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The role of platelets in antiviral immunity
E. V. Slukhanchuk,
V. O. Bitsadze,
J. Kh. Khizroeva,
A. G. Solopova,
V. I. Tsibizova,
F. Yakubova,
C. Ay,
J.-C. Gris,
A. D. Makatsariya https://doi.org/10.17749/2313-7347/ob.gyn.rep.2022.305
Abstract
The main role of platelets is traditionally assigned to participation in hemostasis reactions. In recent years, the data have appeared on the non-hemostatic platelet-related role and their active participation in inflammatory reactions. These platelet functions are predetermined by their ability to activate and secrete various immunomodulatory cytokines and chemokines. In addition, activated platelets can directly interact with viral receptors. Recently, there has been growing the knowledge regarding platelet-related regulation of diverse cell types. The result of this interaction is, among others, the formation of platelet-leukocyte aggregates, the focusing of neutrophils at the sites of injury, and generation of a scaffold for developing extracellular traps. Thus, platelets are not only participants in coagulation processes, but also important players in the inflammatory process. This lecture details the issues of platelets controlling and modulating host response to viral infection, as well as potential targets for therapeutic intervention.
Supporting agencies: The work was funded by RFBR, project number 20-04-60274.
For citations:
Slukhanchuk E.V., Bitsadze V.O., Khizroeva J.Kh., Solopova A.G., Tsibizova V.I., Yakubova F., Ay C., Gris J., Makatsariya A.D. The role of platelets in antiviral immunity. Obstetrics, Gynecology and Reproduction. 2022;16(2):204–212. https://doi.org/10.17749/2313-7347/ob.gyn.rep.2022.305
Platelet biology / Биология тромбоцитов
Platelets are small non-nucleated cells derived from megakaryocytes that play a crucial role in primary hemostasis. Megakaryocyte fragmentation is regulated by thrombopoietin receptor binding [1]. Any platelet contains no nucleus, however being enriched in mitochondrial DNA as well as RNA the latter accounting for protein synthesis [2]. About 750 billion platelets circulate in the human body, and about 200 billion new cells are formed daily in the bone marrow [3] and lungs [4]. Platelets circulate for 10 days to be subsequently utilized in the liver and spleen. While aging platelets gradually lose membrane-bound sialic acid and reduce thrombopoietin accumulation.
In recent years, there have been emerged increasing evidence regarding the role of platelets in pathological processes such as autoimmune reactions [5], tumor growth [6], and infectious processes [7]. Small molecules, nucleic acids, lipid mediators, and proteins are stored in diverse platelet organelles – alpha granules, dense granules, and lysosomal vesicles [8]. Upon activation, platelets rapidly change shape and release into the extracellular environment such factors either soluble or encapsulated in bioactive microvesicles [9]. The ability of platelets to participate in immune responses is executed due to release of various proinflammatory and bioactive molecules stored in their granules. Released mediators attract and modulate the activity of circulating leukocytes [10]. Platelets also act as independent immune effector cells [11]. Megakaryocytes and platelets express several immuneassociated molecules and receptors, including Fcreceptors [12], complement receptors [13], chemokine receptors [14], and some toll-like receptors (TLRs) [15].
Platelets and immune response / Тромбоциты и иммунный ответ
Platelets contain various membrane receptors such as TLRs capable of detecting PAMPs (pathogenassociated molecular patterns) and DAMPs (damageassociated molecular patterns) [16]. In addition to direct binding to pathogens, platelets are involved in pathogen elimination by coordinating activity of immune cells such as neutrophils, which bind to activated platelets via P-selectin glycoprotein ligand-1 (PSGL-1, CD162) and migrate to inflammatory sites [17]. Similar interaction leads to formation of neutrophilic vesicles filled with arachidonic acid, which are rapidly internalized by platelets via macrophage-1 antigen (Mac-1). Being internalized, arachidonic acid is converted to thromboxane A2 (TXA2). Then, platelet-derived TXA2 activates neutrophils by upregulating ICAM-1 (intercellular adhesion molecule 1) expression followed by enhanced migration, and extravasation [18].
