Noroviruses—The State of the Art, Nearly Fifty Years after Their Initial Discovery

Figure 1. Schematic diagram of the Norovirus genus within the Caliciviridae family. The ten established genera (GI—GX), as defined by Chhabra et al. 2019, are shown, as well as the species wherein each genogroup has been detected.

Figure 2. Schematic diagram showing the organisation of norovirus genomes. (Above) The human norovirus genome is covalently attached to genome-linked viral protein VPg at the 5′ end and is polyadenlyated at the 3′ end. The genome is divided into three open reading frames (ORFs). ORF1 is translated as a polyprotein, which is cleaved by the viral protease (Pro) to produce the nonstructural proteins (p48, NTPase, p22, VPg, Pro, and Pol). ORF2 and ORF3 are translated from a subgenomic RNA. They encode the major structural protein, VP1, and the minor structural protein, VP2, respectively. The 5′ and 3′ genome extremities contain short untranslated regions (UTRs). (Below) The murine norovirus shares a similar genome organisation but has an additional fourth ORF, which overlaps with ORF2 and is also translated primarily from subgenomic RNA into the virulence factor 1 (VF1) protein; adapted from Thorne and Goodfellow 2014 [21].

Figure 3. Outline of the norovirus replication cycle. Human and murine noroviruses (turquoise hexagons) attach to the cell surface using carbohydrate attachment factors and cofactors (1). To mediate entry, binding to a protein receptor is required (2). After entry (3) and uncoating (4), the incoming viral genome is translated through interactions with genome-linked protein VPg (nonstructural protein NS5, red triangle) at the 5′ end of the genome and the cellular translation machinery (5). The open-reading frame 1 polyprotein is co- and post-translationally cleaved by the viral protease (NS6, blue flash) (6). The replication complex is formed by recruitment of cellular membranes to the perinuclear region of the cell, through interactions with NS1/2 (rose shape) and NS4 (yellow shape) (7). Genome replication occurs via a negative-strand intermediate (dashed line) (8), and genomic and subgenomic RNA (unbroken lines) are generated by the viral RNA-dependent RNA polymerase (NS7, green jagged circle), using de novo and VPg- or internal promoter-dependent mechanisms (9). Replicated genomes are translated or packaged into the capsid (in the case of whole-length genomes), composed mainly of viral…

Figure 4. Norovirus transmission. Transmission routes of human noroviruses (solid arrows) and animal noroviruses (dashed arrows) are shown. Unconfirmed transmission is indicated by a question mark. The dashed arrow indicating transmission between domestic/wild animals denotes species-specific transmission; the question mark accompanying it indicates putative interspecies transmission. Adapted from Mathijs et al., 2012 [220] and Ludwig-Begall et al., 2018 [182].