The Procoagulant Envelope Virus Surface: Contribution to Enhanced Infection

doi:10.1016/j.thromres.2014.03.010

Thrombosis Research

Volume 133, Supplement 1, May 2014, Pages S15-S17

https://doi.org/10.1016/j.thromres.2014.03.010 Get rights and content

Abstract

Many virus types are covered by a lipid bilayer. This structure called an envelope, is derived from the host cell and includes host- and virus-encoded proteins. Because envelope components first interact with the host, it is the trigger for infection, immunity and pathology. The roles of especially host-derived constituents are poorly understood. Focusing on herpes simplex type 1 (HSV1) as a model, we have shown that the envelope acquires the physiological initiators of coagulation from the host cell; tissue factor (TF) and procoagulant phospholipid (proPL). Unlike resting cells, where TF and proPL accessibility is carefully restricted, their expression is constitutive on the purified virus enabling factor VIIa (FVIIa)-dependant factor Xa (FXa) and thrombin generation. Interestingly, HSV1-encoded glycoprotein C (gC) on the virus enhances FXa production. In addition to coagulation proteases, HSV1 also facilitates fibrinolytic plasmin generation. HSV1 TF and gC combine to optimally enhance cultured cell infection when both FVIIa and FXa are available through protease activated receptor (PAR) 2. Plasmin also increases infection through PAR2, whereas thrombin provides an additive effect via PAR1. Thus, depending on the host cell, TF and proPL may be a general feature of enveloped viruses, enabling coagulation protease activation and PAR-mediated effects on infection.

Introduction

Many types of virus acquire a covering as they “bud” from the host cell. This structure, called an envelope, consists of a cell-derived lipid bilayer and the associated membrane-bound proteins, which are encoded by both viral and host genes. Since the host cell and the respective membrane are not constant, the envelope proteome is variable, and consequently the roles of host-encoded envelope proteins in the virus life-cycle and pathology are poorly understood. Numerous enveloped viruses affect hemostasis, such as herpes simplex virus types 1 (HSV1) [1] and 2 [2], cytomegalovirus [3], dengue virus [4], Ebola virus [5], hepatitis C virus [6], human immunodeficiency viruses 1 and 2 [7] and influenza virus [8]. As a model envelope virus, our focus has been primarily on HSV1, which uses host- and virus-encoded proteins to activate plasma coagulation proteases on its surface. Here we review our studies showing that HSV1 envelope receptors exploit these proteases to enhance cellular infection by triggering host signaling mechanisms.

Section snippets

Envelope Procoagulant Phospholipid

The essential roles of thrombin in biology are highly regulated, requiring procoagulant phospholipid (proPL; e.g. phosphatidylserine) as a focal point for binding and assembly of the enzyme-cofactor-substrate complex that activates its precursor, prothrombin, and upstream proteases. ProPL serves to localize and concentrate clotting proteins to sites of vascular damage, where agonists induce its controlled accessibility. In contrast, we showed that purified HSV1, and other members of the herpes

Coagulation Proteases Increase HSV1 Infection

Thrombin, FVIIa, FXa and other proteases such as fibrinolytic plasmin, stimulate many cell types by exposing a “tethered-ligand” at the N-terminus of G-protein-linked protease activated receptors (PARs) [19]. Due to the procoagulant enzymes generated on the HSV1 envelope, we consequently investigated a role for host cellular PAR1 and PAR2 in infection (Fig. 1). Using purified proteases, synthetic PAR-activating peptides and inhibitory antibodies to PAR-mediated signaling, we showed that

Conflict of Interest Statement

The authors have no conflicts to declare of relevance to this work.