Serotonin plays an essential role in neutrophil adhesion. Platelets are the main source of peripheral serotonin [19]. Platelets cover a large area at the site of endothelial injury; migrating neutrophils use the platelet scaffold to attach and migrate to the site of inflammation [20].
The interaction between platelets and neutrophils has been shown to attract monocytes to the site of inflammation via CD40–CD40L dependent mechanism [21]. Platelets also attract monocytes via plateletderived CCL5 (сhemokine (C-C motif) ligand 5) and neutrophil-derived HNP1 (human neutrophil peptide 1, alpha-defensin) heteromers [22]. Moreover, activated platelets release the contents of alpha granules containing mediators such as adenosine diphosphate (ADP). The binding of ADP to P2Y receptors [23] results in rapid translocation of P-selectin to the plasma membrane, thereby enhancing recruitment of neutrophils, monocytes, and lymphocytes to the injury site [24]. Platelet-released HMGB1 protein (highmobility group protein B1) is also involved in attracting immune cells [25]. Recent in vitro data indicate that CXCL4 (also known as PF4, platelet factor 4), a critical chemokine secreted by activated platelets, may be involved in monocyte migration by binding to the CCR1 receptor (C-C chemokine receptor type 1) [26]. Platelets not only attract immune cells to the site of inflammation but also actively move towards site of damage. Motile platelets are capable of active adhesion to the endothelium assisted by ADP and TXA2. In addition, platelets trap infectious agents and increase phagocyte activity [27]. Bacteria activate platelets, enhancing their interaction with neutrophils, which leads to enhanced phagocytosis [28]. Plateletdeprived model demonstrated that mice were prone to bacteremia caused by Staphylococcus aureus [29]. Thrombin-activated platelets also appear to enhance the uptake and destruction of Gram-positive bacteria by dendritic cells, macrophages, and neutrophils [30]. Platelets can form aggregates with erythrocytes infected with malarial plasmodia and destroy the pathogen [31]. Platelet microvesicles containing nucleic acids, proteins, lipids, and other molecular constituents also derived from megakaryocytes play an essential role in immune responses. Microvesicles containing microRNAs can modulate mRNA transcription in macrophages, reprogramming them for a phagocytic phenotype [32].
Platelets and regulation of immune cell functioning / Тромбоциты и регуляция работы иммунных клеток
Cytokines and chemokines underlie immune cell generation, growth, differentiation and functioning. The adhesion of monocytes to platelets during inflammation leads to nuclear translocation of the transcription factor NF-κB (nuclear factor kappa B) followed by upregulated monocytic expression of CCL2 and IL-8 (interleukin-8). Platelet CCL5 activates the release of monocyte proinflammatory chemokines as well as P-selectindependent interaction [33]. The chemokine CXCL4 (chemokine (C-X-C motif) ligand 4) plays an important role in systemic inflammatory response. During inflammation, platelet Rac-1 (Ras-related C3 botulinum toxin substrate 1) pathway is engaged to release CXCL4 that recruits neutrophils, followed by tissue damage, also resulting in elevated level of CCL5, CXCL1, and CXCL2. Experimental CXCL4 suppression reduces the concentration of pro-inflammatory markers and improves general condition of laboratory animals [34]. Platelets are the source of CD40L (CD154) markedly affecting leukocytes. In systemic lupus erythematosus (SLE), platelets were shown to be activated by immune complexes followed by aggregation with monocytes and dendritic cells. The latter increased release of IFN-α (interferon alfa) via CD40/CD40L-axis. Platelet depletion in mouse SLE models improved the disease course, whereas platelet transfusion exacerbated it [35]. The neutrophil-platelet interaction via CD40 is regulated by the positive feedback loop so that the leukocyte release of superoxide and reactive oxygen species becomes elevated along with platelet stimulated CD40L secretion [36].
