Rotavirus

Rotaviruses are the most common cause of diarrhoeal disease among infants and young children. Nearly every child in the world is infected with a rotavirus at least once by the age of five. Immunity develops with each infection, so subsequent infections are less severe. Adults are rarely affected. The virus is transmitted by the faecal–oral route. It infects and damages the cells that line the small intestine and causes gastroenteritis. Although rotavirus was discovered in 1973 by Ruth Bishop and her colleagues by electron micrograph images and accounts for about one-third of hospitalisations for severe diarrhoea in infants and children, its importance has historically been underestimated within the public health community, particularly in developing countries. In addition to its impact on human health, rotavirus also infects other animals, and is a pathogen of livestock. Rotaviral enteritis is usually an easily managed disease of childhood, but among children under 5 years of age, rotavirus caused an estimated 151,714 deaths worldwide from diarrhoea in 2019. 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. Following rotavirus vaccine introduction in the United States, hospitalisation rates have fallen significantly. Public health campaigns to combat rotavirus focus on providing oral rehydration therapy for infected children and vaccination to prevent the disease. The incidence and severity of rotavirus infections has declined significantly in countries that have added rotavirus vaccine to their routine childhood immunisation policies. Rotavirus is a genus of double-stranded RNA viruses in the family Reoviridae. Eleven species are placed in the genus, usually referred to as RVA, RVB, RVC, RVD, RVF, RVG, RVH, RVI, RVJ, RVK, and RVL. The most common is RVA, and these rotaviruses cause more than 90% of rotavirus infections in humans.

Virology

Types of rotaviruses The 11 species of rotaviruses (sometimes informally called groups) are referred to as RVA, RVB, RVC, RVD, RVF, RVG, RVH, RVI, RVJ, RVK, and RVL. Humans are primarily infected by rotaviruses in the species RVA. This one and the other species cause disease in other animals, for example, species RVH in pigs, RVD, RVF and RVG in birds, RVI in cats and RVJ in bats. Group A rotaviruses contain different strains, called serotypes. As with influenza viruses, 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. Because the two genes that determine G-types and P-types can be passed on separately to progeny viruses, different combinations are found. A whole genome genotyping system has been established for group A rotaviruses, which has been used to determine the origin of atypical strains. The prevalence of the individual G-types and P-types varies between and within countries and years. At least 36 G types and 51 P types are known, but in infections of humans, only a few combinations of G and P types predominate. They are G1P[8], G2P[4], G3P[8], G4P[8], G9P[8], and G12P[8].

Structure The genome of rotaviruses 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 gene 11, which codes for two. The RNA is surrounded by a three-layered icosahedral protein capsid. Viral particles are up to 76.5 nm in diameter and are not enveloped.

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, six nonstructural proteins (NSPs) are only produced in cells infected by rotaviruses. These are called NSP1, NSP2, NSP3, NSP4, NSP5, and NSP6. At least six of the twelve proteins encoded by the rotavirus genome bind RNA. The role of these proteins 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.

Structural proteins VP1 is located in the core of the virus particle and is an RNA-dependent RNA polymerase enzyme. 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. VP2 forms the core layer of the virion and binds the RNA genome. 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. The cap stabilises viral mRNA by protecting it from nucleic acid-degrading enzymes called nucleases. VP4 is on the surface of the virion that protrudes as a spike. It binds to molecules on the surface of cells called receptors and drives the entry of the virus into the cell. 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. VP4 determines how virulent the virus is and it determines the P-type of the virus. In humans, an association exists between the blood group (Lewis antigen system, ABO blood group system, and secretor status) and susceptibility to infection. Nonsecretors seem resistant to infection by types P[4] and P[8], indicating that blood-group antigens are the receptors for these genotypes. This resistance is dependent on the rotavirus genotype. VP6 forms the bulk of the capsid. It is highly antigenic and can be used to identify rotavirus species. This protein is used in laboratory tests for rotavirus infections. 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.

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