Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 8 de 8
Filter
1.
Clin Infect Dis ; 2022 Sep 02.
Article in English | MEDLINE | ID: covidwho-2017871

ABSTRACT

The diagnosis of post-acute sequelae of COVID-19 (PASC) poses an ongoing medical challenge. To identify biomarkers associated with PASC we analyzed plasma samples collected from PASC and COVID-19 patients to quantify viral antigens and inflammatory markers. We detect SARS-CoV-2 spike predominantly in PASC patients up to 12 months post-diagnosis.

2.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-336820

ABSTRACT

High autoantibody levels are found in individuals hospitalized for COVID-19. The temporal trajectories and levels of these autoantibodies months into convalescence after SARS-CoV-2 infection are unclear. It is also unknown if the composite autoantibody signatures of convalescent SARS-CoV-2-infected individuals resemble those with diagnosed autoimmune diseases. We measured the circulating levels of 17 autoantibodies associated with autoimmune connective tissue diseases from SARS-CoV-2 hospitalized and outpatient participants, as well as from individuals with scleroderma (SSc), systemic lupus erythematosus (SLE), and uninfected pre-pandemic controls. Seven of the 17 autoantibodies measured were higher in hospitalized and/or outpatient SARS-CoV-2 individuals an average of six months after symptom onset compared with controls, with multivariate analyses revealing links between SARS-CoV-2 infection and positivity of SSB-La, Sm, Proteinase 3, Myleoperoxidase, Jo-1, and Ku reactive IgG six months post-symptom onset. Autoantibody levels from SARS-CoV-2 infected individuals were followed over time from initial symptom onset for an average of six months, and different temporal autoantibody trajectories were classified. A ‘negative, then positive’ expression pattern was found for at least one autoantibody in 18% of the outpatient and 53% of the hospitalized participants, indicating initiation and durable expression of self-reactive immune responses post-infection, particularly with severe acute illness. Analysis of individual participant autoantibody expression patterns revealed similar patterns between pre-pandemic and convalescent SARS-CoV-2 infected groups that are distinct from participants with both the SSc and SLE. As autoantibody positivity can occur years prior to autoimmune disease onset, the possibility that SARS-CoV-2-associated autoantibodies are a herald of future autoimmune disorders requires further investigation. One Sentence Summary Autoantibody levels rise after acute SARS-CoV-2 infection and remain elevated for at least six months after symptom onset in participants with mild or severe COVID-19.

3.
Elife ; 112022 03 11.
Article in English | MEDLINE | ID: covidwho-1742931

ABSTRACT

Background: Risk of severe COVID-19 increases with age, is greater in males, and is associated with lymphopenia, but not with higher burden of SARS-CoV-2. It is unknown whether effects of age and sex on abundance of specific lymphoid subsets explain these correlations. Methods: Multiple regression was used to determine the relationship between abundance of specific blood lymphoid cell types, age, sex, requirement for hospitalization, duration of hospitalization, and elevation of blood markers of systemic inflammation, in adults hospitalized for severe COVID-19 (n = 40), treated for COVID-19 as outpatients (n = 51), and in uninfected controls (n = 86), as well as in children with COVID-19 (n = 19), recovering from COVID-19 (n = 14), MIS-C (n = 11), recovering from MIS-C (n = 7), and pediatric controls (n = 17). Results: This observational study found that the abundance of innate lymphoid cells (ILCs) decreases more than 7-fold over the human lifespan - T cell subsets decrease less than 2-fold - and is lower in males than in females. After accounting for effects of age and sex, ILCs, but not T cells, were lower in adults hospitalized with COVID-19, independent of lymphopenia. Among SARS-CoV-2-infected adults, the abundance of ILCs, but not of T cells, correlated inversely with odds and duration of hospitalization, and with severity of inflammation. ILCs were also uniquely decreased in pediatric COVID-19 and the numbers of these cells did not recover during follow-up. In contrast, children with MIS-C had depletion of both ILCs and T cells, and both cell types increased during follow-up. In both pediatric COVID-19 and MIS-C, ILC abundance correlated inversely with inflammation. Blood ILC mRNA and phenotype tracked closely with ILCs from lung. Importantly, blood ILCs produced amphiregulin, a protein implicated in disease tolerance and tissue homeostasis. Among controls, the percentage of ILCs that produced amphiregulin was higher in females than in males, and people hospitalized with COVID-19 had a lower percentage of ILCs that produced amphiregulin than did controls. Conclusions: These results suggest that, by promoting disease tolerance, homeostatic ILCs decrease morbidity and mortality associated with SARS-CoV-2 infection, and that lower ILC abundance contributes to increased COVID-19 severity with age and in males. Funding: This work was supported in part by the Massachusetts Consortium for Pathogen Readiness and NIH grants R37AI147868, R01AI148784, F30HD100110, 5K08HL143183.