Another important regulatory cytokine is IL-1β being mainly produced by leukocytes in the human body. Platelets may elevate expression of this leukocyte cytokine, whereas P-selectin level was shown to be associated with higher concentrations of IL-1β and IL-6 after ex vivo stimulation [37]. During viral infection, platelets release microvesicles filled with IL-1β resulting from NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) activation by reactive oxygen species [38].
In addition to platelet-related pro-inflammatory effect on immune cells, platelets also exhibit antiinflammatory effects due to direct interaction or release of various factors. In particular, platelets and their derivatives were experimentally shown to reduce level of pro-inflammatory cytokines such as TNF-α (tumor necrosis factor-α) and IL-6. Depletion of the platelet pool resulted in increased mortality and multiple organ failure in murine models of septic shock, and conversely, platelet inoculation attenuated the generalized hyperimmune response [39]. Another study demonstrated platelets added to mononuclear cell culture were able to suppress IL-6 and TNF-α production and elevated IL-10 production after stimulation with PAMPs of various origins [40].
Platelets and neutrophil extracellular traps / Тромбоциты и внеклеточные ловушки нейтрофилов
Neutrophil extracellular traps (NETs) consist of extracellular DNA as well as cytoplasmic and nuclear proteins released into the extracellular space by neutrophils upon activation [41]. After the very discovery of this process, platelets were shown to play a fundamental role in the formation of such structures in sepsis by sensing TLR4 ligands and triggering neutrophil adhesion [42]. Later, it was unveiled that such interaction depends on the αLβ2 integrin LFA-1 (lymphocyte function-associated antigen 1, CD11a/CD18) [43]. Platelet microvesicles enriched in HMGB1 also stimulate neutrophils for NETs production [44]. Along with interaction between platelet GPIb (glycoprotein Ib) and neutrophil CD18, release of vWF (von Willebrand factor) and CXCL4 also promotes netosis. At the same time, intensity of netosis is accounted for by TXA2 production and, accordingly, can be suppressed by acting acetylsalicylic acid and prostacyclin [45].
Platelets and viruses / Тромбоциты и вирусы
Antiviral immunity is traditionally associated with the work of leukocytes. However, in various viral infections, including Dengue virus [46], HIV (human immunodeficiency virus), influenza virus [47], and SARS-CoV-2 [48], an increase in platelet activity has been also noted. The main antiviral platelet-related effect is mediated by sequestration of viral particles that limits viral spread. In HIV patients, platelets were proved to bind to and endocytose HIV virions contributing to clearance of viral particles from the circulation [49]. During platelet activation, α-granules are delivered to the cell surface and externalized, thereby releasing a wide range of bioactive molecules, including PF4 (also called the chemokine CXCL4). In addition to being an essential agent in leukocyte chemotaxis, PF4 exerts a direct antiviral activity [50]. Platelets also secrete antimicrobial proteins such as PD1–PD4 (programmed cell death proteins 1–4) exhibiting antiviral against cowpox virus [51]. Recent studies have shown that platelets contain virus-specific immunoglobulin G (IgG) that can potentially neutralize cytomegalovirus (CMV) and influenza A virus both in vitro and in vivo [52]. IgG is localized in α-granules [53]. Megakaryocytes can engulf IgG molecules to be stored in α-granules for subsequent secretion by mature platelets. However, platelet-released vs. serum IgG antibodies is more effective in virus neutralization [52].
Platelets are also capable of directing the local immune response to infectious agents. Cytomegalovirus is recognized by platelet TLR2, leading to platelet degranulation, leukocyte chemotaxis, as well as platelet aggregation with neutrophils, monocytes, B cells, T cells, and dendritic cells [54]. Such platelet-leukocyte interactions allows platelets to present viral antigens on the major histocompatibility complex class I molecule to leukocytes [55] and provide stimulatory signals to antigen-presenting cells [56]. Similar events were also noted in Dengue fever [57].
