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1.
Cell Mol Immunol ; 2022 Jan 05.
Article in English | MEDLINE | ID: covidwho-1603596

ABSTRACT

Since the beginning of the COVID-19 pandemic, multiple SARS-CoV-2 variants have emerged. While some variants spread only locally, others, referred to as variants of concern, disseminated globally and became drivers of the pandemic. All SARS-CoV-2 variants harbor mutations relative to the virus circulating early in the pandemic, and mutations in the viral spike (S) protein are considered of particular relevance since the S protein mediates host cell entry and constitutes the key target of the neutralizing antibody response. As a consequence, mutations in the S protein may increase SARS-CoV-2 infectivity and enable its evasion of neutralizing antibodies. Furthermore, mutations in the S protein can modulate viral transmissibility and pathogenicity.

2.
Front Immunol ; 12: 784989, 2021.
Article in English | MEDLINE | ID: covidwho-1603282

ABSTRACT

Effective treatment strategies for severe coronavirus disease (COVID-19) remain scarce. Hydrolysis of membrane-embedded, inert sphingomyelin by stress responsive sphingomyelinases is a hallmark of adaptive responses and cellular repair. As demonstrated in experimental and observational clinical studies, the transient and stress-triggered release of a sphingomyelinase, SMPD1, into circulation and subsequent ceramide generation provides a promising target for FDA-approved drugs. Here, we report the activation of sphingomyelinase-ceramide pathway in 23 intensive care patients with severe COVID-19. We observed an increase of circulating activity of sphingomyelinase with subsequent derangement of sphingolipids in serum lipoproteins and from red blood cells (RBC). Consistent with increased ceramide levels derived from the inert membrane constituent sphingomyelin, increased activity of acid sphingomyelinase (ASM) accurately distinguished the patient cohort undergoing intensive care from healthy controls. Positive correlational analyses with biomarkers of severe clinical phenotype support the concept of an essential pathophysiological role of ASM in the course of SARS-CoV-2 infection as well as of a promising role for functional inhibition with anti-inflammatory agents in SARS-CoV-2 infection as also proposed in independent observational studies. We conclude that large-sized multicenter, interventional trials are now needed to evaluate the potential benefit of functional inhibition of this sphingomyelinase in critically ill patients with COVID-19.

3.
Cell ; 2021 Dec 24.
Article in English | MEDLINE | ID: covidwho-1588147

ABSTRACT

The rapid spread of the SARS-CoV-2 Omicron variant suggests that the virus might become globally dominant. Further, the high number of mutations in the viral spike protein raised concerns that the virus might evade antibodies induced by infection or vaccination. Here, we report that the Omicron spike was resistant against most therapeutic antibodies but remained susceptible to inhibition by sotrovimab. Similarly, the Omicron spike evaded neutralization by antibodies from convalescent patients or individuals vaccinated with the BioNTech-Pfizer vaccine (BNT162b2) with 12- to 44-fold higher efficiency than the spike of the Delta variant. Neutralization of the Omicron spike by antibodies induced upon heterologous ChAdOx1 (Astra Zeneca-Oxford)/BNT162b2 vaccination or vaccination with three doses of BNT162b2 was more efficient, but the Omicron spike still evaded neutralization more efficiently than the Delta spike. These findings indicate that most therapeutic antibodies will be ineffective against the Omicron variant and that double immunization with BNT162b2 might not adequately protect against severe disease induced by this variant.

4.
Clin Infect Dis ; 73(11): 2000-2008, 2021 12 06.
Article in English | MEDLINE | ID: covidwho-1559548

ABSTRACT

BACKGROUND: Vaccine-induced neutralizing antibodies are key in combating the coronavirus disease 2019 (COVID-19) pandemic. However, delays of boost immunization due to limited availability of vaccines may leave individuals vulnerable to infection and prolonged or severe disease courses. The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC)-B.1.1.7 (United Kingdom), B.1.351 (South Africa), and P.1 (Brazil)-may exacerbate this issue, as the latter two are able to evade control by antibodies. METHODS: We assessed humoral and T-cell responses against SARS-CoV-2 wild-type (WT), VOC, and endemic human coronaviruses (hCoVs) that were induced after single and double vaccination with BNT162b2. RESULTS: Despite readily detectable immunoglobulin G (IgG) against the receptor-binding domain of the SARS-CoV-2 S protein at day 14 after a single vaccination, inhibition of SARS-CoV-2 S-driven host cell entry was weak and particularly low for the B.1.351 variant. Frequencies of SARS-CoV-2 WT and VOC-specific T cells were low in many vaccinees after application of a single dose and influenced by immunity against endemic hCoV. The second vaccination significantly boosted T-cell frequencies reactive for WT and B.1.1.7 and B.1.351 variants. CONCLUSIONS: These results call into question whether neutralizing antibodies significantly contribute to protection against COVID-19 upon single vaccination and suggest that cellular immunity is central for the early defenses against COVID-19.

