Rotavirus

Rotavirus
A single particle; it is spherical and has regularly spaced, short protrusions on its surface
Computer–aided reconstruction of a rotavirus based on several electron micrographs
Virus classification
Group:
Group III (dsRNA)
Order:
Unassigned
Family:
Subfamily:
Genus:
Rotavirus
Type species
Rotavirus A
Species
  • Rotavirus A
  • Rotavirus B
  • Rotavirus C
  • Rotavirus D
  • Rotavirus E
  • Rotavirus F
  • Rotavirus G
  • Rotavirus H
  • Rotavirus I

Rotavirus is the most common cause of diarrhoeal disease among infants and young children.[1] It is a genus of double-stranded RNA viruses in the family Reoviridae. Nearly every child in the world is infected with rotavirus at least once by the age of five.[2] Immunity develops with each infection, so subsequent infections are less severe; adults are rarely affected.[3] There are nine species of this virus, referred to as A, B, C, D, E, F, G, H and I. Rotavirus A, the most common species, causes more than 90% of rotavirus infections in humans.

The virus is transmitted by the faecal-oral route. It infects and damages the cells that line the small intestine and causes gastroenteritis (which is often called "stomach flu" despite having no relation to influenza). Although rotavirus was discovered in 1973 by Ruth Bishop and her colleagues by electron micrograph images[4] and accounts for approximately one third of hospitalisations for severe diarrhoea in infants and children,[5] its importance has historically been underestimated within the public health community, particularly in developing countries.[6] In addition to its impact on human health, rotavirus also infects animals, and is a pathogen of livestock.[7]

Rotaviral enteritis is usually an easily managed disease of childhood, but in 2013, rotavirus caused 37 percent of deaths of children from diarrhoea and 215,000 deaths worldwide,[8] and almost two million more become severely ill.[6] Most of these deaths occurred in developing countries.[9] In the United States, before initiation of the rotavirus vaccination programme in the 2000s, rotavirus caused about 2.7 million cases of severe gastroenteritis in children, almost 60,000 hospitalisations, and around 37 deaths each year.[10] Following rotavirus vaccine introduction in the United States, hospitalisation rates have fallen significantly.[11][12] Public health campaigns to combat rotavirus focus on providing oral rehydration therapy for infected children and vaccination to prevent the disease.[13] The incidence and severity of rotavirus infections has declined significantly in countries that have added rotavirus vaccine to their routine childhood immunisation policies.[14][15][16]

Virology

Types of rotavirus

There are nine species of rotavirus, referred to as groups A, B, C, D, E, F, G, H and I.[17] Humans are primarily infected by species A, B and C, most commonly by species A. A–E species cause disease in other animals,[18] species E and H in pigs, D, F and G in birds and I in cats.[19][20][21] Within rotavirus A there are different strains, called serotypes.[22] As with influenza virus, a dual classification system is used based on two proteins on the surface of the virus. The glycoprotein VP7 defines the G serotypes and the protease-sensitive protein VP4 defines P serotypes.[23] Because the two genes that determine G-types and P-types can be passed on separately to progeny viruses, different combinations are found.[23] A whole genome genotyping system has been established for group A rotaviruses, which has been used to determine the origin of atypical strains.[24] The prevalence of rotavirus the individual G-types and P-types varies between, and within, countries and years.[25]

Structure

The genome of rotavirus consists of 11 unique double helix molecules of RNA (dsRNA) which are 18,555 nucleotides in total. Each helix, or segment, is a gene, numbered 1 to 11 by decreasing size. Each gene codes for one protein, except genes 9, which codes for two.[26] The RNA is surrounded by a three-layered icosahedral protein capsid. Viral particles are up to 76.5 nm in diameter[27][28] and are not enveloped.

