Challenging the notion of endothelial infection by SARS-CoV-2: insights from the current scientific evidence

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: Feb. 4, 2025

IntroductionCoronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, is a public health emergency with phenotypes ranging from asymptomatic to severe sequelae that can lead multiple organ failure and death (1, 2). SARS-CoV-2 efficiently infects airway epithelial cells alveolar pneumocytes, causing in high viral loads inflammatory responses, including the interferon response (3). In hospitalized patients, COVID-19 increases risk of venous arterial thromboembolic events due vascular barrier failure, edema, endotheliitis, thrombosis, cell infiltration (4, 5). Hypercoagulation micro- macro-circulatory thrombosis are major causes (6). Although many people have survived without long-term symptoms, considerable portion survivors reportedly continuing cardiovascular issues such as coagulopathy or bleeding disorders (7). This suggests that, addition respiratory epithelium, endothelium lining blood vessels may also be impacted infection. The pathophysiology has been explored recent reviews (reviewed (8, 9)). Due conflicting data, there ongoing controversy about endothelial tropism (refers ability interact cells) productive infection (viral replication within ECs) SARS-CoV-2. Here, we share our perspective on challenging notion infection, drawing insights current scientific evidence.Endothelial dysfunction hypercoagulation COVID-19The endothelium, which lines inside arteries, crucial for controlling tone preserving homeostasis (10). Disseminated intravascular coagulation (DIC), vasculitis, all attributable damage (11, 12). Numerous prevalent viruses bacteria found directly infect ECs, necrosis, apoptosis and/or vessel wall (13-15). Upon Dengue, Hantaan, Marburg, Lassa, Ebola, both immune non-immune (including cells, monocytes, macrophages) express tissue factor (TF), leading often culminating disseminated (DIC) (16-20). Studies demonstrated Marburg (ECs) replicate them, reviewed detail elsewhere (13, 21, 22). However, it remains unclear whether exhibits similar phenomenon observations. less studied than epithelium pneumocytes (10, 23-25). Despite thromboprophylaxis, 31-49% care patients had thromboembolism (26-30). shows impairment must addressed aggressively prevent thrombosis. driven lung-induced systemic inflammation upon injury direct Several pro-inflammatory cytokines TNF-α, IL-1α, IL-1β, IL-6, IL-8, MCP-1, IFN- responsible cytokine storm (31, 32) induce COVID-19-associated (CAC) via expression TF macrophages T (33-40). IL-6 signaling complex damages liver sinusoidal ECs produces injury, suggesting cause (41). Syrian hamster model showed type I dysregulation non-respiratory tissues like heart kidney, shedding light multiorgan possible post-acute (42). Spike Nucleocapsid protein activate inducing mitochondrial dysfunction, vasculopathy, (43, 44) (Figure 1). Furthermore, study early host declines aging, potentially contributing increased severity (45).Proposed novel (co)-receptors entry SARS-CoV utilize human ACE2 an receptor TMPRSS2, primarily expressed digestive tracts, co-factor degrade extracellular matrix proteins (46). variably smooth muscle pericytes across organs, facilitating dissemination into circulatory system. studies, in-house immunohistochemistry, humanized mice hACE2 brain but not lung, gastrointestinal, renal vessels, employ hACE2-dependent independent mechanisms (47) 1B). Low TMPRSS2 limits (48). Thus, variations different microvascular beds, alternative receptors facilitate infectious particles. Supporting this concept, numerous additional identified over past three years relevant particle ECs. Endosomal cysteine peptidases cathepsins B L spike (S) protein, enhancing (49-51). binds heparan sulfate, sialic acid-containing glycoproteins, gangliosides (52, 53). Proteolytic cleavage at furin-type sites S exposes conserved motif interacts Neuropilin-1/2 receptors, significantly increasing infectivity (54, 55). Vimentin, CD147, TMEM106B co-receptors though role pathology lacks experimental validation (56-59). Further research needed confirm these vivo relevance.Controversies Endotheliitis regarded immune-inflammatory forming inner surface association consequence pathogen invasion. Systemic endotheliitis (60). Human autopsies, non-human primates (NHPs) models sporadic consistently observed hamsters (61, 62). Compared healthy individuals, circulating markers platelet activation elevated (63). Evidence myeloid polarization, levels shed CD16 CD163, linked proinflammatory related poor clinical outcomes (64). Elevated D-dimer thrombocytopenia could explained dysregulated microthrombus formation complicated (65). Consecutively, COVID-19, hypoxia pulmonary might classic acute distress syndrome (ARDS) (66). compared controls, isolated lungs challenged lipopolysaccharide tumor necrosis alpha pro-coagulant activity PAI-1, decreased fibrinolytic potential, emphasizing features ARDS (67).Earlier studies support particles were detected highly vascularized organs plays fundamental (24, 68-76). Initial transmission electron microscopy (TEM) revealed presence kidney autopsy samples (76-78). owing challenges interpreting TEM variability experience those images, debatable (76, 79, 80). Irrespective controversies, evidence indicate coated vesicles multivesicular bodies closely mimic even lung uncommonly misinterpreted (81). thrombo-inflammatory phenotype, no definitive animal biopsies yet shown (82-85). macrovascular resistant overexpression necessary (86-89). Montezano et al. recombinant protein-1 induced enzymatic vitro (90). On ex cultures patient who signs virus following immunohistochemical labeling (91). primed (IL-1) produced more cytokines, (92). two separate investigations (MOI=0.5-3 after 2 hours adsorption) (93, 94).Based findings, hypothesize prior reports universal hallmark illness restricted certain groups episodes. this, carefully evaluated immunoreactivity (N) Protein slices translational preclinical (transgenic K18-hACE2 (expression cells), hACE2-KI (global knock-in replacing mouse ACE2), hamsters, African green monkeys (AGM) postmortem samples. A board-certified veterinary pathologist (N.A.C.) immunohistochemically analyzed hundreds previous each species (45, 61, 62, 69, 95-99). PCR-positive clear hyaline membrane AGMs 7 days post-infection (dpi) N Protein, antigen only present during phase 2A 2B). K18-hACE2, NHPs, ACE2-KI varying decreasing hamsters. No antigens 2C-E). To further absence performed duplex fluorescent IHC targeting (CD34 CD31) protein. AGM mouse, luminal exclusively displayed evidenced colocalization 4DPI 2F-G). EC mediators COVID-19Collectively, findings group others question universality SARS- CoV-2's infectivity. Because active associated pro-inflammation, activating immunothrombosis complement activation, antiphospholipid antibodies, so on. treated sera (n=118) anti-cardiolipin IgG/IgM anti-phosphatidlyserine/prothrombin (anti-PS/PT) IgG/IgM-driven elevation adhesion E-selectin, VCAM-1, ICAM-1 (100-102). Infection-induced IL1β, TNFα, stimulate coagulation, influence thrombin generation, fibrin formation, TF-dependent responses protease-activated (PARs) (6, 103-107) 2H). induces production superoxide anion release DNA (mtDNA), Toll-like 9 (TLR9) NFκ-B. Consequently, orchestrates genes, pathological processes (108). highlighted changes lipid profiles COVID-19. Among most commonly reductions serum cholesterol ApoA1 levels, coupled triglycerides (109). Lipidomic analysis eicosanoids potential contributor dysfunction. aberrant (ECM) controls balance repair (110). confirmed Hyaluronan important compound ECM vital systems (111). characterized MMP-1 growth (VEGF)-A, correlated (112). More 50% experienced moderate cases reduced diffusion fibrotic changes, (113). detailed (114).The glycocalyx (EG) maintaining homeostasis, (115). EG surface, plasma components syndecan-1, hyaluronan. These biomarkers, along hsCRP, procalcitonin, mortality (116-118). despite underlying still fully understood (118-122). several drugs, heparin tocilizumab, already being used treatment protect (123-126). Marine algae extracts, fucoidan rhamnan sulfate (RS) restore (127, 128). Specifically, fucoidan, (HS) mimetic, reduce restoration serum(125). Vascular targeted therapy (84, 129, 130). drugs exhibit multifunctional properties; however, agents specifically aimed improving structure integrity reported date. Nevertheless, regimens protection applied practice patients. approaches comprehensively (129, 131). Most extracellularvesicles (EVs) originate platelets erythrocytes (132). Under physiological conditions, proportion EVs secreted relatively low, notably conditions marked released contain markers, endoglin/CD105, E-selectinCD62E, S-endo/CD146, cadherin/CD144, molecule 1/ CD31, intercellular 1 /CD54 (133). carrying bloodstream thereby COVID-19-related (134, 135). Given critical prospective appears preexisting various states (e.g., diabetes, atherosclerosis, hypertension) vulnerable course (136). For instance, among comorbidities, diabetes mellitus (DM) was frequently (10.9% cases) condition (137). China, Europe, UK US when DM acquire they likely develop complications, require ICU hospitalization, die (138-140). root chronic together SARS-CoV-2-mediated result microcirculation multi-organ failure.ConclusionExperimental unlikely productively cells. Instead, mediators, components, vesicles, lipids/lipoproteins, thrombin, primary drivers Additionally, accumulating indicates disrupts altering permeability, adhesion, mechanosensing, antithrombotic anti-inflammatory functions.Given mixed involvement (co)-receptors, needed. First, developing better demonstrate help identify validate Second, possibility enters effective replication. trigger significant signaling, rapid RNA degradation render undetectable. hypotheses warrant investigation.Besides, variation detection methodological differences, sampling techniques, sensitivity methods, models. addition, biological variability, differences population severity, lay studies. systematic review required contributes discrepancies. tested researchers dissect out pathogen-host interactions effects interventions, progression, between animals humans relevance findings.Alternatively, infected cleared system mechanisms, phagocytosis macrophages, through responses. make detect infections layer, removed before adequately identified. considering typically sample time points, likelihood occurring low. investigate draw well-informed conclusion, ensuring clearance accounted analysis.Nonetheless, confirms making therapeutic target. Addressing individuals hyperinflammation hypercoagulation. mitigate pro-thrombotic International Society Thrombosis Haemostasis (ISTH) recommends standard thromboprophylaxis low molecular weight unfractionated (LMWH/UFH) unless contraindicated (141).