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Tissue factor in COVID-19-associated coagulopathy
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Evidence of micro- and macro-thrombi in the arteries and veins of critically ill COVID-19 patients and in autopsies highlight the occurrence of COVID-19-associated coagulopathy (CAC). Clinical findings of critically ill COVID-19 patients point to various mechanisms for CAC; however, the definitive underlying cause is unclear. Multiple factors may contribute to the prothrombotic state in patients with COVID-19. Aberrant expression of tissue factor (TF), an initiator of the extrinsic coagulation pathway, leads to thrombotic complications during injury, inflammation, and infections. Clinical evidence suggests that TF-dependent coagulation activation likely plays a role in CAC. Multiple factors could trigger abnormal TF expression and coagulation activation in patients with severe COVID-19 infection. Proinflammatory cytokines that are highly elevated in COVID-19 (IL-1β, IL-6 and TNF-α) are known induce TF expression on leukocytes (e.g. monocytes, macrophages) and non-immune cells (e.g. endothelium, epithelium) in other conditions. Antiphospholipid antibodies, TF-positive extracellular vesicles, pattern recognition receptor (PRR) pathways and complement activation are all candidate factors that could trigger TF-dependent procoagulant activity. In addition, coagulation factors, such as thrombin, may further potentiate the induction of TF via protease-activated receptors on cells. In this systematic review, with other viral infections, we discuss potential mechanisms and cell-type-specific expressions of TF during SARS-CoV-2 infection and its role in the development of CAC.
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This excess complement activation might explain why patients with these conditions display similar reactions to COVID-19. Moreover, the virus surface is known to have procoagulant activity, similar to historic descriptions of herpesviruses.38,39 Additionally, the Middle East respiratory syndrome (MERS) was associated with a high incidence of venous thromboembolism.40
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is associated with specific coagulopathy that frequently occurs during the different phases of coronavirus disease 2019 (COVID-19) and can result in thrombotic complications and/or death. This COVID-19-associated coagulopathy (CAC) exhibits some of the features associated with thrombotic microangiopathy, particularly complement-mediated hemolytic-uremic syndrome. In some cases, due to the anti-phospholipid antibodies, CAC resembles catastrophic anti-phospholipid syndrome. In other patients, it exhibits features of hemophagocytic syndrome. CAC is mainly identified by: increases in fibrinogen, D-dimers, and von Willebrand factor (released from activated endothelial cells), consumption of a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13 (ADAMTS13), over activated and dysregulated complement, and elevated plasma cytokine levels. CAC manifests as both major cardiovascular and/or cerebrovascular events and dysfunctional microcirculation, which leads to multiple organ damage. It is not clear whether the mainstay of COVID-19 is complement overactivation, cytokine/chemokine activation, or a combination of these activities. Available data have suggested that non-critically ill hospitalized patients should be administered full-dose heparin. In critically ill, full dose heparin treatment is discouraged due to higher mortality rate. In addition to anti-coagulation, four different host-directed therapeutic pathways have recently emerged that influence CAC: (1) Anti-von Willebrand factor monoclonal antibodies; (2) activated complement C5a inhibitors; (3) recombinant ADAMTS13; and (4) Interleukin (IL)-1 and IL-6 antibodies. Moreover, neutralizing monoclonal antibodies against the virus surface protein have been tested. However, the role of antiplatelet treatment remains unclear for patients with COVID-19.
In silico thrombin generation: Plasma composition imbalance and mortality in human immunodeficiency virus
2018, Research and Practice in Thrombosis and Haemostasis
Effective HIV treatment with antiretroviral therapy has prolonged survival and shifted causes of death to non‐AIDS illnesses such as cardiovascular disease. We have shown that inflammation and HIV viral load associate with pro‐ and anticoagulant factor imbalances resulting in increased thrombin generation when mathematically modeled. We explore the hypothesis that factor compositional imbalance, corresponding to increased in silico thrombin generation, predicts mortality among HIV+ persons.
In a nested case‐control study of HIV+ individuals on continuous antiretroviral therapy in two large trials, we evaluated cases (any non‐violent mortality, n = 114) and matched controls (n = 318). Thrombin generation in response to a tissue‐factor initiator for each individual was calculated by a mathematical model incorporating levels of factors (F)II, V, VII, VIII, IX, X, antithrombin, tissue factor pathway inhibitor, and protein C (PC) measured at study entry to the trials. In silico thrombin generation metrics included clot time, maximum rate (MaxR), maximum level (MaxL), and area under the curve (AUC).
