ABSTRACT
The global propagation of SARS-CoV-2 leads to an unprecedented public health emergency. Despite that the lungs are the primary organ targeted by COVID-19, systemic endothelial inflammation and dysfunction is observed particularly in patients with severe COVID-19, manifested by elevated endothelial injury markers, endotheliitis, and coagulopathy. Here, we review the clinical characteristics of COVID-19 associated endothelial dysfunction; and the likely pathological mechanisms underlying the disease including direct cell entry or indirect immune overreactions after SARS-CoV-2 infection. In addition, we discuss potential biomarkers that might indicate the disease severity, particularly related to the abnormal development of thrombosis that is a fatal vascular complication of severe COVID-19. Furthermore, we summarize clinical trials targeting the direct and indirect pathological pathways after SARS-CoV-2 infection to prevent or inhibit the virus induced endothelial disorders.
Subject(s)
COVID-19/pathology , Endothelium, Vascular/pathology , SARS-CoV-2 , Adolescent , Adult , Aged , Angiotensin-Converting Enzyme 2/physiology , Animals , COVID-19/blood , COVID-19/complications , COVID-19/physiopathology , COVID-19/therapy , Clinical Trials as Topic , Endothelial Cells/pathology , Endothelial Cells/virology , Endothelium, Vascular/immunology , Endothelium, Vascular/physiopathology , HMGB1 Protein/physiology , Humans , Macaca mulatta , Mice , Neuropilin-1/physiology , Oxidative Stress , Reactive Oxygen Species , Receptors, Virus/physiology , Scavenger Receptors, Class B/physiology , Severity of Illness Index , Signal Transduction , Systemic Inflammatory Response Syndrome/pathology , Systemic Inflammatory Response Syndrome/physiopathology , Thrombophilia/etiology , Thrombophilia/physiopathology , Vascular Endothelial Growth Factor A/physiology , Vasculitis/etiology , Vasculitis/immunology , Vasculitis/physiopathology , Young AdultABSTRACT
Neutrophil extracellular traps (NETs) have been identified as one pathogenetic trigger in severe COVID-19 cases and therefore well-described animal models to understand the influence of NETs in COVID-19 pathogenesis are needed. SARS-CoV-2 infection causes infection and interstitial pneumonia of varying severity in humans and COVID-19 models. Pulmonary as well as peripheral vascular lesions represent a severe, sometimes fatal, disease complication of unknown pathogenesis in COVID-19 patients. Furthermore, neutrophil extracellular traps (NETs), which are known to contribute to vessel inflammation or endothelial damage, have also been shown as potential driver of COVID-19 in humans. Though most studies in animal models describe the pulmonary lesions characterized by interstitial inflammation, type II pneumocyte hyperplasia, edema, fibrin formation and infiltration of macrophages and neutrophils, detailed pathological description of vascular lesions or NETs in COVID-19 animal models are lacking so far. Here we report different types of pulmonary vascular lesions in the golden Syrian hamster model of COVID-19. Vascular lesions included endothelialitis and vasculitis at 3 and 6 days post infection (dpi), and were almost nearly resolved at 14 dpi. Importantly, virus antigen was present in pulmonary lesions, but lacking in vascular alterations. In good correlation to these data, NETs were detected in the lungs of infected animals at 3 and 6 dpi. Hence, the Syrian hamster seems to represent a useful model to further investigate the role of vascular lesions and NETs in COVID-19 pathogenesis.