Language: Английский

Superficial Vein Thrombosis in an Asymptomatic Case of Cholangiocarcinoma with Recent History of COVID-19

Life, Journal Year: 2024, Volume and Issue: 14(9), P. 1095 - 1095

Published: Aug. 30, 2024

The COVID-19 pandemic brought into prominence several emergent medical and surgical entities, but, also, it served as trigger contributor for numerous apparently unrelated ailments such arterial venous thromboembolic complications. Additional risk factors these thrombotic traits may be concurrent (known or unknown) malignancies, including at hepatic level. Among these, cholangiocarcinoma (CCA), a rare cancer of intra- extra-hepatic biliary ducts, represents very aggressive condition that typically associates local distant advanced stages on first presentation requiring prompt diagnosis stratified management. This neoplasia has been reported to present large spectrum paraneoplastic syndromes in terms dermatologic, renal, systemic, neurologic, endocrine, cardiovascular settings, that, overall, are exceptional their epidemiologic impact when compared other cancers. Our aim was introduce most unusual case CCA-associated thrombosis male adult who initially considered experience COVID-19-related features while having history obesity bariatric surgery. is hybrid type paper: this clinical vignette accompanied by two distinct sample-focused analyses basis discussion; they each had different methods depending current level statistical evidence. We only included English-published articles PubMed, follows: Firstly, we conducted search reports similar the case, regarding vein CCA, from inception until time. performed literature using keywords “cholangiocarcinoma”, “thrombosis”, “Trousseau’s syndrome” identified 20 cases across 19 original papers; hence, evidence remains low Secondly, searched highest concerning thrombosis/thromboembolism patients underwent infection (key were “COVID-19”, alternatively, “coronavirus”, “SARS-CoV-2”, “thromboembolism”) recent systematic reviews meta-analyses published 2024 (from 1 January 8 July 2024). After excluding data vaccination against coronavirus long syndrome, six articles. To conclude, presented probably unique malignancy with an initial manifestation consisting recurrent superficial under anticoagulation therapy, no gastrointestinal manifestations, patient notable multiple episodes SARS-CoV-2 prior endocrine (gastric) our knowledge, identification CCA specific circumstances.

Language: Английский