Rotavirus Interactions With Host Intestinal Epithelial Cells

Abstract

Rotavirus (RV) is the foremost enteric pathogen associated with severe diarrheal illness in young children (<5years) and animals worldwide. RV primarily infects mature enterocytes in the intestinal epithelium causing villus atrophy, enhanced epithelial cell turnover and apoptosis. Intestinal epithelial cells (IECs) being the first physical barrier against RV infection employs a range of innate immune strategies to counteract RVs invasion, including mucus production, toll-like receptor signaling and cytokine/chemokine production. Conversely, RVs have evolved numerous mechanisms to escape/subvert host immunity, seizing translation machinery of the host for effective replication and transmission. RV cell entry process involve penetration through the outer mucus layer, interaction with cell surface molecules and intestinal microbiota before reaching the IECs. For successful cell attachment and entry, RVs use sialic acid, histo-blood group antigens, heat shock cognate protein 70 and cell-surface integrins as attachment factors and/or (co)-receptors. In this review, a comprehensive summary of the existing knowledge of mechanisms underlying RV-IECs interactions, including the role of gut microbiota, during RV infection is presented. Understanding these mechanisms is imperative for developing efficacious strategies to control RV infections, including development of antiviral therapies and vaccines that target specific immune system antagonists within IECs.

Keywords: immune evasion; immune receptors; immunity; intestinal epithelial cells; rotaviruses pathogenesis.

Figure 1

The rotavirus replication cycle. The RV attaches to SAs and HBGAs on the host cell surface, then interacts with integrins and Hsc70 receptors where it is internalized by receptor-mediated endocytosis. Removal of the outer layer results in the release of double-layered particles (DLPs) in the cytoplasm where it undergoes mRNA transcription. mRNAs are translated into viral proteins, replicated and packaged viroplasms as DLPs. Then, the DLPs bind to NSP4 and bud into the endoplasmic reticulum (ER) where transient membranes are removed as VP4 and VP7 proteins assemble, leading to maturation of the TLP virion. The newly formed TLP virions are removed through cell lysis and in polarized epithelial cells, through Golgi-independent non-classical vesicular transport mechanism.

Figure 2

Rotavirus interactions with host innate immune system. RV enters cells, where it is recognized by RIG-I and MDA-5 receptors triggering the transcription factors IRF3 and NF-kB through signaling facilitated by MAVS. The activated IRF3 and NF-kB moves to the nucleus and upregulate the expression of type I and III IFNs which stimulates the synthesis of IFN stimulatory genes. Activation of NF-κB pathway by PRRs results in the production of proinflammatory cytokines and chemokines such as IL-6, IL-8, MCP-1, CXCL10. The IRF3 and NF-kB are degraded through interaction with viral NSP1. IFNs are then released and binds their receptors leading to activation of STAT-1, STAT-2, and IRF9 which further promote IFN production and creating ‘antiviral state’.

Figure 3

Rotavirus-IECs-gut microbiome Interactions: Gut epithelial surface covered by mucus layer containing glycoproteins (mucins) which provide a physical barrier between viruses and IECs. Mucin production is influenced by the gut microbiome composition of which some of the microbiota have antiviral properties. (a) In the IECs, RVs are recognized by the pattern recognition receptors (PRRs) and initiate mechanisms that induce IFN responses. (b) Beneficial microbiota inhibit viral attachment to host epithelial cells; they produce antimicrobial compounds which have antiviral effects; and also modulate innate and adaptive immune systems. (c) RV immune evasion strategy via blocking IFN responses through degradation of IFN Regulatory Factors (IRFs) and inhibition of nuclear accumulation of NF−κB, STAT1 and STAT2. RVs form pools of virions cloaked in extracellular vesicles to enhance multiplicity of infection, and RVs also utilize intercellular calcium waves and purinergic signaling to amplify intestinal pathophysiology.