Dysregulation of Cell Barrier Function Due to Virus Infection

Dear Colleagues,

Cell adhesion is central to the development of multicellular organisms. Specific cell adhesion molecules regulate unique interactions, whereby integrins support cell adhesion to the extracellular matrix. Tight junctions (TJ) and adherens junctions (AJ) govern cell-cell adhesions and collectively form adherens junction complexes (AJCs). Vascular endothelial (VE)-cadherin is a component of endothelial cell-cell adherens junctions, and it plays a vital role in the maintenance of vascular integrity.

Despite obstructed accessibility, several viruses use integrins and junctional proteins as receptors for infection. Virus binding to these receptors likely disrupts their homotypic trans-interactions, leading to increased permeability after infection. There are many elegant mechanisms by which viral infections cause dysregulated cell barrier function. An interesting and well-known strategy used by viruses such as coxsackieviruses, adenoviruses, and orthohantaviruses to access junctional or basolateral receptors from the apical side, involves virus binding to co-receptors such as decay-accelerating factor (DAF/CD55), which is located on the apical surface of polarized cells. DAF causes the disruption of junctional integrity in an Abl kinase and RhoGTPase dependent mechanism. Alternately, other viruses can induce loss of cell barrier function by merely interacting with components of TJs, such as SARS-CoV, but first must engage apical ACE2 receptors.

Dysregulation of the endothelial-cell barrier function due to inflammatory cytokines is a common feature of viral infection. Proinflammatory cytokines such as Interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) are known to induce vascular permeability through various mechanisms, including one involving the remodeling of TJs. In another context, TNF-α and IFN-γ are known to induce a prothrombotic state in the vascular endothelium. The thrombotic state, in turn, elicits the activation of proteinases, such as tissue plasminogen activator and urokinase plasminogen activator, and subsequent release of Plasminogen Activator Inhibitor (PAI-1) to inactivate fibrinolysis. Activation of the coagulation system is an integral component of the innate immune response to viral infection. Viruses, such as Ebola, Coxsackievirus, Dengue, influenza A/H1N1, and orthohantaviruses, have been shown to induce tissue factor (TF) expression in infected cells, thereby activating the coagulation system. Expression or secretion of the above factors has a significant influence on endothelial barrier integrity.

Small GTPases RhoA, Rac1, and Rap1 play a vital role in the control of endothelial cell (EC) permeability due to virus-induced inflammatory insults. Sphingosine-1-phosphate (S1P) found in human plasma, is a promiscuous multifunctional receptor ligand, with shifting roles in health and disease. In one example, S1P elicits opposing signaling effects based on the type of the cognate G-protein-coupled receptor. For example, S1P binding to Gαi-coupled S1PR1, elicits cell-barrier function strengthening Rac1 and Cdc42 dependent responses. However, S1P binding to a Gα_12/13 coupled S1PR2 receptor induces RhoA activity, which causes loss of barrier function and inflammation, by suppressing Gαi-mediated signaling. Thus, a shift in the balance of expression of these receptors in various patients, or tissues, of the same host may cause divergent outcomes in infected patients.

The regulation of cell barrier function in health and disease is well studied; however, the mechanisms by which viral infection disrupts vascular integrity is not well understood. Furthermore, discoveries of the functional mechanisms of proteins used by viruses to dysregulate cell-barrier function will provide new insights for clinical intervention. The end stages of many viral diseases include vascular permeability, coagulopathies, hemorrhage, and circulatory shock. Thus, an understanding of the underlying mechanisms of dysregulation is critical for life-saving treatment.

This Special Issue seeks all types of manuscripts (e.g., reviews, research articles, and short communications) on virus-host interactions that lead to a loss of cell barrier functions in humans and animals. The topics might include context-dependent mechanisms of virus-induced loss of cell barrier function, either due to direct contact between the virus and host, or pathogenesis.

Dr. Tione Buranda
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

• Vascular permeability
• Inflammation
• cell-cell adhesion
• coagulopathy
• PAI-1
• uPA
• inflammatory cytokines
• tight junctions
• virus infection
• cell barrier function