Subject(s)
COVID-19/pathology , Disease Models, Animal , Extracellular Traps/immunology , Lung/pathology , SARS-CoV-2/pathogenicity , Vasculitis/pathology , Animals , COVID-19/immunology , COVID-19/virology , Cricetinae , Lung/immunology , Lung/virology , Mesocricetus , Vasculitis/immunology , Viral Proteins/metabolismABSTRACT
PURPOSE OF REVIEW: Over the course of the coronavirus disease (COVID-19) pandemic, it has become increasingly clear that there is a high prevalence of neurological complications in people infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). RECENT FINDINGS: Studies of central nervous system (CNS) tissue in brain model systems and from adults with acute SARS-CoV-2 infection have begun to uncover potential mechanisms for neurological damage during COVID-19. These studies suggest that direct viral invasion of the CNS occurs in a subset of cases but does not frequently cause overt viral meningoencephalitis. Vascular abnormalities including microvascular thrombi and endothelial activation, as well as parainfectious processes, including CNS specific immune responses, may contribute to neurological symptoms during acute SARS-CoV-2 infection. SUMMARY: Neuroimmune perturbations and vascular inflammation observed in people with COVID-19 may warrant investigation of immune-modulating interventions to ameliorate neurological complications associated with acute SARS-CoV-2 infection. These therapies may also impact the trajectory of potential long-term complications of COVID-19.
Subject(s)
COVID-19/complications , Nervous System Diseases/etiology , Nervous System Diseases/pathology , Humans , Immunotherapy , Nervous System Diseases/immunology , Nervous System Diseases/therapy , Vasculitis/etiology , Vasculitis/immunologyABSTRACT
OBJECTIVE: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to severe pneumonia, but also thrombotic complications and non-pulmonary organ failure. Recent studies suggest intravascular neutrophil activation and subsequent immune cell-triggered immunothrombosis as a central pathomechanism linking the heterogenous clinical picture of coronavirus disease 2019 (COVID-19). We sought to study whether immunothrombosis is a pathognomonic factor in COVID-19 or a general feature of (viral) pneumonia, as well as to better understand its upstream regulation. APPROACH AND RESULTS: By comparing histopathological specimens of SARS-CoV-2 with influenza-affected lungs, we show that vascular neutrophil recruitment, NETosis, and subsequent immunothrombosis are typical features of severe COVID-19, but less prominent in influenza pneumonia. Activated neutrophils were typically found in physical association with monocytes. To explore this further, we combined clinical data of COVID-19 cases with comprehensive immune cell phenotyping and bronchoalveolar lavage fluid scRNA-seq data. We show that a HLADRlow CD9low monocyte population expands in severe COVID-19, which releases neutrophil chemokines in the lungs, and might in turn explain neutrophil expansion and pulmonary recruitment in the late stages of severe COVID-19. CONCLUSIONS: Our data underline an innate immune cell axis causing vascular inflammation and immunothrombosis in severe SARS-CoV-2 infection.
Subject(s)
COVID-19/immunology , Immunity, Innate , Influenza, Human/immunology , Lung/immunology , Neutrophils/immunology , Thrombosis/immunology , Vasculitis/immunology , COVID-19/diagnosis , COVID-19/virology , Diagnosis, Differential , Host-Pathogen Interactions , Humans , Influenza, Human/diagnosis , Influenza, Human/virology , Lung/pathology , Lung/virology , Neutrophils/virology , Predictive Value of Tests , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Thrombosis/virology , Vasculitis/virologySubject(s)
Antibodies, Viral/immunology , Arthritis, Reactive/immunology , COVID-19/immunology , Immunoglobulin G/immunology , SARS-CoV-2/immunology , Skin Diseases, Vascular/immunology , Vasculitis/immunology , Aged , Arthritis, Reactive/diagnosis , Arthritis, Reactive/drug therapy , C-Reactive Protein/immunology , COVID-19 Serological Testing , Female , Glucocorticoids/therapeutic use , Humans , Knee Joint , Leg Dermatoses/immunology , Prednisolone/therapeutic use , Purpura/immunology , Skin Diseases, Vascular/diagnosis , Skin Diseases, Vascular/drug therapy , Vasculitis/diagnosis , Vasculitis/drug therapySubject(s)