5.
Biomedicines ; 9(12)2021 Dec 05.
Article in English | MEDLINE | ID: covidwho-1554994

ABSTRACT

In critically ill patients, liver dysfunction often results in coagulopathy and encephalopathy and is associated with high mortality. Extracorporeal clearance of hepatotoxic metabolites, including bilirubin and ammonia, aims to attenuate further hepatocyte damage and liver injury, resulting in decreased mortality. The efficacy of hemadsorption combined with conventional hemodialysis to eliminate bilirubin and ammonia to support the liver's excretory function in acute liver injury has been described previously. However, the optimal use of liver support systems in chronic liver dysfunction due to secondary sclerosing cholangitis in critically ill patients (SSC-CIP) has not been defined yet. We herein describe the kinetics of successful bilirubin and ammonia elimination by hemadsorption in a patient with SSC-CIP after extracorporeal membrane oxygenation (ECMO) therapy for severe acute respiratory distress syndrome (ARDS) in a patient with coronavirus disease 2019 (COVID-19). During the course of the disease, the patient developed laboratory signs of liver injury during ECMO therapy before clinically detectable jaundice or elevated bilirubin levels. A diagnosis of SSC-CIP was confirmed by endoscopic retrograde cholangiopancreatography (ERCP) based on intraductal filling defects in the intrahepatic bile ducts due to biliary casts. The patient showed stable elevations of bilirubin and ammonia levels thereafter, but presented with progressive nausea, vomiting, weakness, and exhaustion. Based on these laboratory findings, hemadsorption was combined with hemodialysis treatment and successfully eliminated bilirubin and ammonia. Moreover, direct comparison revealed that ammonia is more efficiently eliminated by hemadsorption than bilirubin levels. Clinical symptoms of nausea, vomiting, weakness, and exhaustion improved. In summary, bilirubin and ammonia were successfully eliminated by hemadsorption combined with hemodialysis treatment in SSC-CIP following ECMO therapy and severe COVID-19. This observation is particularly relevant since it has been reported that a considerable subset of critically ill patients with COVID-19 suffer from liver dysfunction associated with high mortality.

6.
Scand J Trauma Resusc Emerg Med ; 29(1): 155, 2021 Oct 30.
Article in English | MEDLINE | ID: covidwho-1486111

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a highly contagious airborne virus inducing pandemic coronavirus disease 2019 (COVID-19). This is most relevant for medical staff working under harmful conditions in emergencies often dealing with patients and an undefined SARS-CoV-2 status. We aimed to measure the effect of high-class filtering facepieces (FFP) in emergency medical service (EMS) staff by analyzing seroprevalence and history of positive polymerase chain reaction (PCR) for SARS-CoV-2. METHOD: This observational cohort study included workers in EMS, who were compared with hospital staff (HS) and staff, which was not directly involved in patient care (NPC). All direct patient contacts of EMS workers were protected by FFP2/N95 (filtering face piece protection class 2/non-oil-based particulates filter efficiency 95%) masks, whereas HS was protected by FFP2/N95 exclusively when a patient had a proven or suspected SARS-CoV-2 infection. NPC was not protected by higher FFP. The seroprevalence of SARS-CoV-2 antibodies was analyzed by immunoassay by end of 12/2020 together with the history of a positive PCR. In addition, a self-assessment was performed regarding the quantity of SARS-CoV-2 positive contacts, about flu symptoms and personal belief of previous COVID-19 infections. RESULTS: The period in which contact to SARS-CoV-2 positive patients has been possible was 10 months (March to December 2020)-with 54,681 patient contacts documented for EMS-either emergencies (n = 33,241) or transportation services (n = 21,440). Seven hundred-thirty (n = 730) participants were included into the study (n = EMS: 325, HS: 322 and NPC: 83). The analysis of the survey showed that the exposure to patients with an unknown and consecutive positive SARS-CoV-2 result was significantly higher for EMS when compared to HS (EMS 55% vs. HS 30%, p = 0.01). The incidence of a SARS-CoV-2 infection in our cohort was 1.2% (EMS), 2.2% (HS) and 2.4% (NPC) within the three groups (ns) and lowest in EMS. Furthermore, the belief of previous COVID-19 was significant higher in EMS (19% vs. 10%), CONCLUSION: The consistent use of FFP2/N95 in EMS is able to prevent work-related SARS-CoV-2 infections in emergency situations. The significance of physical airway protection in exposed medical staff is still relevant especially under the aspect of new viral variants and unclear effectiveness of new vaccines.


