Rotavirus Entry: a Deep Journey into the Cell with Several Exits

Abstract

Rotaviruses are the leading etiological agents of acute gastroenteritis in infants and young children worldwide. These nonenveloped viruses enter cells using different types of endocytosis and, depending on the virus strain, travel to different endosomal compartments before exiting to the cytosolic space. In this Gem, we review the viral and cellular factors involved in the different stages of a productive virus cell entry and share with the readers the journey that we have taken into the cell to learn about virus entry. R otaviruses (RVs) are nonenveloped viruses, members of the family Reoviridae, and the leading etiological agents of viral gastroenteritis. In vivo, these viruses infect primarily mature enterocytes in the intestinal epithelium. They are composed of a triple-layered protein capsid that surrounds the viral genome. The outermost layer is formed by VP7, which makes the smooth surface of the virus, and by the spike protein VP4, which functions as the virus attachment protein. VP4 is cleaved by trypsin into two subunits, VP8 and VP5, and this cleavage is required for the virus to enter the cell (1).The initial step in a viral infection is the attachment of the virus to specific receptors on the cell surface, an interaction that frequently triggers cellular signaling cascades that facilitate either virus entry or replication. In most instances, regardless of whether the virus is enveloped or not, virus internalization proceeds through an endocytic pathway that delivers the viral particle to early endosomes (EEs), characterized by the presence of the GTPase Rab5 and early endosomal antigen 1 (EEA1) (2). Some viruses then traffic from these EE compartments to late endosomes (LEs), which are enriched in the GTPase Rab7 (2). The switch from Rab5 to Rab7 occurs via formation of hybrid endosomes that carry both Rab GTPases in separate domains (2) and are known as maturing endosomes (MEs) (3). Some MEs contain intraluminal vesicles (ILVs) that are formed by the endosomal sorting complex required for transport (ESCRT) machinery (4).The study of RV entry and vesicular traffic has been challenging and its advancement slow because a robust reverse genetic system to manipulate the genome of the virus is lacking. This limitation has been partially overcome, however, by use of RNA interference (RNAi) technology to explore the function of individual viral and cellular genes involved in this process, as well as by determination of the three-dimensional structures of the RV surface proteins. ATTACHMENT AND POSTATTACHMENT INTERACTIONSRV cell entry is a multistep process involving cellular glycans for cell binding and several coreceptors during postattachment steps (5) (Fig. 1, step a). The VP8 domain of VP4 mediates the initial interaction of the virus with the cell surface, whereas VP5 and likely the surface glycoprotein VP7 interact with downstream coreceptors (5). Several glycans have been identified as receptors for rotavirus; RV strains were classified initially as neuraminidase (NA) sensitive or NA resistant, dep...

Rotavirus infection

“…The susceptibility of mature enterocytes and enteroendocrine cells to infection has been shown in mice, in a transformed human enteroendocrine cell line and in human intestinal enteroid (HIE) cultures 35,36 (BOX 1). Rotavirus attachment to host cells is mediated by the outer capsid protein VP4 (through its VP8* domain 37 ) and binding partners on the host cell surface, including sialoglycans (such as gangliosides GM1 and GD1a) and histo-blood group antigens (HBGAs) 38 (FIG. 4).…”

“…After initial binding, VP7 and the VP5* domain of VP4 can interact with several of these co-receptors, which are concentrated at lipid rafts to mediate viral entry. Depending on the strain of rotavirus, the virus is internalized into cells by clathrin-dependent or clathrin-independent and caveolin-independent endocytic pathways 38,214 . The low calcium levels inside the endosome trigger the removal of the outer capsid layer, which releases the transcriptionally active double-layered particle (DLP) into the cytoplasm.…”

Rhesus rotavirus VP6 regulates ERK-dependent calcium influx in cholangiocytes

“…The virus then interacts with α2β1, αVβ3, and αXβ2 and heat shock protein-70 (Arias et al, 2015). During entry into the cholangiocyte cytoplasm, the virus is liberated from its outer capsid (composed of VP4 and VP7), producing active double-layer particles.…”

Human Milk Oligosaccharides as Promising Antivirals

“…P[8] is the dominant genotype infecting humans, whereas rotaviruses of the P[4] and P[6] genotypes are less common. In the host gastrointestinal tract, VP4 is further processed by trypsin‐like proteases into two subunits, VP5 and VP8* . The VP8* domain initiates cell invasion through adherence to a specific surface glycan.…”