MCAT Biological and Biochemical Foundations of Living Systems: Passage 20 — Flashcards

Use the following information to answer questions:

The epithelial cells of the oral, digestive, respiratory, and urinary tracts are the target cell type of many viruses, bacteria, and other pathogenic microorganisms. These cells are polarized, meaning their plasma membranes are divided into distinct apical (top) and basolateral (bottom) regions that feature distinct sets of cell surface proteins. This quality is an important early-defense cellular mechanism against infection. For example, several viruses depend on host factors for cell entry that are located in a plasma membrane domain to which circulating viruses do not have access. In addition to viruses, polarized cells restrict the passage of ions, solutes, and macromolecules across the epithelium.

Cell polarity is created through the specific sorting, trafficking, and retention of proteins to their appropriate membrane domains. Junctions where neighboring cells interact with each other, via transmembrane proteins, create barriers that are also essential for polarity. In the complex tissue architecture, the apical domain faces the lumen, whereas the basolateral side is in contact with the extracellular matrix. Actin filaments, which are part of the cytoskeleton, are associated with the apical domain; they also help block viruses from entering the cell and are important for maintaining polarity. The filaments directly interact with the intracellular domain of transmembrane proteins involved in cell junctions.

Given the fact that cell junction proteins are inaccessible from the extracellular space, it seems paradoxical that many viruses, including coxsackievirus, hepatitis C virus (HCV), and rotavirus, would specifically require these proteins. Yet a theme is emerging from years of research: viruses manage to make their way to junction proteins in a step-wise cell entry process. In the example of coxsackievirus, virions bind first to apically located cell surface protein, and this binding weakens the cellular transepithelial resistance (a measure of polarity) and helps bring the virion to another entry factor that is normally situated in hard-to-reach cell junctions. Following the association with junction proteins, the virion is endocytosed into the cell in a complex that includes these proteins. Similarly, in the early steps of HCV cell entry, virions bind to receptors that are normally accessible, and this association results in the translocation of virions to cell junctions, where they are endocytosed. Not surprisingly, the process of viral entry appears to disrupt polarity. Although the disruption is temporary and the epithelium likely recovers its polarized state, the loss is responsible for symptoms associated with infection. For example, rotavirus is the most common cause of severe gastroenteritis among young children globally. As the virions enter the gastrointestinal epithelium, they disrupt the integrity of cell junctions and the actin cytoskeleton, resulting in increased permeability across cells. These changes can be induced not just by virions but also by individual viral proteins and are sufficient to cause diarrhea, the hallmark characteristic of infection, in mice.