{"doi":"10.3389/fimmu.2025.1443932","title":"Challenging the notion of endothelial infection by SARS-CoV-2: insights from the current scientific evidence","abstract":"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 to multiple organ failure and death (1, 2). SARS-CoV-2 efficiently infects airway epithelial cells and alveolar pneumocytes, causing in high viral loads and inflammatory responses, including the interferon response (3). In hospitalized patients, COVID-19 increases the risk of venous and arterial thromboembolic events due to vascular barrier failure, edema, endotheliitis, thrombosis, and inflammatory cell infiltration (4, 5). Hypercoagulation and micro- and macro-circulatory thrombosis are major causes of multiple organ failure in COVID-19 (6). Although many people have survived COVID-19 without long-term symptoms, a considerable portion of COVID-19 survivors reportedly have continuing cardiovascular issues such as coagulopathy or bleeding disorders (7). This suggests that, in addition to the respiratory epithelium, the endothelium lining of blood vessels may also be impacted by SARS-CoV-2 infection. The pathophysiology of COVID-19 has been explored in recent reviews (reviewed in (8, 9)). Due to the conflicting data, there is ongoing controversy about the endothelial tropism (refers to the ability of SARS-CoV-2 to interact with endothelial cells) and productive endothelial infection (viral replication within the ECs) of SARS-CoV-2. Here, we share our perspective on challenging the notion of endothelial tropism and productive endothelial infection, drawing insights from the current scientific evidence.Endothelial dysfunction and hypercoagulation in COVID-19The endothelium, which lines the inside of arteries, is crucial for controlling vascular tone and preserving vascular homeostasis (10). Disseminated intravascular coagulation (DIC), vasculitis, and thrombosis can all be attributable to endothelial damage (11, 12). Numerous prevalent viruses and bacteria have been found to directly infect ECs, causing necrosis, apoptosis and/or damage to the vessel wall (13-15). Upon infection by viruses such as Dengue, Hantaan, Marburg, Lassa, and Ebola, both immune and non-immune cells (including endothelial cells, monocytes, and macrophages) express tissue factor (TF), leading to hypercoagulation and often culminating in disseminated intravascular coagulation (DIC) (16-20). Studies have demonstrated that Dengue, Ebola, and Marburg viruses can directly infect endothelial cells (ECs) and replicate within them, as reviewed in detail elsewhere (13, 21, 22). However, it remains unclear whether SARS-CoV-2 exhibits a similar phenomenon due to conflicting observations. SARS-CoV-2 infection of endothelium is less studied than airway epithelium and alveolar pneumocytes (10, 23-25). Despite thromboprophylaxis, 31-49% of COVID-19 emergency care patients had arterial and venous thromboembolism (26-30). This shows that endothelial impairment must be addressed aggressively to prevent thrombosis. However, it is unclear whether the hypercoagulation is driven by lung-induced systemic inflammation upon infection, or by endothelial injury or dysfunction due to direct SARS-CoV-2 infection. Several pro-inflammatory cytokines including TNF-α, IL-1α, IL-1β, IL-6, IL-8, MCP-1, IFN- that are responsible for the cytokine storm in COVID-19 (31, 32) may induce COVID-19-associated coagulopathy (CAC) via expression of TF on ECs, monocytes, macrophages and T cells (33-40). The IL-6 signaling complex damages liver sinusoidal ECs and produces liver injury, suggesting that endothelial dysfunction and hypercoagulation may cause severe COVID-19 (41). SARS-CoV-2 infection in the Syrian hamster model showed inflammation and type I interferon dysregulation in respiratory and non-respiratory tissues like the heart and kidney, shedding light on COVID-19 as a multiorgan disease and possible post-acute sequelae (42). SARS-CoV-2 Spike and Nucleocapsid protein directly activate ECs, inducing mitochondrial dysfunct","journal":"Frontiers in Immunology","year":2025,"id":538693,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9618,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1191239,"name":"Asha Jose","orcid":"0000-0001-8519-9386","position":1,"is_corresponding":false},{"id":471417,"name":"Devin Kenney","orcid":"0000-0002-8758-1930","position":2,"is_corresponding":false},{"id":817251,"name":"Aoife K. O’Connell","orcid":"0000-0001-7027-4267","position":3,"is_corresponding":false},{"id":232297,"name":"Markus Bosmann","orcid":"0000-0003-2773-1033","position":4,"is_corresponding":false},{"id":642525,"name":"Florian Douam","orcid":"0000-0002-4791-6767","position":5,"is_corresponding":false},{"id":559047,"name":"Nicholas A. Crossland","orcid":"0000-0003-3873-9188","position":6,"is_corresponding":false},{"id":714112,"name":"Saravanan Subramaniam","orcid":"0000-0002-0194-5044","position":0,"is_corresponding":true}],"reference_count":139,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:52:25.799399Z","pmid":"39967675","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}