Viruses evolved mechanisms to evade platelet recognition as a part of platelet-mediated antiviral immunity. Viruses interact with platelet surface receptors. In particular, Dengue virus and HIV bind to platelet surface lectin receptors and DC-SIGN (dendritic cell-specific intercellular adhesion molecule- 3-grabbing nonintegrin) [58]. Such interactions lead to internalization of viral particles, so that viruses such as HIV, CMV, and hepatitis C virus (HCV) can continue to replicate both inside megakaryocytes and platelets [58]. Along with using platelets for replication, some viruses may be carried inside circulating platelets to avoid immune detection as it was shown for influenza virus [59] and HIV, which form latent viral reservoirs. The hepatitis C virus is believed to use circulating platelets for transport to the liver, where interactions between platelets and hepatocytes prolong HCV persistence [60].
Thrombocytopenia in viral infection / Тромбоцитопения при вирусной инфекции
Thrombocytopenia is a common symptom observed in severe viral infections. The mechanisms for its development are as follows:
- neuraminidase activity of the influenza virus and herpes simplex virus (HSV) shortens platelet lifespan, ensuring their rapid clearance in the liver and spleen [61];
- neuraminidase activity alters megakaryocyte ploidy, as well as future platelet morphology and size [62];
- herpes simplex viruses, affecting thrombopoietin activity reduce megakaryocyte colony formation [63] as well as relevant cell survival and differentiation [64];
- impaired megakaryocyte differentiation also occurs due to changes in cytokine expression in the bone marrow, particularly during infection with Dengue virus [65];
- upon infection with Dengue virus, HIV, etc., it is noted to alter megakaryocyte development, platelet activation, accompanied by mitochondrial dysfunction, decreased cellular integrity and increased apoptosis [66][67].
Impaired platelet aggregation and activation in viral infection / Нарушения процессов агрегации и активации тромбоцитов при вирусной инфекции
Viral infection also affects platelet function [68].
- Coxsackie B virus (CVB) binds to and enters platelets via the Coxsackie adrenoreceptor. CVB is unable to replicate inside platelets, but may modulate activity and enhance P-selectin release and phosphatidylserine-related effects, which together promote platelet-leukocyte interactions, leading to platelet destruction and thrombocytopenia [69].
- The cowpox virus also invades platelets [68]. In vitro studies showed decreased platelet aggregation and subsequently increased release of serotonin after infection. In vivo studies demonstrated that infection with the cowpox virus resulted in increased intravascular coagulation [70] associated with enhanced platelet response. This discrepancy may indicate that the cowpox virus may affect endothelial function critical for regulating platelet function in vivo [71].
- Increased platelet activation during influenza infection is partly due to the release of monocyte cytokines, which further activate platelets [72].
- The immune response to infection with hepatitis C, HIV, CMV, HSV, and coronaviruses includes production of neutralizing antibodies against viral glycoproteins. Glycoprotein-specific antibodies cross-react with platelet integrins, leading to the development of antibody-dependent thrombocytopenia [73].
- By damaging the endothelium, viruses indirectly affect platelet functioning. For instance, Dengue virus infects endothelial cells promoting endothelial activation, endothelial-platelet interactions, and increased vascular permeability [38, 74]. Impaired integrity of blood vessels infected with the virus promotes platelet activation and may underlie one of the mechanisms for increased platelet clearance.
- Patients with chronic viral infection such as that caused by HIV require continuous suppression of viral replication. Studies showed that some antiretroviral drugs increase the risk of myocardial infarction [75] due to elevated platelet activation and aggregation [76]. Moreover, antiretroviral therapy may be further affect endothelial functions [77].
Thus, both viral infection and antiviral drugs can affect platelet activation.