Subject(s)
COVID-19 , Lymphopenia , Amphiregulin , COVID-19/complications , Child , Female , Humans , Immunity, Innate , Inflammation , Male , SARS-CoV-2 , Systemic Inflammatory Response Syndrome , T-Lymphocyte Subsets
4.
Kidney Int Rep ; 6(12): 3002-3013, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1549765

ABSTRACT

INTRODUCTION: Acute kidney injury (AKI) is common in COVID-19 and associated with increased morbidity and mortality. We investigated alterations in the urine metabolome to test the hypothesis that impaired nicotinamide adenine dinucleotide (NAD+) biosynthesis and other deficiencies in energy metabolism in the kidney, previously characterized in ischemic, toxic, and inflammatory etiologies of AKI, will be present in COVID-19-associated AKI. METHODS: This is a case-control study among the following 2 independent populations of adults hospitalized with COVID-19: a critically ill population in Boston, Massachusetts, and a general population in Birmingham, Alabama. The cases had AKI stages 2 or 3 by Kidney Disease Improving Global Outcomes (KDIGO) criteria; the controls had no AKI. Metabolites were measured by liquid chromatography-mass spectrometry. RESULTS: A total of 14 cases and 14 controls were included from Boston and 8 cases and 10 controls from Birmingham. Increased urinary quinolinate-to-tryptophan ratio (Q/T), found with impaired NAD+ biosynthesis, was present in the cases at each location and pooled across locations (median [interquartile range]: 1.34 [0.59-2.96] in cases, 0.31 [0.13-1.63] in controls, P = 0.0013). Altered energy metabolism and purine metabolism contributed to a distinct urinary metabolomic signature that differentiated patients with and without AKI (supervised random forest class error: 2 of 28 in Boston, 0 of 18 in Birmingham). CONCLUSION: Urinary metabolites spanning multiple biochemical pathways differentiate AKI versus non-AKI in patients hospitalized with COVID-19 and suggest a conserved impairment in NAD+ biosynthesis, which may present a novel therapeutic target to mitigate COVID-19-associated AKI.

5.
iScience ; 24(10): 103205, 2021 Oct 22.
Article in English | MEDLINE | ID: covidwho-1446744

ABSTRACT

T cell exhaustion and dysfunction are hallmarks of severe COVID-19. To gain insights into the pathways underlying these alterations, we performed a comprehensive transcriptome analysis of peripheral-blood-mononuclear-cells (PBMCs), spleen, lung, kidney, liver, and heart obtained at autopsy from COVID-19 patients and matched controls, using the nCounter CAR-T-Characterization panel. We found substantial gene alterations in COVID-19-impacted organs, especially the lung where altered TCR repertoires are noted. Reduced TCR repertoires are also observed in PBMCs of severe COVID-19 patients. ENTPD1/CD39, an ectoenzyme defining exhausted T-cells, is upregulated in the lung, liver, spleen, and PBMCs of severe COVID-19 patients where expression positively correlates with markers of vasculopathy. Heightened ENTPD1/CD39 is paralleled by elevations in STAT-3 and HIF-1α transcription factors; and by markedly reduced CD39-antisense-RNA, a long-noncoding-RNA negatively regulating ENTPD1/CD39 at the post-transcriptional level. Limited TCR repertoire and aberrant regulation of ENTPD1/CD39 could have permissive roles in COVID-19 progression and indicate potential therapeutic targets to reverse disease.

