish TfR1 as a cellular receptor for North American arenaviruses, highlight an "arms race" between these viruses and their host species, support the association of North American arenavirus with fatal human infections, and suggest that these viruses have a higher potential to emerge and cause human diseases than has previously been appreciated. IMPORTANCEhTfR1 use is a key determinant for a NW arenavirus to cause hemorrhagic fevers in humans. All known pathogenic NW arenaviruses are transmitted in South America by their host rodents. North American arenaviruses are generally considered nonpathogenic, but some of these viruses have been tentatively implicated in human fatalities. We show that these North American arenaviruses use the TfR1 orthologs of their rodent host species and identify TfR1 polymorphisms suggesting an ongoing "arms race" between these viruses and their hosts. We also show that a close relative of a North American arenavirus suggested to have caused human fatalities, the Whitewater Arroyo species complex virus AV96010151, uses human TfR1. Moreover, we present data that imply that modest changes in other North American arenaviruses might allow these viruses to infect humans. Collectively, our data suggest that North American arenaviruses have a higher potential to cause human disease than previously assumed.
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