Tight Junctions, the Key Factor in Virus-Related Disease

Abstract

Tight junctions (TJs) are highly specialized membrane structural domains that hold cells together and form a continuous intercellular barrier in epithelial cells. TJs regulate paracellular permeability and participate in various cellular signaling pathways. As physical barriers, TJs can block viral entry into host cells; however, viruses use a variety of strategies to circumvent this barrier to facilitate their infection. This paper summarizes how viruses evade various barriers during infection by regulating the expression of TJs to facilitate their own entry into the organism causing infection, which will help to develop drugs targeting TJs to contain virus-related disease.

Keywords: anti-viral drugs; infection; physical barriers; tight junctions; viruses.

Figure 1

TJs expression is regulated by different viruses. The expression of TJs varies during infection by different viruses. Most viral infections downregulate the expression of TJs, but a few viruses promote their infection by upregulating the expression of TJs, such as HCV upregulates CLDN6, 9, 12, ZIKV-H upregulates ZO-1, PEDV upregulates OCLN, hPIV2 upregulates CLDN1. ↓: downregulated;↑: upregulated.

Figure 2

Multiple viruses regulate TJs expression through the innate immune pathway. HIV infection can activate MAPK, thereby upregulating NF-κB, and disrupting TJs, and the NF-κB and MAPK pathways involved by IL-17 participate in the repair process of the barrier. ZIKV infection can over activate the ERK/MAPK pathway and destroy BTB. Inflammatory cytokines/chemokines caused by JEV infection, such as IP-10 can regulate the expression of TJs, which is considered as the main cause of BBB destruction. Early JEV infection leads to significant upregulation of IP-10, which induces TNF-α via the JNK-c-Jun signaling pathway, and TNF-α directly contributes to BBB decomposition by inhibiting the expression of ZO-1, OCLN, and CLDN-5. DENV infection downregulates the ex-pression of TNF-α, cause a significant decrease in ZO-1 expression and peripheral localization in epithelial and endothelial cells. In the process of RABV infection, IFN-λ maintains the integrity of ZO-1 in the BBB to reduce neuroinflammation. Meanwhile, the downregulation of ZO-1 and OCLN is resulted from the activating JNK/MAPK pathway by PCV2 infection.