Proteins

A cut-up image of a single rotavirus particle showing the RNA moecules surrounded by the VP6 protein and this in turn surrounded by the VP7 protein. The V4 protein protrudes from the surface of the spherical particel.
A simplified diagram of the location of rotavirus structural proteins

There are six viral proteins (VPs) that form the virus particle (virion). These structural proteins are called VP1, VP2, VP3, VP4, VP6 and VP7. In addition to the VPs, there are six nonstructural proteins (NSPs), that are only produced in cells infected by rotavirus. These are called NSP1, NSP2, NSP3, NSP4, NSP5 and NSP6.[18]

At least six of the twelve proteins encoded by the rotavirus genome bind RNA.[29] The role of these proteins play in rotavirus replication is not entirely understood; their functions are thought to be related to RNA synthesis and packaging in the virion, mRNA transport to the site of genome replication, and mRNA translation and regulation of gene expression.[30]

Structural proteins

An electron micrograph of many rotavirus particles, two of which have several smaller, black spheres which appear to be attached to them
Electron micrograph of gold nanoparticles attached to rotavirus. The small dark circular objects are gold nanoparticles coated with a monoclonal antibody specific for rotavirus protein VP6.

VP1 is located in the core of the virus particle and is an RNA polymerase enzyme.[31] In an infected cell this enzyme produces mRNA transcripts for the synthesis of viral proteins and produces copies of the rotavirus genome RNA segments for newly produced virus particles.[32]

VP2 forms the core layer of the virion and binds the RNA genome.[33]

VP3 is part of the inner core of the virion and is an enzyme called guanylyl transferase. This is a capping enzyme that catalyses the formation of the 5' cap in the post-transcriptional modification of mRNA.[34] The cap stabilises viral mRNA by protecting it from nucleic acid degrading enzymes called nucleases.[35]

VP4 is on the surface of the virion that protrudes as a spike.[36] It binds to molecules on the surface of cells called receptors and drives the entry of the virus into the cell.[37] VP4 has to be modified by the protease enzyme trypsin, which is found in the gut, into VP5* and VP8* before the virus is infectious.[38] VP4 determines how virulent the virus is and it determines the P-type of the virus.[39] In humans there is an association between the blood group secretor status and susceptibility to infection. Non-secretors seem resistant to infection by types P[4] and P[8], indicating that blood group antigens are the receptors for these genotypes.[40]

VP6 forms the bulk of the capsid. It is highly antigenic and can be used to identify rotavirus species.[41] This protein is used in laboratory tests for rotavirus A infections.[42]

VP7 is a glycoprotein that forms the outer surface of the virion. Apart from its structural functions, it determines the G-type of the strain and, along with VP4, is involved in immunity to infection.[27]

Nonstructural viral proteins

NSP1, the product of gene 5, is a nonstructural RNA-binding protein.[43] NSP1 also blocks the interferon response, the part of the innate immune system that protects cells from viral infection. NSP1 causes the proteosome to degrade key signaling components required to stimulate production of interferon in an infected cell and to respond to interferon secreted by adjacent cells. Targets for degradation include several IRF transcription factors required for interferon gene transcription.[44]

NSP2 is an RNA-binding protein that accumulates in cytoplasmic inclusions (viroplasms) and is required for genome replication.[45][33]

NSP3 is bound to viral mRNAs in infected cells and it is responsible for the shutdown of cellular protein synthesis.[46] NSP3 inactivates two translation initiation factors essential for synthesis of proteins from host mRNA. First, NSP3 ejects poly(A)-binding protein (PABP) from the translation initiation factor eIF4F. PABP is required for efficient translation of transcripts with a 3' poly(A) tail, which is found on most host cell transcripts. Second, NSP3 inactivates eIF2 by stimulating its phosphorylation.[47] Efficient translation of rotavirus mRNA, which lacks the 3' poly(A) tail, does not require either of these factors.[48]

NSP4 is a viral enterotoxin that induces diarrhoea and was the first viral enterotoxin discovered.[49]

NSP5 is encoded by genome segment 11 of rotavirus A. In virus-infected cells NSP5 accumulates in the viroplasm.[50]

NSP6 is a nucleic acid binding protein[51] and is encoded by gene 11 from an out-of-phase open reading frame.[52]

