Influenza Virus Infection Induces Platelet-Endothelial Adhesion Which Contributes to Lung Injury

Abstract

Lung injury after influenza infection is characterized by increased permeability of the lung microvasculature, culminating in acute respiratory failure. Platelets interact with activated endothelial cells and have been implicated in the pathogenesis of some forms of acute lung injury. Autopsy studies have revealed pulmonary microthrombi after influenza infection, and epidemiological studies suggest that influenza vaccination is protective against pulmonary thromboembolism; however, the effect of influenza infection on platelet-endothelial interactions is unclear. We demonstrate that endothelial infection with both laboratory and clinical strains of influenza virus increased the adhesion of human platelets to primary human lung microvascular endothelial cells. Platelets adhered to infected cells as well as to neighboring cells, suggesting a paracrine effect. Influenza infection caused the upregulation of von Willebrand factor and ICAM-1, but blocking these receptors did not prevent platelet-endothelial adhesion. Instead, platelet adhesion was inhibited by both RGDS peptide and a blocking antibody to platelet integrin ␣ 5 ␤ 1 , implicating endothelial fibronectin. Concordantly, lung histology from infected mice revealed viral dose-dependent colocalization of viral nucleoprotein and the endothelial marker PECAM-1, while platelet adhesion and fibronectin deposition also were observed in the lungs of influenza-infected mice. Inhibition of platelets using acetylsalicylic acid significantly improved survival, a finding confirmed using a second antiplatelet agent. Thus, influenza infection induces platelet-lung endothelial adhesion via fibronectin, contributing to mortality from acute lung injury. The inhibition of platelets may constitute a practical adjunctive strategy to the treatment of severe infections with influenza. Here, we show that this infection causes platelets to adhere to the lung endothelium. Importantly, blocking platelets using two distinct antiplatelet drugs improved survival in a mouse model of severe influenza infection. Thus, platelet inhibition may constitute a novel therapeutic strategy to improve the host response to severe infections with influenza.

Amicus or Adversary Revisited: Platelets in Acute Lung Injury and Acute Respiratory Distress Syndrome

“…Infection of lung endothelial cells by virus, resulting in adhesion of platelets, is suggested to be a mechanism in influenza-induced ALI on the basis of parallel in vitro studies of human lung microvascular endothelial cells and mice infected with H3N2 influenza A (111). ASA improved survival in the in vivo model described in this report, suggesting that antiplatelet therapy may be a useful adjunctive strategy in severe influenza (111).…”

“…ASA, other pharmacologic platelet inhibitors, and endogenous ASA-induced lipoxins ameliorate ALI in a variety of experimental models, as demonstrated in reports profiled in this review and others we have not discussed (32,43,57,59,69,104,111,132,169,170). In addition, some but not all retrospective and observational studies suggest that antiplatelet agents are beneficial in clinical ARDS and in predisposing conditions (171)(172)(173)(174)(175)(176).…”

“…Lung hemorrhage, microvascular thrombosis, and DAD are observed in severe clinical influenza, generating the proposal that activated platelets mediate aberrant hemostasis and maladaptive, "hyper" inflammation by interacting with leukocytes and endothelial cells in severe influenza infection (110). Infection of lung endothelial cells by virus, resulting in adhesion of platelets, is suggested to be a mechanism in influenza-induced ALI on the basis of parallel in vitro studies of human lung microvascular endothelial cells and mice infected with H3N2 influenza A (111). ASA improved survival in the in vivo model described in this report, suggesting that antiplatelet therapy may be a useful adjunctive strategy in severe influenza (111).…”

Role of hematological parameters in the diagnosis of influenza virus infection in patients with respiratory tract infection symptoms

“…This was the first study to present real laboratory data to confirm other reports on the mechanism of platelet inhibition induced by influenza virus. It has been reported that influenza virus could induce uncontrolled platelet activation to fuel a harmful inflammatory response in the respiratory tract . We hypothesized that such excessive activation of platelets by influenza virus may lead to a markedly decreased platelet count compared with other respiratory tract infections.…”

Multi-Omics Studies towards Novel Modulators of Influenza A Virus–Host Interaction

“…Interestingly, 41 of the 199 druggable cellular factors were shown to be implicated in IAV infection (Table S2) [10,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,...…”