Subject(s)
COVID-19 , Emergencies , Cohort Studies , Health Personnel , Humans , SARS-CoV-2 , Seroepidemiologic Studies
9.
Cell Rep ; 37(2): 109825, 2021 10 12.
Article in English | MEDLINE | ID: covidwho-1439920

ABSTRACT

The Delta variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), B.1.617.2, emerged in India and has spread to over 80 countries. B.1.617.2 replaced B.1.1.7 as the dominant virus in the United Kingdom, resulting in a steep increase in new infections, and a similar development is expected for other countries. Effective countermeasures require information on susceptibility of B.1.617.2 to control by antibodies elicited by vaccines and used for coronavirus disease 2019 (COVID-19) therapy. We show, using pseudotyping, that B.1.617.2 evades control by antibodies induced upon infection and BNT162b2 vaccination, although to a lesser extent as compared to B.1.351. We find that B.1.617.2 is resistant against bamlanivimab, a monoclonal antibody with emergency use authorization for COVID-19 therapy. Finally, we show increased Calu-3 lung cell entry and enhanced cell-to-cell fusion of B.1.617.2, which may contribute to augmented transmissibility and pathogenicity of this variant. These results identify B.1.617.2 as an immune evasion variant with increased capacity to enter and fuse lung cells.


Subject(s)
COVID-19/immunology , Immune Evasion/immunology , SARS-CoV-2/immunology , Adult , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/metabolism , COVID-19/therapy , COVID-19 Vaccines/immunology , Cell Fusion , Cell Line , Female , HEK293 Cells , Humans , Immune Evasion/physiology , Immunization, Passive/methods , Lung/pathology , Lung/virology , Male , Middle Aged , Neutralization Tests , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/immunology , Vaccination/methods
10.
Cell Rep ; 36(3): 109415, 2021 07 20.
Article in English | MEDLINE | ID: covidwho-1283976

ABSTRACT

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants threatens efforts to contain the coronavirus disease 2019 (COVID-19) pandemic. The number of COVID-19 cases and deaths in India has risen steeply, and a SARS-CoV-2 variant, B.1.617, is believed to be responsible for many of these cases. The spike protein of B.1.617 harbors two mutations in the receptor binding domain, which interacts with the angiotensin converting enzyme 2 (ACE2) receptor and constitutes the main target of neutralizing antibodies. Therefore, we analyze whether B.1.617 is more adept in entering cells and/or evades antibody responses. B.1.617 enters two of eight cell lines tested with roughly 50% increased efficiency and is equally inhibited by two entry inhibitors. In contrast, B.1.617 is resistant against bamlanivimab, an antibody used for COVID-19 treatment. B.1.617 evades antibodies induced by infection or vaccination, although less so than the B.1.351 variant. Collectively, our study reveals that antibody evasion of B.1.617 may contribute to the rapid spread of this variant.


Subject(s)
Angiotensin-Converting Enzyme 2/pharmacology , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Viral/pharmacology , COVID-19/drug therapy , Esters/pharmacology , Guanidines/pharmacology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Antibodies, Monoclonal, Humanized/immunology , Antibodies, Viral/immunology , COVID-19/immunology , Cell Line , Humans , Protease Inhibitors/pharmacology , Protein Binding , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Vaccination
11.
Lancet Respir Med ; 9(6): 622-642, 2021 06.
Article in English | MEDLINE | ID: covidwho-1219780

ABSTRACT

The zoonotic SARS-CoV-2 virus that causes COVID-19 continues to spread worldwide, with devastating consequences. While the medical community has gained insight into the epidemiology of COVID-19, important questions remain about the clinical complexities and underlying mechanisms of disease phenotypes. Severe COVID-19 most commonly involves respiratory manifestations, although other systems are also affected, and acute disease is often followed by protracted complications. Such complex manifestations suggest that SARS-CoV-2 dysregulates the host response, triggering wide-ranging immuno-inflammatory, thrombotic, and parenchymal derangements. We review the intricacies of COVID-19 pathophysiology, its various phenotypes, and the anti-SARS-CoV-2 host response at the humoral and cellular levels. Some similarities exist between COVID-19 and respiratory failure of other origins, but evidence for many distinctive mechanistic features indicates that COVID-19 constitutes a new disease entity, with emerging data suggesting involvement of an endotheliopathy-centred pathophysiology. Further research, combining basic and clinical studies, is needed to advance understanding of pathophysiological mechanisms and to characterise immuno-inflammatory derangements across the range of phenotypes to enable optimum care for patients with COVID-19.


