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1.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-331621

ABSTRACT

Post-acute lung sequelae of COVID-19 are challenging many survivors across the world, yet the mechanisms behind are poorly understood. Our results delineate an inflammatory cascade of events occurring along disease progression within fibrovascular niches. It is initiated by endothelial dysfunction, followed by heme scavenging of CD163+ macrophages and production of CCL18. This chemokine synergizes with local CCL21 upregulation to influence the stromal composition favoring endothelial to mesenchymal transition. The local immune response is further modulated via recruitment of CCR7+ T cells into the expanding fibrovascular niche and imprinting an exhausted, T follicular helper like phenotype in these cells. Eventually, this culminates in the formation of tertiary lymphoid structures, further perpetuating chronic inflammation. Thus, our work presents misdirected immune-stromal interaction mechanisms promoting a self-sustained and non-resolving local immune response that extends beyond active viral infection and leads to profound tissue repurposing and chronic inflammation.

2.
Nature ; 600(7888): 295-301, 2021 12.
Article in English | MEDLINE | ID: covidwho-1626235

ABSTRACT

SARS-CoV-2 is a single-stranded RNA virus that causes COVID-19. Given its acute and often self-limiting course, it is likely that components of the innate immune system play a central part in controlling virus replication and determining clinical outcome. Natural killer (NK) cells are innate lymphocytes with notable activity against a broad range of viruses, including RNA viruses1,2. NK cell function may be altered during COVID-19 despite increased representation of NK cells with an activated and adaptive phenotype3,4. Here we show that a decline in viral load in COVID-19 correlates with NK cell status and that NK cells can control SARS-CoV-2 replication by recognizing infected target cells. In severe COVID-19, NK cells show defects in virus control, cytokine production and cell-mediated cytotoxicity despite high expression of cytotoxic effector molecules. Single-cell RNA sequencing of NK cells over the time course of the COVID-19 disease spectrum reveals a distinct gene expression signature. Transcriptional networks of interferon-driven NK cell activation are superimposed by a dominant transforming growth factor-ß (TGFß) response signature, with reduced expression of genes related to cell-cell adhesion, granule exocytosis and cell-mediated cytotoxicity. In severe COVID-19, serum levels of TGFß peak during the first two weeks of infection, and serum obtained from these patients severely inhibits NK cell function in a TGFß-dependent manner. Our data reveal that an untimely production of TGFß is a hallmark of severe COVID-19 and may inhibit NK cell function and early control of the virus.


Subject(s)
COVID-19/immunology , Killer Cells, Natural/immunology , SARS-CoV-2/immunology , Transforming Growth Factor beta/immunology , Atlases as Topic , Gene Expression Regulation/immunology , Humans , Immunity, Innate , Influenza, Human/immunology , Killer Cells, Natural/pathology , RNA-Seq , Single-Cell Analysis , Time Factors , Transforming Growth Factor beta/blood , Viral Load/immunology , Virus Replication/immunology
3.
JAMA Neurol ; 79(1): 92-93, 2022 01 01.
Article in English | MEDLINE | ID: covidwho-1527399
4.
Nature ; 600(7888): 295-301, 2021 12.
Article in English | MEDLINE | ID: covidwho-1483137

ABSTRACT

SARS-CoV-2 is a single-stranded RNA virus that causes COVID-19. Given its acute and often self-limiting course, it is likely that components of the innate immune system play a central part in controlling virus replication and determining clinical outcome. Natural killer (NK) cells are innate lymphocytes with notable activity against a broad range of viruses, including RNA viruses1,2. NK cell function may be altered during COVID-19 despite increased representation of NK cells with an activated and adaptive phenotype3,4. Here we show that a decline in viral load in COVID-19 correlates with NK cell status and that NK cells can control SARS-CoV-2 replication by recognizing infected target cells. In severe COVID-19, NK cells show defects in virus control, cytokine production and cell-mediated cytotoxicity despite high expression of cytotoxic effector molecules. Single-cell RNA sequencing of NK cells over the time course of the COVID-19 disease spectrum reveals a distinct gene expression signature. Transcriptional networks of interferon-driven NK cell activation are superimposed by a dominant transforming growth factor-ß (TGFß) response signature, with reduced expression of genes related to cell-cell adhesion, granule exocytosis and cell-mediated cytotoxicity. In severe COVID-19, serum levels of TGFß peak during the first two weeks of infection, and serum obtained from these patients severely inhibits NK cell function in a TGFß-dependent manner. Our data reveal that an untimely production of TGFß is a hallmark of severe COVID-19 and may inhibit NK cell function and early control of the virus.


