Advances in the development of antivirals for rotavirus infection

Abstract

Rotavirus (RV) causes 200,000 deaths per year and imposes a serious burden to public health and livestock farming worldwide. Currently, rehydration (oral and intravenous) remains the main strategy for the treatment of rotavirus gastroenteritis (RVGE), and no specific drugs are available. This review discusses the viral replication cycle in detail and outlines possible therapeutic approaches including immunotherapy, probiotic-assisted therapy, anti-enteric secretory drugs, Chinese medicine, and natural compounds. We present the latest advances in the field of rotavirus antivirals and highlights the potential use of Chinese medicine and natural compounds as therapeutic agents. This review provides an important reference for rotavirus prevention and treatment.

Keywords: Chinese medicine; diarrhoea; immunotherapy; natural compounds; rotavirus; viral replication cycle.

Figure 1

The Countries with the Greatest Number of Rotavirus Deaths as a Proportion of All Global Rotavirus Deaths in Children under 5. 53% of rotavirus-associated deaths worldwide occurred in three countries (Nigeria, India, Democratic Republic of Congo). [https://preventrotavirus.org/rotavirus-disease/global-burden/].

Figure 2

Rotavirus structure. Rotavirus consists of three concentric coat layers surrounded by 11 segmented double-stranded RNA fragments with a genome length of 18,500 bp which encodes 6 structural proteins (VP1-4, VP6-7) and 5-6 non-structural proteins (NSP1-5/6). The capsid structure consists of an inner capsid layer (VP2), a middle capsid layer (VP6), and an outer capsid layer (capsid glycoprotein VP7 and hemagglutinin spike protein VP4). VP4 is cleaved into VP5* and VP8* by the action of trypsin which enhances rotavirus infectivity. The bottom of the VP5* protein is half-buried inside the VP6 protein.

Figure 3

Rotavirus life cycle. The entry stage of rotavirus replication is complex. 1). The first step in infection is the recognition of rotavirus and host surface molecules, including sialic acid, α2β1, and histo-blood group antigens (HBGAs). Rotavirus invades cells through two different endocytosis pathways (clathrin-dependent or dynamin-dependent, depending on the strain), and a mode of direct penetration. VP5* contains a hydrophobic structural domain that promotes rotavirus penetration into cells. 2). Triple-layered particles (TLPs) entering the cytoplasm enter the same endosome and migrate from early endosomes (EEs) to mature endosomes (MEs) and late endosomes (LEs) with Rab5/7 transformation. MEs exist in Rab5 and Rab7. As the Ca²⁺ level decreases, the viral outer capsid disintegrates and double-layered particles (DLPs) are released into the cytoplasm which triggers viral translation and replication. 3). The viroplasm is the main site of rotavirus genome replication and packaging. The interaction of NSP2/NSP5 with lipid droplets (LDs) is the first step in the formation of viral plasmids. 4). The virus precursor DLPs completes the outer capsid assembly in the endoplasmic reticulum (ER). 5). Mature viral particles are released by cell lysis in polarized cells such as monkey embryonic kidney cells MA-104. In contrast, mature viral particles are released by budding in non-polarized cells such as human intestinal cells Caco-2 which does not cleave host cells.

Figure 4

Immunotherapy inhibits rotavirus infection. (A) 1) Cyclosporine A may inhibit rotavirus infection by regulating the expression of IFN-β to activate the intracellular IFN1-based immune response; 2) Interleukin-22 (IL-22) inhibits rotavirus infection by activating the STAT3 signaling pathway and upregulates the expression of antimicrobial genes in the gut, including antimicrobial peptide β-defensin (BD-2), cytokine IL-18, and interferon-λ (IFN-λ); 3) Interferon-λ and IL-22 synergistically induce interferon-stimulated genes (ISG) and control rotavirus infection; (B) IL-22 extrudes cells from tissues by stimulating the proliferation of infected intestinal epithelial cells (IECs) and their migration toward the tips of the villi; (C) IL-18 promotes death of infected IECs to directly interrupt the viral replication cycle.