Seyma Caglayan Rotaviruses

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**Şeyma Çağlayan- 1605A045**
F. Greber - Physical Virology Virus Structure and Mechanics (2019)
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# ROTAVIRUSES

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## CONTENT

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## What is rotavirus?

Rotaviruses are non-enveloped dsRNA viruses that infect the mature intestinal epithelium. They are major etiologic agents of diarrheal disease in human infants, as well as in young individuals of various avian and mammalian species.

The segmented double-stranded (ds) RNA viruses of the Reoviridae family have non-enveloped multi-layered icosahedral capsids. These viruses present a replication cycle that is regulated through an ordered, stepwise disassembly and assembly of the viral particle layers. In this context, the outer shell of the virions is responsible for orchestrating the entry into the host cell.

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This process has been structurally and functionally well characterized for Rotavirus (RV), an important human and animal gastrointestinal pathogen. In the past years, a number of studies using NMR, X-ray crystallography, and cryo-electron microscopy (cryoEM) have resolved the structure of the RV virion, its subviral particles, and individual proteins of the RV entry machinery alone, or complexed with different ligands.

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### Rotavirus Structure

RV is a major model for the Reoviridae family. RV has a ~18,500 bp segmented genome with 11 double-stranded (ds) RNA molecules that encode six structural proteins (VP1, VP2, VP3, VP4, VP6, and VP7) and six nonstructural proteins (NSP1 to NSP6).


All segments are monocistronic with the exception of segment 11 that in some strains has two overlapping open reading frames (ORFs) encoding NSP5 and NSP6 . The infectious entity is a non-enveloped icosahedral triple-layered particle (TLP) with ~100 nm in diameter (Fig.1a) that resembles a wheel (lat. rota) when observed by electron microscopy.

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Source: S. Libersou, X. Siebert, M. Ouldali, L. F. Estrozi, J. Navaza, A. Charpilienne, P. Garnier, D. Poncet, and J. Lepault, “Geometric Mismatches within the Concentric Layers of Rotavirus Particles: a Potential Regulatory Switch of Viral Particle Transcription Activity,” Journal of Virology, vol. 82, no. 6, pp. 2844–2852, 2020.

Images and 3-D reconstructions of rotavirus particles. DLPs and TLPs were visualized by cryo-EM (a and b, respectively). The 3-D reconstructions at a resolution of about 2.5 nm show the layered structure of the particles (c and d).

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### Rotavirüs Genome And Gene Products on Virion
Source: U. Desselberger, “Differences of Rotavirus Vaccine Effectiveness by Country: Likely Causes and Contributing Factors”, Pathogens, vol. 6, no. 4, p. 65, 2017.*

Structural organization of rotavirus. (a) Rotavirus dsRNA migration pattern by SDS-PAGE and gene-protein assignment (SA11 strain). (b) Surface representation and (c) cut-away of rotavirus structure (based on reconstructions from cryo-electron micrographs).

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### Rotavirus Cell Attachment and Entry Model

Two models for RV entry. RV entry starts in both models with the interaction of the infectious particle with a glycan attachment molecule.


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RV entry into the host cell is a multistep process that implicates the sequential interaction of the VP4-derived peptides (VP5* and VP8*) and VP7 with different cell surface molecules. VP8* has been implicated in the initial attachment to the host cell through the interaction with glycans, whereas VP5* and VP7 have been associated in post-attachment interactions.

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**In model A

|  | (A1), This short initial period of interaction allows lateral movements of the particle, which is immobilized by the insertion of the hydrophobic loops of the VP4 molecule,  (A2) initiating the engulfment of the virus in a tight-fitting membrane.

(A3) In this model, virus components direct this engulfment. 

(A4) Probably due to the destabilizing effect on the membrane of the inserted loops, calcium ions leach from the vesicle to the cytoplasm producing a progressive diminution of the calcium concentration which ultimately leads to the disassembling of the VP7 layer. Without de VP7 layer, the VP4 spike is able to perform the fold back transition. 

(A5). The movement of the hydrophobic loops during this conformational change impels the membrane to increase its area, leading to the generation of a local bubble. Ultimately, this strain is shared among the vesicle membrane which accumulates the distortion.

(A6) When, due to the progressive fold back of VP4 spikes, the accumulated stress surpasses the bursting point of the bilayer the vesicle bursts.

 (A7) and the DLP is released to the cellular cytoplasm, initiating transcription.
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**In model B

(B1) After interaction with the glycan attachment molecule, the incoming particle is internalized by clathrin-dependent, or -independent endocytosis, depending on the virus strain.
(B2) Regardless of the endocytic pathway, the particles reach an early endosome.

(B3) and progress to maturing endosomes.

(B4).from which some strains (termed early-penetration strains) are able to be released to the cell cytoplasm and initiate transcription.

(B5), Late-penetration strains must reach late endosomes, (B6)before they are released to initiate a productive infection.

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### **Disease**

Rotavirus spreads easily among infants and young children. The virus can cause severe watery diarrhea, vomiting, fever, and abdominal pain. Children who get rotavirus disease can become dehydrated and may need to be hospitalized.

Source: “Rotavirus Vaccination,” Centers for Disease Control and Prevention, 25-Jul-2018. \[Online\]. Available: https://www.cdc.gov/vaccines/vpd/rotavirus/index.html. \[Accessed: 03-Jun-2021\].

Source: Centers for Disease Control and Prevention. [Addition of history of intussusception as a contraindication for rotavirus vaccination](https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6041a5.htm). MMWR. 2011 Oct 21;60(41):1427.**

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Good hygiene like handwashing and cleanliness are important but are not enough to control the spread of the disease. Rotavirus vaccine is the best way to protect your child against rotavirus disease. Most children (about 9 out of 10) who get the vaccine will be protected from severe rotavirus disease. About 7 out of 10 children will be protected from rotavirus disease of any severity.


Source: A. Cunningham, “Rotavirus vaccines may lower kids' chances of getting type 1 diabetes,” Science News, 08-Aug-2019. \[Online\]. Available: https://www.sciencenews.org/article/rotavirus-vaccine-kids-type-1-diabetes. \[Accessed: 03-Jun-2021\].*

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