COVID-19/diagnosis , SARS-CoV-2/isolation & purification , Skin Diseases, Vascular/diagnosis , Vasculitis/diagnosis , COVID-19/complications , COVID-19/immunology , COVID-19/virology , Diagnosis, Differential , Erythema Multiforme/diagnosis , Exanthema/diagnosis , Humans , Male , Middle Aged , Mouth Mucosa/blood supply , Mouth Mucosa/pathology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Skin/blood supply , Skin/pathology , Skin Diseases, Vascular/immunology , Skin Diseases, Vascular/pathology , Vasculitis/immunology , Vasculitis/pathologyABSTRACT
The COVID-19 pandemic now totaling 13,000,000 cases and over 571,000 deaths has continued to teach the medical, scientific and lay communities about viral infectious disease in the modern era. Among the many lessons learned for the medical community is the potential for transmissibility and host infectivity of the SARS-CoV-2 virus. Moreover, it has become clear that the virus can affect any organ including the circulatory system, directly via either tissue tropism or indirectly stemming from inflammatory responses in the form of innate immunity, leukocyte debris such as cell-free DNA and histones and RNA viral particles. The following review considers COVID-19-associated vasculitis and vasculopathy as a defining feature of a virus-induced systemic disease with acute, subacute and potential chronic health implications.
Subject(s)
Betacoronavirus/pathogenicity , Blood Vessels/virology , Coronavirus Infections/virology , Pneumonia, Viral/virology , Vasculitis/virology , Animals , Betacoronavirus/immunology , Blood Coagulation , Blood Vessels/immunology , Blood Vessels/pathology , Blood Vessels/physiopathology , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/immunology , Coronavirus Infections/physiopathology , Host-Pathogen Interactions , Humans , Inflammation Mediators/blood , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/immunology , Pneumonia, Viral/physiopathology , Prognosis , Risk Factors , SARS-CoV-2 , Vasculitis/diagnosis , Vasculitis/immunology , Vasculitis/physiopathologySubject(s)
Antigen-Antibody Complex/biosynthesis , Betacoronavirus/pathogenicity , Coronavirus Infections/immunology , Cytokine Release Syndrome/immunology , Immune Complex Diseases/immunology , Pneumonia, Viral/immunology , Severe Acute Respiratory Syndrome/immunology , Vasculitis/immunology , Antibodies, Viral/biosynthesis , Antigen-Antibody Complex/drug effects , Betacoronavirus/immunology , Blood Vessels/drug effects , Blood Vessels/immunology , Blood Vessels/pathology , Blood Vessels/virology , COVID-19 , Complement C3/antagonists & inhibitors , Complement C3/biosynthesis , Complement Inactivating Agents/therapeutic use , Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/virology , Humans , Immune Complex Diseases/complications , Immune Complex Diseases/drug therapy , Immune Complex Diseases/virology , Immunity, Humoral/drug effects , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Interleukin-6/antagonists & inhibitors , Interleukin-6/biosynthesis , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Receptors, Interleukin-1/antagonists & inhibitors , Receptors, Interleukin-1/biosynthesis , SARS-CoV-2 , Severe Acute Respiratory Syndrome/complications , Severe Acute Respiratory Syndrome/drug therapy , Severe Acute Respiratory Syndrome/virology , Severity of Illness Index , Vasculitis/complications , Vasculitis/drug therapy , Vasculitis/virologyABSTRACT
Coronavirus Disease 2019 (COVID-19) is an ongoing public health emergency and new knowledge about its immunopathogenic mechanisms is deemed necessary in the attempt to reduce the death burden, globally. For the first time in worldwide literature, we provide scientific evidence that in COVID-19 vasculitis a life-threatening escalation from type 2 T-helper immune response (humoral immunity) to type 3 hypersensitivity (immune complex disease) takes place. The subsequent deposition of immune complexes inside the vascular walls is supposed to induce a severe inflammatory state and a cytokine release syndrome, whose interleukin-6 is the key myokine, from the smooth muscle cells of blood vessels.