Platelets and SARS-CoV-2 / Тромбоциты и SARS-CoV-2
Activation of inflammation and coagulation combined with the activation of multiple immune cells at the site of the infection was coined an “immunothrombosis” that was first described in 2013 by B. Engelmann and S. Massberg [78].
COVID-19 is a viral infection with a polymorphic clinical picture determined by the amplitude of immunothrombosis and degree of tissue damage. Studies conducted suggest that coagulopathy in COVID-19 combines local platelet consumption in the lungs, disseminated intravascular coagulation, and thrombotic microangiopathy.
Severe lung inflammation and obstructive pulmonary microvascular immunothrombosis in COVID-19 patients lead to pulmonary thrombosis/thromboembolism, underlying multiple organ failure, and mortality [79].
SARS-CoV-2 mRNA was found in platelets collected from patients with COVID-19 [80]. It is not entirely clear whether SARS-CoV-2 enters platelets via receptormediated endocytosis. SARS-CoV-2 enters host cells by binding to the angiotensin-converting enzyme 2 (ACE2) receptor [81]. Some studies have shown that neither mRNA nor protein ACE2 were found in platelets [82]. Other studies reported platelet ACE2 expression that promoted direct platelet activation by SARSCoV- 2 [83]. This discrepancy may be due to difference in preparation protocol used for washed platelets or genetic differences between patient cohorts.
Platelet activation is one of the arms in COVID-19 pathophysiology. In particular, patients with COVID-19 have abnormal platelet morphology, with large, hyperchromic, and vacuolated platelets [84]. A study found that patients with COVID-19 vs. control subjects had increased platelet activity [85]. Higher number of platelet-monocytic and platelet-granulocyte aggregates indicative of increased systemic platelet activation was observed in patients with COVID-19-associated pneumonia [86]. Platelets during COVID-19 contribute to increased concentration of fibrinogen, von Willebrand factor, and factor XII, which contributes to enhanced XII-dependent coagulation [86]. Platelets from patients with severe COVID-19 induce tissue factor expression in vivo [66].
Various circulating biomarkers such as fibrin/ fibrinogen, D-dimer, P-selectin, von Willebrand factor multimers, soluble thrombomodulin, and tissue factor are of special interest. The basis to consider them as biomarkers is related to cognate receptors and signaling pathways in endothelial cells, platelets, monocytes, and erythrocytes. An open question remains is whether hemostasis may be directly virally affected or whether hemostatic activation occurs secondary to the inflammatory response.
Currently, no consensus on platelet ACE2 expression has been reached yet. Does SARS-CoV-2 bind directly to platelets via ACE2, or are there alternative pathways? Studies in this field may uncover mechanisms of hypercoagulability in cytokine storm. Management of the cytokine storm in severe COVID-19 may include antiplatelet therapy [87]. Acetylsalicylic acid has been shown to reduce the need for mechanical ventilation, the rate of admission to the intensive care unit, and in-hospital mortality in patients hospitalized with COVID-19 [88]. A deeper insight into contribution of platelets to antiviral immunity will increase therapeutic effectiveness of viral infections (Fig. 1).
Figure 1. Platelets and COVID-19 [drawn by authors].
Note: ACE2 – angiotensin-converting enzyme 2 receptors on platelet.
Рисунок 1. Тромбоциты и COVID-19 [рисунок авторов].
Примечание: ACE2 – рецептор ангиотензинпревращающего фермента 2 на тромбоците.
Conclusion / Заключение
Previously recognized as a part of the hemostasis system, in recent years platelets acquired another understanding owing to findings that allowed to put them together with most critical players in the immune response.
Platelets are participants in anti-infective immunity, pathogenesis of autoimmune and chronic inflammatory diseases. The growing interest in platelets is also related to the fact that they may be a new target for developing anti-inflammatory therapy with promising results.