Subject(s)
COVID-19 , Multiple Organ Failure , SARS-CoV-2/pathogenicity , COVID-19/immunology , COVID-19/physiopathology , Endothelium/physiopathology , Humans , Immunity , Multiple Organ Failure/etiology , Multiple Organ Failure/physiopathology , Patient Acuity , Severity of Illness Index
12.
EBioMedicine ; 66: 103291, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1163667

ABSTRACT

Many milestones in medical history rest on animal modeling of human diseases. The SARS-CoV-2 pandemic has evoked a tremendous investigative effort primarily centered on clinical studies. However, several animal SARS-CoV-2/COVID-19 models have been developed and pre-clinical findings aimed at supporting clinical evidence rapidly emerge. In this review, we characterize the existing animal models exposing their relevance and limitations as well as outline their utility in COVID-19 drug and vaccine development. Concurrently, we summarize the status of clinical trial research and discuss the novel tactics utilized in the largest multi-center trials aiming to accelerate generation of reliable results that may subsequently shape COVID-19 clinical treatment practices. We also highlight areas of improvement for animal studies in order to elevate their translational utility. In pandemics, to optimize the use of strained resources in a short time-frame, optimizing and strengthening the synergy between the preclinical and clinical domains is pivotal.


Subject(s)
COVID-19 Vaccines , COVID-19/drug therapy , COVID-19/etiology , Disease Models, Animal , SARS-CoV-2/genetics , Age Factors , Animals , Antiviral Agents/pharmacology , COVID-19/physiopathology , COVID-19/therapy , COVID-19 Vaccines/pharmacology , Clinical Trials as Topic , Cricetinae , Ferrets , Humans , Mice , Mutation , Primates
13.
Cell ; 184(9): 2384-2393.e12, 2021 04 29.
Article in English | MEDLINE | ID: covidwho-1141659

ABSTRACT

The global spread of SARS-CoV-2/COVID-19 is devastating health systems and economies worldwide. Recombinant or vaccine-induced neutralizing antibodies are used to combat the COVID-19 pandemic. However, the recently emerged SARS-CoV-2 variants B.1.1.7 (UK), B.1.351 (South Africa), and P.1 (Brazil) harbor mutations in the viral spike (S) protein that may alter virus-host cell interactions and confer resistance to inhibitors and antibodies. Here, using pseudoparticles, we show that entry of all variants into human cells is susceptible to blockade by the entry inhibitors soluble ACE2, Camostat, EK-1, and EK-1-C4. In contrast, entry of the B.1.351 and P.1 variant was partially (Casirivimab) or fully (Bamlanivimab) resistant to antibodies used for COVID-19 treatment. Moreover, entry of these variants was less efficiently inhibited by plasma from convalescent COVID-19 patients and sera from BNT162b2-vaccinated individuals. These results suggest that SARS-CoV-2 may escape neutralizing antibody responses, which has important implications for efforts to contain the pandemic.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , SARS-CoV-2/immunology , Animals , COVID-19/immunology , COVID-19/therapy , COVID-19/virology , Cell Line , Drug Resistance, Viral , Humans , Immunization, Passive , Kinetics , Membrane Fusion , Models, Molecular , Neutralization Tests , Serine Endopeptidases/metabolism , Solubility , Spike Glycoprotein, Coronavirus/immunology , Vaccination , Virus Internalization
14.
Nat Neurosci ; 24(2): 168-175, 2021 02.
Article in English | MEDLINE | ID: covidwho-1060446

ABSTRACT

The newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a pandemic respiratory disease. Moreover, thromboembolic events throughout the body, including in the CNS, have been described. Given the neurological symptoms observed in a large majority of individuals with COVID-19, SARS-CoV-2 penetrance of the CNS is likely. By various means, we demonstrate the presence of SARS-CoV-2 RNA and protein in anatomically distinct regions of the nasopharynx and brain. Furthermore, we describe the morphological changes associated with infection such as thromboembolic ischemic infarction of the CNS and present evidence of SARS-CoV-2 neurotropism. SARS-CoV-2 can enter the nervous system by crossing the neural-mucosal interface in olfactory mucosa, exploiting the close vicinity of olfactory mucosal, endothelial and nervous tissue, including delicate olfactory and sensory nerve endings. Subsequently, SARS-CoV-2 appears to follow neuroanatomical structures, penetrating defined neuroanatomical areas including the primary respiratory and cardiovascular control center in the medulla oblongata.


