Trophoblastic extracellular vesicles and viruses: Friends or foes?

Abstract

Cells produce cytoplasmic vesicles to facilitate the processing and transport of RNAs, proteins, and other signaling molecules among intracellular organelles. Moreover, most cells release a range of extracellular vesicles (EVs) that mediate intercellular communication in both physiological and pathological settings. In addition to a better understanding of their biological functions, the diagnostic and therapeutic prospects of EVs, particularly the nano-sized small EVs (sEVs, exosomes), are currently being rigorously pursued. While EVs and viruses such as retroviruses might have evolved independently, they share a number of similar characteristics, including biogenesis pathways, size distribution, cargo, and cell-targeting mechanisms. The interplay of EVs with viruses has profound effects on viral replication and infectivity. Our research indicates that sEVs, produced by primary human trophoblasts, can endow other non-placental cell types with antiviral response. Better insights into the interaction of EVs with viruses may illuminate new ways to attenuate viral infections during pregnancy, and perhaps develop new antiviral therapeutics to protect the feto-placental unit during critical times of human development.

Keywords: Placenta; extracellular vesicles; microRNA; trophoblast; viruses.

Figure 1.. A general schematic illustrating how EVs and viruses enter cells via endocytosis and fusion-triggered endosomal escape for cargo release and subsequent processing.

EVs and viruses, including lipid enveloped or non-enveloped forms, enter their target cell by binding to specific receptors on the plasma membrane (1). They are subsequently internalized into endosomal vesicles through multiple endocytosis pathways, mainly including clathrin-mediated endocytosis, caveolin-mediated endocytosis, and macropinocytosis (2). Direct virus and plasma membrane fusion-mediated cell entry, utilized by certain viruses, is not shown, but described in the text. This is followed by trafficking within the endosomal network, including early endosome, late endosome or endolysosome (3), EVs and viruses reach the low-pH endosomal compartment (4) where fusogenic proteins on the surface membrane of EVs or viruses trigger membrane fusion (5), with subsequent cargo release to the cytosol (6). EV cargo, including diverse coding or non-coding RNA types, are released and likely execute their function in target recipient cells. In contrast, viral DNA or RNA genomes are released and processed for transcription and replication. The processing of EV or viral proteins is not shown. Unlike the arrival of EVs to their “final destination”, viruses can usurp host cell machinery to synthesize viral nonstructural proteins such as viral polymerase and/or integrase to support viral replication. Consequently, assembled viral genome and proteins may begin replication (7). Lastly, progeny virions utilize exocytosis pathways, cell budding or cell lysis for exit and virus dissemination (8). Additional similarities and dissimilarities in EV and virus pathways are detailed in the text. This figure was created with BioRender.com.