Subject(s)
COVID-19/immunology , Killer Cells, Natural/immunology , SARS-CoV-2/immunology , Transforming Growth Factor beta/immunology , Atlases as Topic , Gene Expression Regulation/immunology , Humans , Immunity, Innate , Influenza, Human/immunology , Killer Cells, Natural/pathology , RNA-Seq , Single-Cell Analysis , Time Factors , Transforming Growth Factor beta/blood , Viral Load/immunology , Virus Replication/immunology
5.
Nat Commun ; 12(1): 3818, 2021 06 21.
Article in English | MEDLINE | ID: covidwho-1279876

ABSTRACT

Viruses manipulate cellular metabolism and macromolecule recycling processes like autophagy. Dysregulated metabolism might lead to excessive inflammatory and autoimmune responses as observed in severe and long COVID-19 patients. Here we show that SARS-CoV-2 modulates cellular metabolism and reduces autophagy. Accordingly, compound-driven induction of autophagy limits SARS-CoV-2 propagation. In detail, SARS-CoV-2-infected cells show accumulation of key metabolites, activation of autophagy inhibitors (AKT1, SKP2) and reduction of proteins responsible for autophagy initiation (AMPK, TSC2, ULK1), membrane nucleation, and phagophore formation (BECN1, VPS34, ATG14), as well as autophagosome-lysosome fusion (BECN1, ATG14 oligomers). Consequently, phagophore-incorporated autophagy markers LC3B-II and P62 accumulate, which we confirm in a hamster model and lung samples of COVID-19 patients. Single-nucleus and single-cell sequencing of patient-derived lung and mucosal samples show differential transcriptional regulation of autophagy and immune genes depending on cell type, disease duration, and SARS-CoV-2 replication levels. Targeting of autophagic pathways by exogenous administration of the polyamines spermidine and spermine, the selective AKT1 inhibitor MK-2206, and the BECN1-stabilizing anthelmintic drug niclosamide inhibit SARS-CoV-2 propagation in vitro with IC50 values of 136.7, 7.67, 0.11, and 0.13 µM, respectively. Autophagy-inducing compounds reduce SARS-CoV-2 propagation in primary human lung cells and intestinal organoids emphasizing their potential as treatment options against COVID-19.


Subject(s)
COVID-19/metabolism , COVID-19/virology , SARS-CoV-2/metabolism , Animals , Antinematodal Agents/pharmacology , Autophagosomes/metabolism , Autophagy , Autophagy-Related Proteins/metabolism , COVID-19/drug therapy , COVID-19/pathology , Cells, Cultured , Chlorocebus aethiops , Cricetinae , Disease Models, Animal , Humans , Lung/metabolism , Lung/pathology , Lung/virology , Metabolome , Niclosamide/pharmacology , Organoids , SARS-CoV-2/isolation & purification , Spermidine/pharmacology , Spermine/pharmacology
6.
JAMA Neurol ; 78(8): 948-960, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1265359

