Platelets and Immunity
2020; Lippincott Williams & Wilkins; Volume: 40; Issue: 7 Linguagem: Inglês
10.1161/atvbaha.120.314620
ISSN1524-4636
AutoresMilka Koupenova, Jane E. Freedman,
Tópico(s)Inflammasome and immune disorders
ResumoHomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 40, No. 7Platelets and Immunity Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBPlatelets and ImmunityGoing Viral Milka Koupenova and Jane E. Freedman Milka KoupenovaMilka Koupenova From the Department of Medicine, University of Massachusetts Medical School, Worcester. and Jane E. FreedmanJane E. Freedman Correspondence to: Jane Freedman, MD, University of Massachusetts Medical School, Albert Sherman Center, 368 Plantation St, S7-1051, Worcester, MA 01605. Email E-mail Address: [email protected] From the Department of Medicine, University of Massachusetts Medical School, Worcester. Originally published24 Jun 2020https://doi.org/10.1161/ATVBAHA.120.314620Arteriosclerosis, Thrombosis, and Vascular Biology. 2020;40:1605–1607This article is a commentary on the followingPlatelets Endocytose Viral Particles and Are Activated via TLR (Toll-Like Receptor) SignalingPlatelets are the major blood component bridging immunity and thrombosis. Abundant in the circulation, platelets encounter pathogens at a higher rate than any circulating leukocyte. Viral particles of various blood-borne pathogens such as HIV,1 dengue,2 or even respiratory viruses such as influenza3 are found inside human platelets. Viral infections with these viruses,4 as well as the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), can lead to thrombocytopenia5 along with thrombotic complications6–8 in patients. The presence of internalized viral particles, thrombocytopenia, and thrombosis implicates platelets as active participants in immunity during viral infections.See accompanying article on page 1635Influenza, HIV, and SARS-CoV-2 are classified as single-stranded RNA (ssRNA) viruses. Although there are differences in the overall immunity to blood-borne versus respiratory RNA viruses, the initial response to these pathogens by the host's cells is achieved by the endosomal TLR (Toll-like receptors).9 In human cells, TLR7 and TLR8 are the receptors that mediate a response to degraded viral ssRNA.9,10 Endosomal TLRs require the acidic pH of these compartments for proper vRNA (viral RNA) recognition, activation, and signaling. Another endosomal receptor, TLR9, is activated by microbial (bacterial or viral) or mitochondrial DNA.9The involvement of platelets in the initial viral immune response is evident by the expression of functional TLRs. Human platelets can express all 10 TLRs,11 and platelets mediate the initial response to single-stranded viruses such as influenza or encephalomyocarditis through TLR7.3,12 Activation of platelet-TLR7 leads to AKT (protein kinase B) and p38-MAPK (p38 MAP kinase) phosphorylation,12 α-granule release,3,12 P-selectin and CD40L surface expression,12 complement C3 release,3 platelet-neutrophil aggregate formation,12 and platelets-mediated neutrophil DNA release.3 Although the ssRNA viral activation of platelet-TLR7 and the consequent neutrophil engagement have been described, the precise mechanism of platelet viral uptake and granule release remains unknown.In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Banerjee et al13 provide a mechanism by which platelets endocytose viral particles such as HIV and elucidate the downstream TLR7-signaling cascade. Using HIV pseudo particles (HIVpp), the authors elegantly show that the proteins important for the endocytic internalization of HIV are ARF6 (ADP ribosylation factor 6) and VAMP3 (vesicle-associated membrane protein 3),13 proteins generally responsible for endocytosis in platelets.14,15 Interestingly, Banerjee et al13 show that platelets contain early (Rab4) and late endosomes (Rab7), suggesting that lysosomes are not the only organelles of the endocytic membrane transport pathway. As with stimulation by the TLR7-specific agonist loxoribine,12 activation of TLR7 by HIVpp required acidic pH.12,13 Using various genetically modified murine models, the authors show that platelet-TLR7 needs MyD88 (myeloid differentiation primary response 88) to relay the downstream signal in a IRAK4-IKKb-SNAP-23 (interleukin 1 receptor-associated kinase/inhibitor of nuclear factor kappa-B kinase/synaptosome-associated protein 23) manner.13 Activation of this signaling cascade resulted in α-granule release, P-selectin surface expression, and interaction of platelets with leukocytes.13 Similarly to TLR7, platelet-TLR9 engaged the same signaling mechanism and also led to platelet-leukocyte aggregate formation.13 Because TLR7 and TLR9 mediate a response to different pathogen species (RNA viruses versus bacteria or DNA viruses, respectively), additional work is needed to clarify the similarities or differences in consequent platelet-leukocyte interactions. Banerjee et al also observed an increase in α2bβ3 (glycoprotein IIb/IIIa) activation when platelets were stimulated with HIVpp.13 Interestingly, increase in α2bβ3 activation and aggregation are not observed when human platelets are stimulated by a TLR7-specific agonist.12 This is not surprising as TLR7 is a dual receptor with distinct ligand-binding sites, the first recognizes guanosine and the second binds to uridine in single-stranded vRNA, enhancing the affinity of the first.16 Differences in TLR7 agonist– versus HIVpp-stimulated platelets can also indicate that there are additional receptors, such as TLR8, that may be involved in the mediation of an immune response to different RNA viruses.Active participation of platelets in a response to ssRNA viruses takes on greater importance during the current COVID-19 pandemic. SARS-CoV-2 is also an ssRNA virus but, contrary to HIV, it does