Levels of antithrombin and PC decreased, while FV and FVIII were higher in cases vs controls. This resulted in a more procoagulant phenotype with increased MaxR, MaxL, and AUC in cases compared to controls (P<0.05 for all).
Antithrombin, FV, FVIII, and PC were the major contributors to the increased thrombin generation associated with mortality risk. Our results suggest that mortality in HIV is associated with an increase in in silico thrombin generation via altered balance of pro‐ and anticoagulant factors, likely due to an inflammatory response signal, and resulting coagulopathy.
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Citation Excerpt :
Tissue factor may also be synthesized by platelets in response to stimulation [30], but this has been debated. The broad distribution of tissue factor has linked it to numerous pathologies predominantly involving PAR2 signalling, including tumor growth/progression [2–4], cancer metastasis [5–7], venous thromboembolism [8], obesity [31], pain [32] and viral infection [33]. Similarly, tissue factor-bearing microparticles produced after cell stimulation are correlated to diseases such as cirrhosis [9], leukemia [10] and interstitial lung disease [1], which explains increased procoagulant activity and inflammation leading to organ impairment or injury.
Hemostasis is the physiological control of bleeding and is initiated by subendothelial exposure. Platelets form the primary vascular seal in three stages (localization, stimulation and aggregation), which are triggered by specific interactions between platelet surface receptors and constituents of the subendothelial matrix. As a secondary hemostatic plug, fibrin clot formation is initiated and feedback-amplified to advance the seal and stabilize platelet aggregates comprising the primary plug. Once blood leakage has been halted, the fibrinolytic pathway is initiated to dissolve the clot and restore normal blood flow. Constitutive and induced anticoagulant and antifibrinolytic pathways create a physiological balance between too much and too little clot production. Hemostatic imbalance is a major burden to global healthcare, resulting in thrombosis or hemorrhage.
Maestro tissue factor reaches new hEIGHT
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Evasion and interactions of the humoral innate immune response in pathogen invasion, autoimmune disease, and cancer
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Enveloped viruses acquire envelopes from host cells, thus expressing and utilizing host cell and cell membrane properties. Herpes simplex virus 1 uses host components to activate thrombin and enhance infection and encodes glycoprotein C which contributes to the enhancement of Factor X activation [83]. Adenovirus type 5 also uses a host coagulation factor to overcome a complement-mediated blockade and infect the liver.
The humoral innate immune system is composed of three major branches, complement, coagulation, and natural antibodies. To persist in the host, pathogens, such as bacteria, viruses, and cancers must evade parts of the innate humoral immune system. Disruptions in the humoral innate immune system also play a role in the development of autoimmune diseases. This review will examine how Gram positive bacteria, viruses, cancer, and the autoimmune conditions systemic lupus erythematosus and anti-phospholipid syndrome, interact with these immune system components. Through examining evasion techniques it becomes clear that an interplay between these three systems exists. By exploring the interplay and the evasion/disruption of the humoral innate immune system, we can develop a better understanding of pathogenic infections, cancer, and autoimmune disease development.

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Regular ArticleThe Procoagulant Envelope Virus Surface: Contribution to Enhanced Infection

Abstract

Introduction

Section snippets

Envelope Procoagulant Phospholipid

Coagulation Proteases Increase HSV1 Infection

Conflict of Interest Statement

Lancet

Lancet

Blood

Curr Opin Virol

Cell

Blood

J Thromb Haemost

J Thromb Haemost

J Thromb Haemost

Chlamydia pneumoniae, herpes simplex virus type 1, and cytomegalovirus and incident myocardial infarction and coronary heart disease death in older adults - The Cardiovascular Health Study

Circulation

Coagulation initiated on herpesviruses

Proc Natl Acad Sci U S A

A prospective study of cytomegalovirus, herpes simplex virus 1 and coronary heart disease

Arch Intern Med

Activation of coagulation factor XI, without detectable cntact activation in dengue haemorrhagic fever

Br J Haematol

Acute brachial artery thrombosis as the initial manifestation of human immunodeficiency virus infection

Am J Hematol

Regular Article
The Procoagulant Envelope Virus Surface: Contribution to Enhanced Infection