ABSTRACT

Importance: Myalgia, increased levels of creatine kinase, and persistent muscle weakness have been reported in patients with COVID-19. Objective: To study skeletal muscle and myocardial inflammation in patients with COVID-19 who had died. Design, Setting, and Participants: This case-control autopsy series was conducted in a university hospital as a multidisciplinary postmortem investigation. Patients with COVID-19 or other critical illnesses who had died between March 2020 and February 2021 and on whom an autopsy was performed were included. Individuals for whom informed consent to autopsy was available and the postmortem interval was less than 6 days were randomly selected. Individuals who were infected with SARS-CoV-2 per polymerase chain reaction test results and had clinical features suggestive of COVID-19 were compared with individuals with negative SARS-CoV-2 polymerase chain reaction test results and an absence of clinical features suggestive of COVID-19. Main Outcomes and Measures: Inflammation of skeletal muscle tissue was assessed by quantification of immune cell infiltrates, expression of major histocompatibility complex (MHC) class I and class II antigens on the sarcolemma, and a blinded evaluation on a visual analog scale ranging from absence of pathology to the most pronounced pathology. Inflammation of cardiac muscles was assessed by quantification of immune cell infiltrates. Results: Forty-three patients with COVID-19 (median [interquartile range] age, 72 [16] years; 31 men [72%]) and 11 patients with diseases other than COVID-19 (median [interquartile range] age, 71 [5] years; 7 men [64%]) were included. Skeletal muscle samples from the patients who died with COVID-19 showed a higher overall pathology score (mean [SD], 3.4 [1.8] vs 1.5 [1.0]; 95% CI, 0-3; P < .001) and a higher inflammation score (mean [SD], 3.5 [2.1] vs 1.0 [0.6]; 95% CI, 0-4; P < .001). Relevant expression of MHC class I antigens on the sarcolemma was present in 23 of 42 specimens from patients with COVID-19 (55%) and upregulation of MHC class II antigens in 7 of 42 specimens from patients with COVID-19 (17%), but neither were found in any of the controls. Increased numbers of natural killer cells (median [interquartile range], 8 [8] vs 3 [4] cells per 10 high-power fields; 95% CI, 1-10 cells per 10 high-power fields; P < .001) were found. Skeletal muscles showed more inflammatory features than cardiac muscles, and inflammation was most pronounced in patients with COVID-19 with chronic courses. In some muscle specimens, SARS-CoV-2 RNA was detected by reverse transcription-polymerase chain reaction, but no evidence for a direct viral infection of myofibers was found by immunohistochemistry and electron microscopy. Conclusions and Relevance: In this case-control study of patients who had died with and without COVID-19, most individuals with severe COVID-19 showed signs of myositis ranging from mild to severe. Inflammation of skeletal muscles was associated with the duration of illness and was more pronounced than cardiac inflammation. Detection of viral load was low or negative in most skeletal and cardiac muscles and probably attributable to circulating viral RNA rather than genuine infection of myocytes. This suggests that SARS-CoV-2 may be associated with a postinfectious, immune-mediated myopathy.


Subject(s)
COVID-19/pathology , Muscle, Skeletal/pathology , Myocarditis/pathology , Myocardium/pathology , Myositis/pathology , Aged , Aged, 80 and over , Autopsy , CD8-Positive T-Lymphocytes/pathology , COVID-19/metabolism , COVID-19 Nucleic Acid Testing , COVID-19 Serological Testing , Case-Control Studies , Female , Histocompatibility Antigens Class I/metabolism , Histocompatibility Antigens Class II/metabolism , Humans , Killer Cells, Natural/pathology , Leukocytes/pathology , Macrophages/pathology , Male , Middle Aged , Muscle, Skeletal/metabolism , Myocarditis/metabolism , Myocardium/metabolism , Myositis/metabolism , RNA, Viral/metabolism , SARS-CoV-2 , Sarcolemma/metabolism , Time Factors
7.
Int J Infect Dis ; 108: 274-281, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1253010

ABSTRACT

OBJECTIVES: Studies on coronavirus disease 2019 (COVID-19) usually focus on middle-aged and older adults. However, younger patients may present with severe COVID-19 with potentially fatal outcomes. For optimized, more specialized therapeutic regimens in this particular patient group, a better understanding of the underlying pathomechanisms is of utmost importance. METHODS: Our study investigated relevant, pre-existing medical conditions, clinical histories, and autopsy findings, together with SARS-CoV-2-RNA, determined by qPCR, and laboratory data in six COVID-19 decedents aged 50 years or younger, who were autopsied at the Charité University Hospital. RESULTS: From a total of 76 COVID-19 patients who underwent an autopsy at our institution, six (7.9%) were 50 years old or younger. Most of these younger COVID-19 decedents presented with pre-existing medical conditions prior to SARS-CoV-2 infection. These included overweight and obesity, arterial hypertension, asthma, and obstructive sleep apnea, as well as graft-versus-host disease following cancer and bone marrow transplantation. Furthermore, clinical histories and autopsy results revealed a disproportionally high prevalence of thromboembolism and ischemic organ damage in this patient cohort. Histopathology and laboratory results indicated coagulopathies, signs of immune dysregulation, and liver damage. CONCLUSIONS: In conclusion, pre-existing health conditions may increase the risk of severe and fatal COVID-19 in younger patients, who may be especially prone to developing thromboembolic complications, immune dysregulation, and liver damage.


Subject(s)
COVID-19 , Hypertension , Aged , Autopsy , Humans , Middle Aged , Overweight , SARS-CoV-2
8.
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
9.
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
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