not incorporate into the host's DNA, is short lived, and, similar to influenza, is classified as a respiratory virus. Despite these differences, if SARS-CoV-2 is internalized by platelets via receptor-mediated endocytosis, the initial response to the vRNA would likely be mediated by TLR7; however, this remains to be investigated. Based on known interactions between influenza and human platelets,3 SARS-CoV-2 would likely crossover into the circulation and become internalized by platelets. Transmission electron micrographs of human platelets in the presence of influenza3 suggest that the endocytic/lysosomal pathway described by Banerjee et al is likely a uniform mechanism of viral endocytosis. As with influenza infection, the internalized SARS-CoV-2 could activate platelet-TLR7 and initiate granule release of complement C3 (C3),3 which, in turn, could lead to NETosis.3 Although NETosis is beneficial to the host,17 when dysregulated, it can become highly thrombotic.18 It is possible that SARS-CoV-2 initiates a similar cascade of events after TLR7 activation (Figure). As COVID-19 progresses, NETosis could be amplified through tissue factor release from the damaged tissue. Tissue factor–mediated thrombin generation is known to increase platelet aggregation, C3 release from platelets,3 and C3 activation.19 Such activation of the complement cascade7 and endothelial compromise are evident in COVID-19 patients.20 However, while receptors for influenza and HIV are expressed on platelets, it remains unclear if the receptor for SARS-CoV-2, ACE2 (angiotensin-converting enzyme 2), is present. Studies are necessary to determine if platelet-TLR7 mediates the response to SARS-CoV-2 in a MyD88-IRAK-IKKb-SNAP23-C3–dependent manner and if this virus gets internalized similarly to HIVpp or influenza.Download figureDownload PowerPointFigure. Activation of platelets by HIV pseudo particles (HIVpp) and influenza and proposed activation of platelet-TLR7 (Toll-like receptor 7) by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). If SARS-CoV-2 (similarly to influenza or HIVpp) can be endocytosed by platelets, its degraded ssRNA would be first recognized by TLR7. Activation of TLR7 in a MyD88-IRAK-IKKb-SNAP23 (myeloid differentiation primary response 88/interleukin 1 receptor-associated kinase/inhibitor of nuclear factor kappa-B kinase/synaptosome-associated protein 23)–dependent signaling would lead to P-selectin/CD40L surface expression and complement C3 release from α-granules. P-selectin and CD40L would mediate platelet-leukocyte interactions (predominantly neutrophils). C3 release would increase neutrophil DNA release and ensures viral capture and removal. As viral infection progresses, C3-mediated NETosis may be augmented by thrombin generated as a result of tissue factor (TF) released from damaged tissue; thrombin will also directly increase thrombosis. During coronavirus disease 2019 (COVID-19), TLR9 (Toll-like receptor 9) could also contribute to platelet activation and possible C3 release. TLR9 can be activated by mitochondrial-DNA, and mitochondrial-DNA levels can be increased with tissue damage (or in the setting of obesity). Platelet-TLR9, similarly to TLR7, signals through the MyD88-IRAK-IKKb-SNAP23 pathway, leading to granule release. It is not currently known if platelets can release C3 or NETosis in a TLR9-dependent manner. IRAK1 indicates interleukin 1 receptor-associated kinase 1; IRAK4, interleukin 1 receptor-associated kinase 4; TAK1, transforming growth factor β-activated kinase 1; and TRAF6, tumor necrosis factor receptor (TNFR)-associated factor 6.In summary, the study by Banerjee et al adds to the understanding of functional platelet-TLR73,12,13 and provides evidence for the endocytic membrane transport pathway in platelets.13 Activation of TLR7 by ssRNA from various viruses leads to platelet-neutrophil aggregates,12,14 NETosis,3 and eventual thrombocytopenia.12 Although removal of viral particles from the circulation by NETosis is a vital part of the immune process, under settings of dysregulation, it can lead to pathological thrombosis and vessel occlusion. The ability of platelets to carefully balance immunity and thrombosis demonstrates their increasingly important role during viral infections.Sources of FundingM. Koupenova and J.E. Freedman are funded by an American Heart Association (AHA) coronavirus disease 2019 (COVID-19) Rapid Response Award.DisclosuresNone.FootnotesFor Sources of Funding and Disclosures, see page 1607.Correspondence to: Jane Freedman, MD, University of Massachusetts Medical School, Albert Sherman Center, 368 Plantation St, S7-1051, Worcester, MA 01605. Email jane.[email protected]eduReferences1. Youssefian T, Drouin A, Massé JM, Guichard J, Cramer EM. Host defense role of platelets: engulfment of HIV and Staphylococcus aureus occurs in a specific subcellular compartment and is enhanced by platelet activation.Blood. 2002; 99:4021–4029. doi: 10.1182/blood-2001-12-0191CrossrefMedlineGoogle Scholar2. Noisakran S, Gibbons RV, Songprakhon P, Jairungsri A, Ajariyakhajorn C, Nisalak A, Jarman RG, Malasit P, Chokephaibulkit K, Perng GC. Detection of dengue virus in platelets isolated from dengue patients.Southeast Asian J Trop Med Public Health. 2009; 40:253–262.MedlineGoogle Scholar3. 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Arteriosclerosis, Thrombosis, and Vascular Biology. 2020;40:1635-1650 July 2020Vol 40, Issue 7 Advertisement Article InformationMetrics © 2020 American Heart Association, Inc.https://doi.org/10.1161/ATVBAHA.120.314620PMID: 32579477 Originally publishedJune 24, 2020 Keywordsblood-borne pathogensCOVID-19plateletsEditorialsthrombosisHIVPDF download Advertisement SubjectsCardiovascular SurgeryNuclear Cardiology and PETVascular Disease
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