Virus-associated disruption of mucosal epithelial tight junctions and its role in viral transmission and spread

Figures & data

Figure 1. Detection of tight junction proteins in oral (buccal, tonsil), cervical and intestinal (jejunal region) epithelia. Representative immunofluorescence images of tight junction proteins occludin (red) in multistratified buccal, tonsil, and ectocervical mucosal epithelia and ZO-1 (red) in a single-cell layer of intestinal epithelium are shown. Oral (buccal and tonsil) squamous mucosal epithelia have well-developed tight junctions in the strata granulosum, spinosum, and parabasal layers. Cervical epithelia form tight junctions in the strata spinosum and parabasal layers. A single-cell layer of intestinal epithelium also has well-developed tight junctions. The tight junctions are localized at the upper lateral membranes of epithelial cells and seal intercellular spaces, preventing paracellular penetration by viruses. Nuclei are stained blue. Dashed white lines separate epithelium from the lamina propria. GR, granulosum; SP, spinosum; BL, basal; LP, lamina propria; EP, epithelium. Confocal microscopy. Original magnification: for buccal, tonsil and cervical x400, for intestinal x630

Figure 2. Model of organization of epithelial tight junctions and their disruption. Tight junctions are formed between epithelial cells of oral, genital, and intestinal mucosa by lateral interaction of integral membrane proteins occludin and claudins, which are associated with the cytoplasmic proteins ZO-1, −2, and −3 (left). These proteins link occludin and claudins to the actin cytoskeleton. Adherens junctions are formed in the lateral membranes of epithelial cells by homophilic interactions of E-cadherins. Junctional adhesion molecules (JAMs), coxsackievirus and adenovirus receptor (CAR), and nectin-1 are also localized at the tight and adherens junctions of mucosal epithelia. They may serve as receptors for reovirus, coxsackievirus/adenovirus, and HSV-1, respectively, and are sequestered within the tight and adherens junctions. Interactions of viral pathogens with mucosal epithelial cells may directly or indirectly cause disruption of epithelial junctions by downregulation of junctional protein expression and/or their mislocalization from assembled junctions, leading to dissociation of tight junction proteins from each other and from actin cytoskeleton (right). Disruption of epithelial tight junctions facilitates (i) opening of the paracellular space between epithelial cells and (ii) paracellular penetration by viruses. Disruption of tight and adherens junctions may release sequestered JAMs, CAR, and nectin-1, which may increase viral accessibility

Table 1. Interaction of human pathogenic viruses with mucosal epithelial junctional proteins

Viruses	Junctional proteins	Potential mechanisms	References
Coronavirus SARS-COV-2	PALS1, ZO-1	The C-terminal domain of SARS-COV-2 E protein binds to PALS1 and ZO-1 proteins, leading to disruption of tight and adherens junctions.	^Citation65–67
Influenza virus (IAV)	Occludin, claudin-4, JAM-A	IAV infection reduces expression of occludin, claudin-4, and JAM-1. IAV NS-1 binds to Dlgl protein, which may reduce claudin-4 expression. IAV upregulates transcription factor Gli1, which reduces expression of ZO-1, occludin, and E-cadherin.	^Citation87,Citation89–91
Rhinovirus	ZO-1	Rhinovirus infection causes a loss of ZO-1 from tight junctions.	^Citation98
Respiratory syncytial virus (RSV)	Claudin-1 and occludin	RSV infection induces downregulation of claudin-1 and occludin expression.	^Citation103
Rotavirus	ZO-1, claudin-1, and occludin	Rotavirus NSP4 and V8 proteins alter the distribution of ZO-1, occludin, and claudin-3, causing disruption of tight junctions.	^110−112
Coxsackievirus group B (CVB) and adenovirus	Occludin, CAR, and CAR^ExCitation8	CVB infection induces occludin internalization and disruption of tight junctions, which leads to release of sequestered viral receptor CAR and facilitating viral entry. Adenovirus (Ad) fiber protein binding to the CAR^ExCitation8 may initiate subsequent viral binding to entry receptors αvβ3, αvβ5, α5β1, and αvβ1 integrins.	^Citation121,Citation122,Citation124–130
Reovirus	JAM-A	Reovirus protein σ1 binds to JAM-A, initiating virus infection.	^Citation137–141
Herpes simplex virus 1 (HSV-1)	ZO-1	HSV-1 infection induces ZO-1/tight junction disruption, which is critical for virus spread.	^Citation145,Citation146
Human cytomegalovirus (HCMV)	ZO-1	HCMV disrupts tight junctions by downregulating ZO-1 expression, which facilitates viral infection and spread.	^Citation161
Human papillomavirus (HPV)	PATJ, MAGI1, MAGI2, MUPP1, ZO-1, and occludin	HPV16 and −18 oncoproteins E6 bind to PATJ, MAGI1, MAGI2, and MUPP1 via PDZ domains and induce disruption of ZO-1 and occludin.	^Citation30,Citation170–172
HIV	ZO-1, occludin, and claudin-1	HIV-1 gp120 and tat proteins activate MAPK and NF-κB signaling and proinflammatory cytokines TNF-α, IL-6, and IL-8, downregulating ZO-1, occludin, and claudin-1 and disrupting tight junctions. HIV-induced disruption of tight junctions facilitates HSV-1 and HPV16 infection and spread.	^Citation1,Citation4,Citation41,Citation147,Citation189,Citation190

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