Dengue Virus Induces the Release of sCD40L and Changes in Levels of Membranal CD42b and CD40L Molecules in Human Platelets

Abstract

Platelets are considered as significant players in innate and adaptive immune responses. The adhesion molecules they express, including P-selectin, CD40L, and CD42b, facilitate interactions with many cellular effectors. Upon interacting with a pathogen, platelets rapidly express and enhance their adhesion molecules, and secrete cytokines and chemokines. A similar phenomenon occurs after exposure of platelets to thrombin, an agonist extensively used for in vitro activation of these cells. It was recently reported that the dengue virus not only interacts with platelets but possibly infects them, which triggers an increased expression of adhesion molecule P-selectin as well as secretion of IL-1β. In the present study, surface molecules of platelets like CD40L, CD42b, CD62P, and MHC class I were evaluated at 4 h of interaction with dengue virus serotype 2 (DENV-2), finding that DENV-2 induced a sharp rise in the membrane expression of all these molecules. At 2 and 4 h of DENV-2 stimulation of platelets, a significantly greater secretion of soluble CD40L (sCD40L) was found (versus basal levels) as well as cytokines such as GM-CSF, IL-6, IL-8, IL-10, and TNF-α. Compared to basal, DENV-2 elicited more than two-fold increase in these cytokines. Compared to the thrombin-induced response, the level generated by DENV-2 was much higher for GM-CSF, IL-6, and TNF-α. All these events induced by DENV end up in conspicuous morphological changes observed in platelets by confocal microscopy and transmission electron microscopy, very different from those elicited by thrombin in a more physiological scenery.

Platelets Can Associate With SARS-CoV-2 RNA and Are Hyperactivated in COVID-19

“… 81 This may not be unique to SARS-CoV-2 as dengue virus also induces the release of CD40L from human platelets. 82 …”

Effects of the periodontal pathogens Porphyromonas gingivalis and Tannerella forsythia on platelets

“…Surprisingly, an increase in CD42b expression (p<0.01) was observed following bacterial exposure. This is in contrast with previous studies which have documented a decrease in CD42b expression following platelet activation due to ectodomain shedding (Tao et al, 2016) but supports the increase in CD42b expression induced on platelets by the Dengue virus (Núñez-Avellaneda et al, 2018). CD42b also known as glycoprotein Ibα (GPIbα) exists within a non-covalent complex of GPIb-IX-V on the platelet surface membrane (Modderman et al, 1992) and plays a role on platelet adhesion to subendothelial matrix, endothelial cells and leukocytes (Berndt et al, 2001).…”

The Era of Thromboinflammation: Platelets Are Dynamic Sensors and Effector Cells During Infectious Diseases

“…A hallmark of platelet activation is the conformational change of integrin α IIb β 3 , which binds to fibrinogen and von Willebrand factor (vWF), triggering platelet adhesion to vascular endothelial cells and causing thrombosis (61). Activation of platelets also triggers degranulation and the release of a number of proteins including P-selectin, PAF, soluble CD40L (CD154), and serotonin—proteins that are often dichotomized into either pro-thrombotic or pro-inflammatory, but which could fall together under the term “thromboinflammation” (54, 55, 62, 63). P-selectin on platelets engage its ligand, P-selectin glycoprotein ligand (PSGL) on leukocytes, promoting proinflammatory cytokine production such as IL-1β and IL-8 by both platelets and monocytes (40, 62, 64).…”

“…Activation of platelets also triggers degranulation and the release of a number of proteins including P-selectin, PAF, soluble CD40L (CD154), and serotonin—proteins that are often dichotomized into either pro-thrombotic or pro-inflammatory, but which could fall together under the term “thromboinflammation” (54, 55, 62, 63). P-selectin on platelets engage its ligand, P-selectin glycoprotein ligand (PSGL) on leukocytes, promoting proinflammatory cytokine production such as IL-1β and IL-8 by both platelets and monocytes (40, 62, 64). These cytokines induce enhanced permeability of endothelial cells and vascular leakage, and are associated with an increased risk of DHS in patients (64).…”