Endothelial activation and dysfunction in the pathogenesis of influenza A virus infection

Abstract

The development of severe influenza has been attributed, in part, to a heightened innate immune response. Recent evidence suggests that endothelial activation, loss of barrier function, and consequent microvascular leak may also serve important mechanistic roles in the pathogenesis of severe influenza. The aim of this review is to summarize the current evidence in support of endothelial activation and dysfunction as a central feature preceding the development of severe influenza. We also discuss the effect of influenza on platelet-endothelial interactions.

Keywords: acute lung injury; endothelium; influenza A; microvascular leak; platelets; thrombosis.

Figure 1. Mechanisms of endothelial dysfunction in influenza virus infection. (A) Endothelial permeability and activation. Elevated levels of pro-inflammatory cytokines/chemokines can directly induce endothelial leak through disruption of cell–cell junctions and may also cause endothelial cells to express elevated levels of adhesion molecules that promote leukocyte recruitment. Neutrophils release neutrophil extracellular traps (NETs), which can damage endothelial cells. There is in vitro evidence that influenza can directly infect lung endothelial cells and cause activation of NFκB, endothelial apoptosis, and loss of junctional proteins. In vivo, only avian H5N1 influenza has been shown to directly infect endothelial cells. (B) Platelet–endothelial interactions. Circulating cytokines/chemokines cause increased expression of platelet-binding receptors. Influenza virus can directly infect lung endothelium and induce endothelial apoptosis exposing the extracellular matrix, which has a high affinity for platelets. Influenza may directly induce platelet activation and activated platelets bind to endothelium. Activated platelets may interact with neutrophils triggering the production of NETs.