Aberrant coagulation causes a hyper-inflammatory response in severe influenza pneumonia

Abstract

Influenza A virus (IAV) infects the respiratory tract in humans and causes significant morbidity and mortality worldwide each year. Aggressive inflammation, known as a cytokine storm, is thought to cause most of the damage in the lungs during IAV infection. Dysfunctional coagulation is a common complication in pathogenic influenza, manifested by lung endothelial activation, vascular leak, disseminated intravascular coagulation and pulmonary microembolism. Importantly, emerging evidence shows that an uncontrolled coagulation system, including both the cellular (endothelial cells and platelets) and protein (coagulation factors, anticoagulants and fibrinolysis proteases) components, contributes to the pathogenesis of influenza by augmenting viral replication and immune pathogenesis. In this review, we focus on the underlying mechanisms of the dysfunctional coagulatory response in the pathogenesis of IAV.

Figure 1

Cascades of the coagulation system. (a) Resting ECs provide natural anticoagulants (TM, AT and TFPI and ADPase) to inhibit coagulation and keep platelet activation and the coagulation cascade in check. (b) Coagulation is typically initiated by an injury to the vascular ECs, which results in the exposure of TF and collagen from the sub-endothelial tissue to the blood and the release of vWF. (c) Platelets are activated when they are exposed to TF, collagen and vWF. Activated platelets release a number of mediators, such as ADP and vWF stores within their granules, leading to further platelet recruitment, activation, aggregation and plug formation, which is a process termed primary hemostasis. (d) The interaction between TF and factor VII initiates the extrinsic pathway. (e) The exposure of collagen to blood starts the intrinsic pathway. (f) Both the extrinsic and intrinsic pathways result in the initiation of a common pathway, which contains the cascades involved in the production of activated Factor X and thrombin and the formation of fibrin strands. (g) Fibrin strands strengthen the platelet plug and lead to the formation of a stable platelet–fibrin clot. This process is termed secondary hemostasis. (h) Kallikrein, uPA or tPA activate plasminogen to plasmin, which then degrades and reabsorbs the polymerized fibrin strands. It is the eventual process of fibrinolysis that heals wounds. AT, antithrombin; ECs, endothelial cells; TF, tissue factor; TFPI, tissue factor pathway inhibitors; TM, thrombomodulin; tPA, tissue plasminogen activator; uPA, urokinase plasminogen activator; vWF, von Willebrand factor.

Figure 2

Interactions between coagulation and inflammation during IAV infection. (a) Airway and alveolar epithelial cells are the primary targets of IAV infection. IAV can directly infect ECs and/or indirectly induce EC activation and vascular hyperpermeability through PAMPs, DAMPs and inflammatory cytokines. (b) The activation of ECs induces a pro-thrombotic state by down-regulating the anticoagulant components (TM, AT, TFPI and ADPase), the expression of TF and vWF and the exposure of collagen to blood. Thrombin, FXa and FVIIa, produced by the coagulation cascade, augment the inflammatory response by activating platelets, endothelial cells, monocytes, neutrophils, NKT and T cells through PARs. (c) Platelets are activated by exposure to thrombin, TF, collagen and vWF. Then, the coagulation cascades and thrombi formation are initiated. (d) The downregulation of tight junction protein on ECs and apoptosis of ECs induced by inflammatory cytokines lead to vascular hyperpermeability, which results in leakage of plasma and blood cells into the bronchoalveoli (hemorrhage). Decompensated thrombocytopenia is another reason for hemorrhage during an IAV infection. (e) Activated platelets act as pro-inflammatory cells by releasing inflammatory cytokines and promoting the activation, transmigration and cytokine release of neutrophils, T, B and NK cells, DC and monocytes. Activated platelets also modulate EC function to promote an inflammatory response. (f) The cytokine storm of overactivated neutrophils, monocytes and lymphocytes (NK cell, NKT cell and T cell), as well as the overproduction of inflammatory cytokines by these cells, contributes to the high morbidity and mortality during IAV infection. AT, antithrombin; DAMPs, damage-associated molecular patterns; DC, dendritic cell; EC, endothelial cell; IAV, influenza A virus; NK, natural killer; NKT, natural killer T cells; PAMPs, pathogen-associated molecular patterns; PAR, protease-activated receptor; TF, tissue factor; TFPI, tissue factor pathway inhibitor; TM, thrombomodulin; vWF, von Willebrand factor.

Figure 3

The role of the fibrinolytic components in the IAV life cycle. (a) The release of influenza virus particles from the host cell is mediated by NA through the cleavage of sialic acid from glycoproteins. PAI-1 inhibits viral glycoprotein cleavage, reducing the spread of the virus from the host cell to uninfected surrounding cells. (b) HA of the IAV is typically cleaved by trypsin-like proteases to gain viral fusion capacity. Certain influenza viruses can hijack plasmin for cleaving their HA to increase their viral infectivity and spread. PAI-1 acts as an anti-influenza molecule through the inhibition of HA cleavage by plasmin, as PAI-1 is the main inhibitor of the plasminogen activators. HA, hemagglutinin; IAV, influenza A virus; NA, neuraminidase; PAI, plasminogen activator inhibitor-1.