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About the Authors
E. V. Slukhanchuk
Sechenov University; Petrovsky National Research Centre of Surgery
Russian Federation
Russian Federation
Ekaterina V. Slukhanchuk – MD, PhD, Associate Professor, Department of Obstetrics and Gynecology, Filatov Clinical Institute of Children’s Health; Obstetrician-Gynecologist, Department of Abdominal Surgery and Oncology 2
2 bldg. 4, Bolshaya Pirogovskaya Str., Moscow 119991
2 Abrikosovskiy Lane, Moscow 119991
V. O. Bitsadze
Sechenov University
Russian Federation
Russian Federation
Victoria O. Bitsadze – MD, Dr Sci Med, Professor of RAS, Professor, Department of Obstetrics and Gynecology, Filatov Clinical Institute of Children’s Health
Scopus Author ID: 6506003478
Researcher ID: F-8409-2017
2 bldg. 4, Bolshaya Pirogovskaya Str., Moscow 119991
J. Kh. Khizroeva
Sechenov University
Russian Federation
Russian Federation
Jamilya Kh. Khizroeva – MD, Dr Sci Med, Professor, Department of Obstetrics and Gynecology, Filatov Clinical Institute of Children’s Health
Researcher ID: F-8384-2017
2 bldg. 4, Bolshaya Pirogovskaya Str., Moscow 119991
A. G. Solopova
Sechenov University
Russian Federation
Russian Federation
Antonina G. Solopova – MD, Dr Sci Med, Professor, Department of Obstetrics and Gynecology, Filatov Clinical Institute of Children's Health
Scopus Author ID: 6505479504
Researcher ID: Q-1385-2015
2 bldg. 4, Bolshaya Pirogovskaya Str., Moscow 119991
V. I. Tsibizova
Almazov National Medical Research Centre, Health Ministry of Russian Federation
Russian Federation
Russian Federation
Valentina I. Tsibizova – MD, PhD, Obstetrician-Gynecologist, Research Laboratory of Operative Gynecology, Institute of Perinatology and Pediatrics; Physician, Department of Functional and Ultrasound Diagnostics
2 Akkuratova Str., Saint Petersburg 197341
F. Yakubova
Sechenov University
Russian Federation
Russian Federation
Fidan Yakubova – MD, Clinical Resident, Department of Obstetrics and Gynecology, Filatov Clinical Institute of Children’s Health
2 bldg. 4, Bolshaya Pirogovskaya Str., Moscow 119991
C. Ay
University of Vienna
Austria
Austria
Cihan Ay – MD, PhD, Professor, Department of Medicine I, Clinical Division of Haematology and Haemostaseology, Medical University of Vienna
Scopus Author ID: 55356863800
1 Universitatsring, Vienna 1010
J.-C. Gris
Sechenov University; University of Montpellier
France
France
Jean-Christophe Gris – MD, Dr Sci Med, Professor, Department of Obstetrics and Gynecology, Filatov Clinical Institute of Children’s Health
Researcher ID: AAA-2923-2019
2 bldg. 4, Bolshaya Pirogovskaya Str., Moscow 119991
63 Rue Auguste Broussonnet, Montpellier 34090
A. D. Makatsariya
Sechenov University
Russian Federation
Russian Federation
Alexander D. Makatsariya – MD, Dr Sci Med, Academician of RAS, Professor, Head of the Department of Obstetrics and Gynecology, Filatov Clinical Institute of Children’s Health
Scopus Author ID: 57222220144
Researcher ID: M-5660-2016
2 bldg. 4, Bolshaya Pirogovskaya Str., Moscow 119991
Review
For citations:
Slukhanchuk E.V., Bitsadze V.O., Khizroeva J.Kh., Solopova A.G., Tsibizova V.I., Yakubova F., Ay C., Gris J., Makatsariya A.D. The role of platelets in antiviral immunity. Obstetrics, Gynecology and Reproduction. 2022;16(2):204–212. https://doi.org/10.17749/2313-7347/ob.gyn.rep.2022.305
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