Role of Cellular Mechanisms in Dengue Pathogenesis: Focus on Immune Cells Interactions.

Abstract

Dengue is an arbovirus mosquito-borne disease that occurs after an infection with dengue virus. Dengue virus releases E-proteins, which act as binding proteins and enter the host cell after infection. It triggers several cellular reactions and activates the immune system; however, the mechanisms are still poorly understood. Our goal is to find out how these cellular interactions participate in the activation of immune cells and participate in dengue pathogenesis. Once dengue infects the host cell, it follows these steps: (1) dengue virus releases M- protein into the skin of the host, and it infects the Langerhans cells of the skin, which is a dendritic cell which acts as antigen representing cells. (2) After infection with dendritic cells, the virus enters into the blood cells white blood cells (monocytes, lymphocytes, neutrophils, eosinophils, basophils, and macrophages), red blood cells (erythrocytes), and platelets. After blood cell infection, it targets monocytes or macrophage cells and starts replication. Once replication is done, it circulates in all parts of the organ as well as its cells like endothelium (Endotheliocytes), liver (Hepatocytes, Kupffer), tissue macrophages, Bone marrow (Stromal cells) and enhances endothelial permeability possibly by overproducing matrix metalloproteinases (MMPs) and other cellular mediators. (3) Once all monocytes cell of blood gets infected, it activates NK cell, IFNγ and TNF-α response. For the execution of this mechanism, various pattern recognition receptors, such as Toll-like Receptor 3 (in endosome), play a role in pathogen recognition and activation of innate immunity. (4) MDA5 (melanoma differentiation-associated protein 5) MDA5 protein can function as a cytosolic sensor that recognizes viral double-strand RNA and then triggers the transcription of genes encoding type I interferon (IFN) and RIG-I (retinoic acidinducible gene-I) is an intracellular molecule that responds to viral nucleic acids and activates downstream signalling, resulting in the induction of members of the type I interferon (IFN) family. Non-structural part of the virus secretes NS protein, which disrupts the endothelial glycocalyx layer (EGL) by enkindling the upregulation of 3 of the 4 endothelial sialidases (cytosolic (Neu 2), plasma membrane (Neu 3), and lysosomal (Neu 1). These sialidases translocate to the plasma membrane and lead to the hydrolysis of the endothelial glycocalyx layer expressed sialic acid residues, which disrupts the endothelial layer, and as an end result, it increases the pathogenesis of dengue fever. Collectively, the various molecules of the dengue virus activate different cellular components of immune cells, leading to immune dysfunctions and causing severe dengue pathogenesis.