Rotavirus genes and proteins
RNA Segment (Gene) Size (base pairs) Protein Molecular weight kDa Location Copies per particle Function
1 3302 VP1 125 At the vertices of the core 12 RNA-dependent RNA polymerase
2 2690 VP2 102 Forms inner shell of the core 120 RNA binding
3 2591 VP3 88 At the vertices of the core 12 methyltransferase mRNA capping enzyme
4 2362 VP4 87 Surface spike 180 Cell attachment, virulence
5 1611 NSP1 59 Nonstructural 0 5'RNA binding, interferon antagonist
6 1356 VP6 45 Inner Capsid 780 Structural and species-specific antigen
7 1104 NSP3 37 Nonstructural 0 Enhances viral mRNA activity and shut-offs cellular protein synthesis
8 1059 NSP2 35 Nonstructural 0 NTPase involved in RNA packaging
9 1062 VP71 VP72 38 and 34 Surface 780 Structural and neutralisation antigen
10 751 NSP4 20 Nonstructural 0 Enterotoxin
11 667 NSP5 NSP6 22 Nonstructural 0 ssRNA and dsRNA binding modulator of NSP2, phosphoprotein

This table is based on the simian rotavirus strain SA11. RNA-protein coding assignments differ in some strains.

Replication

A simplified drawing of the rotavirus replication cycle. The stages are (1) attachment of the virus to the host cells, which is mediated by VP4 and VP7 (2) penetration of the cell by the virus and uncoating of the viral capsid (3) plus strand ssRNA synthesis ( this acts as the mRNA) synthesis, which is mediated by VP1, VP3 and VP2 (4) formation of the viroplasm, viral RNA packaging and minus strand RNA synthesis and formation of the double-layered virus particles (5) virus particle maturation and release of progeny virions.

The virus enter cells by receptor mediated endocytosis and form a vesicle known as an endosome. Proteins in the third layer (VP7 and the VP4 spike) disrupt the membrane of the endosome, creating a difference in the calcium concentration. This causes the breakdown of VP7 trimers into single protein subunits, leaving the VP2 and VP6 protein coats around the viral dsRNA, forming a double-layered particle (DLP).[53]

The eleven dsRNA strands remain within the protection of the two protein shells and the viral RNA-dependent RNA polymerase creates mRNA transcripts of the double-stranded viral genome. By remaining in the core, the viral RNA evades innate host immune responses including RNA interference that are triggered by the presence of double-stranded RNA.[54]

During the infection, rotavirus produces mRNA for both protein biosynthesis and gene replication. Most of the rotavirus proteins accumulate in viroplasm, where the RNA is replicated and the DLPs are assembled. In the viroplasm the positive sense viral RNAs that are used as templates for the synthesis of viral genomic dsRNA are protected from siRNA-induced RNase degradation.[55] Viroplasm is formed around the cell nucleus as early as two hours after virus infection, and consists of viral factories thought to be made by two viral nonstructural proteins: NSP5 and NSP2. Inhibition of NSP5 by RNA interference in vitro results in a sharp decrease in rotavirus replication. The DLPs migrate to the endoplasmic reticulum where they obtain their third, outer layer (formed by VP7 and VP4). The progeny viruses are released from the cell by lysis.[38][56][57]

Other Languages
العربية: فيروس عجلي
беларуская: Ротавірусы
български: Ротавирус
català: Rotavirus
Deutsch: Rotavirus
eesti: Rotaviirus
Ελληνικά: Ιός Ρότα
español: Rotavirus
euskara: Errotabirus
فارسی: روتاویروس
français: Rotavirus
galego: Rotavirus
հայերեն: Ռոտավիրուս
हिन्दी: रोटावाइरस
italiano: Rotavirus
עברית: Rotavirus
ಕನ್ನಡ: ರೋಟ ವೈರಸ್
Latina: Rotavirus
magyar: Rotavírus
Nederlands: Rotavirus
norsk: Rotavirus
polski: Rotawirusy
português: Rotavirus
română: Rotavirus
русский: Ротавирусы
Simple English: Rotavirus
slovenčina: Rotavírus
slovenščina: Rotavirus
suomi: Rotavirus
svenska: Rotavirus
Tiếng Việt: Virus rota
粵語: 輪狀病毒
中文: 輪狀病毒