The contribution of viral toxins to infection and pathogenesis

The process by which viruses cause disease, viral pathogenesis, is the result of both infection of cells and the host immune response. A less studied but equally important contributor to viral pathogenesis is viral dissemination, the capacity of a virus to move from the primary site of infection, traverse physiological barriers, and gain access to secondary sites of infection. This dictates viral tropism and pathogenesis, but the mechanisms governing barrier crossing are incompletely understood. While the presence of viral receptors on cells is a major determinant of viral tropism and a prerequisite for infection, it does not completely explain the capacity of viruses to enter a tissue. Our recent work has begun to characterize the contribution of soluble viral proteins, acting as "viral toxins," to viral dissemination, tissue tropism, and overall pathogenesis within an infected host. In this review, we discuss the characteristics of these viral toxins, which are soluble or surface-exposed viral proteins that can interact with endothelial and/or epithelial barriers, as well as immune cells, to trigger signaling pathways, resulting in the transient breakdown of cellular structures maintaining barrier integrity. The disruption of these barriers induces vascular leak and facilitates virus dissemination, influencing viral tropism and pathogenesis. Importantly, blocking this process prevents leak, viral dissemination, and severe disease during infection, highlighting the value of therapeutic intervention against viral toxin activity. Here, we summarize our current understanding of recently discovered viral toxins from the <i>Flaviviridae, Coronaviridae, Nairoviridae,</i> and <i>Filoviridae</i>.