Subject(s)
Brain/virology , COVID-19/virology , Olfactory Mucosa/virology , SARS-CoV-2/pathogenicity , Central Nervous System , Humans , RNA, Viral/genetics , Smell/physiology , Virus Internalization
16.
Nat Neurosci ; 24(2): 168-175, 2021 02.
Article in English | MEDLINE | ID: covidwho-952133

ABSTRACT

The newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a pandemic respiratory disease. Moreover, thromboembolic events throughout the body, including in the CNS, have been described. Given the neurological symptoms observed in a large majority of individuals with COVID-19, SARS-CoV-2 penetrance of the CNS is likely. By various means, we demonstrate the presence of SARS-CoV-2 RNA and protein in anatomically distinct regions of the nasopharynx and brain. Furthermore, we describe the morphological changes associated with infection such as thromboembolic ischemic infarction of the CNS and present evidence of SARS-CoV-2 neurotropism. SARS-CoV-2 can enter the nervous system by crossing the neural-mucosal interface in olfactory mucosa, exploiting the close vicinity of olfactory mucosal, endothelial and nervous tissue, including delicate olfactory and sensory nerve endings. Subsequently, SARS-CoV-2 appears to follow neuroanatomical structures, penetrating defined neuroanatomical areas including the primary respiratory and cardiovascular control center in the medulla oblongata.


Subject(s)
Brain/virology , COVID-19/virology , Olfactory Mucosa/virology , SARS-CoV-2/pathogenicity , Central Nervous System , Humans , RNA, Viral/genetics , Smell/physiology , Virus Internalization
17.
EBioMedicine ; 58: 102898, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-665940

ABSTRACT

BACKGROUND: One-third of all deaths in hospitals are caused by sepsis. Despite its demonstrated prevalence and high case fatality rate, antibiotics remain the only target-oriented treatment option currently available. Starting from results showing that low-dose anthracyclines protect against sepsis in mice, we sought to find new causative treatment options to improve sepsis outcomes. METHODS: Sepsis was induced in mice, and different treatment options were evaluated regarding cytokine and biomarker expression, lung epithelial cell permeability, autophagy induction, and survival benefit. Results were validated in cell culture experiments and correlated with patient samples. FINDINGS: Effective low-dose epirubicin treatment resulted in substantial downregulation of the sphingosine 1-phosphate (S1P) degrading enzyme S1P lyase (SPL). Consequent accumulation and secretion of S1P in lung parenchyma cells stimulated the S1P-receptor type 3 (S1PR3) and mitogen-activated protein kinases p38 and ERK, reducing tissue damage via increased disease tolerance. The protective effects of SPL inhibition were absent in S1PR3 deficient mice. Sepsis patients showed increased expression of SPL, stable expression of S1PR3, and increased levels of mucin-1 and surfactant protein D as indicators of lung damage. INTERPRETATION: Our work highlights a tissue-protective effect of SPL inhibition in sepsis due to activation of the S1P/S1PR3 axis and implies that SPL inhibitors and S1PR3 agonists might be potential therapeutics to protect against sepsis by increasing disease tolerance against infections. FUNDING: This study was supported by the Center for Sepsis Control and Care (CSCC), the German Research Foundation (DFG), RTG 1715 (to M. H. G. and I. R.) and the National Institutes of Health, Grant R01GM043880 (to S. S.).


Subject(s)
Aldehyde-Lyases/metabolism , Epirubicin/administration & dosage , Sepsis/drug therapy , Sphingosine-1-Phosphate Receptors/metabolism , Animals , Autophagy , Cell Membrane Permeability , Cells, Cultured , Disease Models, Animal , Down-Regulation , Epirubicin/pharmacology , Extracellular Signal-Regulated MAP Kinases/metabolism , Humans , Mice , Mucin-1/metabolism , Prospective Studies , Pulmonary Surfactant-Associated Protein D/metabolism , Random Allocation , Sepsis/etiology , Sepsis/metabolism , Sphingosine-1-Phosphate Receptors/genetics , Treatment Outcome , p38 Mitogen-Activated Protein Kinases/metabolism
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