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

ABSTRACT

Oropharyngeal, airway, intestinal, and genital mucosal epithelia are the main portals of entry for the majority of human pathogenic viruses. To initiate systemic infection, viruses must first be transmitted across the mucosal epithelium and then spread across the body. However, mucosal epithelia have well-developed tight junctions, which have a strong barrier function that plays a critical role in preventing the spread and dissemination of viral pathogens. Viruses can overcome these barriers by disrupting the tight junctions of mucosal epithelia, which facilitate paracellular viral penetration and initiate systemic disease. Disruption of tight and adherens junctions may also release the sequestered viral receptors within the junctional areas, and liberation of hidden receptors may facilitate viral infection of mucosal epithelia. This review focuses on possible molecular mechanisms of virus-associated disruption of mucosal epithelial junctions and its role in transmucosal viral transmission and spread.

KEYWORDS:

• Virus
• mucosal epithelium
• disruption of epithelial junctions

Abbreviations

ZO-1, −2, and −3, zonula occludens; PALS1, the protein associated with Lin-seven 1; MUPP1, multi-PDZ domain protein 1; MAGI1 and −2, membrane-associated guanylate kinase; PATJ, the protein associated with tight junctions; JAM-1, −2, −3, and -A, junctional adhesion molecules; CAR, coxsackievirus and adenovirus receptor; HSV-1, herpes simplex virus 1; ACE2, angiotensin-converting enzyme II; E, SARS-COV-2 envelope protein; IFN-γ, interferon gamma; TNF-α, tumor necrosis factor alpha; IL-1, −1β, −6, −8, −12, and −18, interleukins; MLCK, myosin light-chain kinase; MLC, myosin light chain; IAV, influenza A virus; TLRs, Toll-like receptors; NS-1, IAV nonstructural protein 1; DLG1, discs large homolog 1 protein; MAPK, mitogen-activated protein kinase; PI3K, phosphoinositide 3-kinase; ICAM-1, intercellular adhesion molecule; RSV, human respiratory syncytial virus; MCP-1, monocyte chemoattractant protein-1; MIP-1α and −1β, macrophage inflammatory protein-1α and −1β; G-CSF, granulocyte colony-stimulating factor; TER, transitional endoplasmic reticulum; CVB, coxsackievirus group B; GPI, glycophosphatidylinositol; MDCK, Madin-Darby canine kidney; HIV, human immunodeficiency virus; NF-κB, transcription factor; MMP-9, matrix metalloproteinase-9; HCMV, human cytomegalovirus; HPV, human papillomavirus; EMT, epithelial–mesenchymal transition; HSPG, heparan sulfate proteoglycan; GalCer, galactosylceramide; PDZ (Postsynaptic density 95, PSD-85; Discs large, Dlg; Zonula occludens-1, ZO-1).

Acknowledgments

I thank Drs. Deborah Greenspan, Piri Veluppillai, Karen Smith-McCuine, and Kristina Rosbe for providing biopsy samples, and Rossana Herrera for excellent technical assistance. This project was supported by the NIDCR R01DE028129 and NCI R01CA232887 grants.

Disclosure conflicts of interest statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the National Cancer Institute [R01CA232887]; National Institute of Dental and Craniofacial Research [R01DE028129].