Virion-associated phosphatidylethanolamine promotes TIM1-mediated infection by Ebola, dengue, and West Nile viruses

Abstract

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...

Insights into the Biosynthesis of Duramycin

“…Of the three proteins investigated (DurM, DurN, and DurX), the Asp hydroxylase DurX is least forgiving in that its activity toward analogs was decreased and that mutation of the Gly residue flanking Asp15 resulted in loss of activity in vitro and in E. coli. Collectively, these findings can be utilized for the design and application of variants of duramycin with improved properties for diagnostic or therapeutic applications (17,20,23).…”

AXL-dependent infection of human fetal endothelial cells distinguishes Zika virus from other pathogenic flaviviruses

“…Although bona fide entry receptors for flaviviruses remain unknown, many cell surface-expressed molecules contribute to infection, including C-type lectins dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) and DC-SIGN-related protein (L-SIGN) (10,11) and phosphatidylserine (PS) receptors (12)(13)(14)(15) . PS receptors, which serve as entry cofactors for flaviviruses, include members of the TIM (T-cell Ig mucin) family and the TAM (TYRO3, AXL, and MERTK) family.…”

“…PS receptors, which serve as entry cofactors for flaviviruses, include members of the TIM (T-cell Ig mucin) family and the TAM (TYRO3, AXL, and MERTK) family. TIMfamily receptors bind PS directly (14,15), whereas TAM-family members bind PS indirectly, through the soluble intermediates Gas6 (growth arrest-specific 6) and protein S present in serum and other bodily fluids (16,17). Whereas Gas6 binds to all three TAM family members with high affinity, protein S binds to TYRO3 and MERTK, but not to AXL (17).…”

Lantibiotics produced by Actinobacteria and their potential applications (a review)

“…They are usually small peptides (<10 kDa) which are cationic and amphipathic [9][10][11][12]. Actinobacterial bacteriocins inhibit the growth of species related to the producer, such as michiganin A [13], although many of them possess a broad spectrum of inhibitory activity that includes non-related bacteria (microbisporicin), protozoans (thiostrepton), yeasts and fungi (cinnamycin) and viruses (labyrinthopeptin A1 and duramycin) [14][15][16][17][18]. In addition to antimicrobial activity, some actinobacterial bacteriocins and their semisynthetic derivatives also exhibit anti-inflammatory [19][20][21], anti-allergic [20], antitumour [22][23][24] and antinociceptive activities [25,26], and may also act in blood pressure regulation [19,27].…”

“…For the West Nile, dengue and ebola viruses, duramycin inhibited the viral entry processes. Therefore, duramycin, as other lantibiotics that bind to PE, has potential to inhibit the activity of tumour cells and viruses [18,91].…”