6.
JCI Insight ; 6(20)2021 10 22.
Article in English | MEDLINE | ID: covidwho-1403154

ABSTRACT

Endothelial dysfunction accompanies the microvascular thrombosis commonly observed in severe COVID-19. Constitutively, the endothelial surface is anticoagulant, a property maintained at least in part via signaling through the Tie2 receptor. During inflammation, the Tie2 antagonist angiopoietin-2 (Angpt-2) is released from endothelial cells and inhibits Tie2, promoting a prothrombotic phenotypic shift. We sought to assess whether severe COVID-19 is associated with procoagulant endothelial dysfunction and alterations in the Tie2/angiopoietin axis. Primary HUVECs treated with plasma from patients with severe COVID-19 upregulated the expression of thromboinflammatory genes, inhibited the expression of antithrombotic genes, and promoted coagulation on the endothelial surface. Pharmacologic activation of Tie2 with the small molecule AKB-9778 reversed the prothrombotic state induced by COVID-19 plasma in primary endothelial cells. Lung autopsies from patients with COVID-19 demonstrated a prothrombotic endothelial signature. Assessment of circulating endothelial markers in a cohort of 98 patients with mild, moderate, or severe COVID-19 revealed endothelial dysfunction indicative of a prothrombotic state. Angpt-2 concentrations rose with increasing disease severity, and the highest levels were associated with worse survival. These data highlight the disruption of Tie2/angiopoietin signaling and procoagulant changes in endothelial cells in severe COVID-19. Our findings provide rationale for current trials of Tie2-activating therapy with AKB-9778 in COVID-19.


Subject(s)
COVID-19/drug therapy , Endothelial Cells/drug effects , Protective Agents/pharmacology , Receptor, TIE-2/metabolism , Adult , Aged , Aged, 80 and over , Angiopoietin-2/metabolism , Aniline Compounds , Female , Gene Expression , Humans , Lung , Male , Middle Aged , Receptor, TIE-2/genetics , SARS-CoV-2 , Signal Transduction , Sulfonic Acids , Vascular Diseases/metabolism , Young Adult
7.
J Infect Dis ; 224(5): 777-782, 2021 09 01.
Article in English | MEDLINE | ID: covidwho-1381012

ABSTRACT

We analyzed plasma levels of interferons (IFNs) and cytokines, and expression of IFN-stimulated genes in peripheral blood mononuclear cells in patients with coronavirus disease 2019 of varying disease severity. Patients hospitalized with mild disease exhibited transient type I IFN responses, while intensive care unit patients had prolonged type I IFN responses. Type II IFN responses were compromised in intensive care unit patients. Type III IFN responses were induced in the early phase of infection, even in convalescent patients. These results highlight the importance of early type I and III IFN responses in controlling coronavirus disease 2019 progression.


Subject(s)
COVID-19/immunology , Interferon Type I/immunology , Interferon-gamma/immunology , Interferons/immunology , COVID-19/blood , Chemokines/blood , Cytokines/blood , Humans , Interferon Type I/blood , Interferon Type I/genetics , Interferon-gamma/blood , Interferon-gamma/genetics , Interferons/blood , Leukocytes, Mononuclear/immunology , SARS-CoV-2/isolation & purification
8.
Proc Natl Acad Sci U S A ; 118(37)2021 09 14.
Article in English | MEDLINE | ID: covidwho-1373495

ABSTRACT

The hallmark of severe COVID-19 is an uncontrolled inflammatory response, resulting from poorly understood immunological dysfunction. We hypothesized that perturbations in FoxP3+ T regulatory cells (Treg), key enforcers of immune homeostasis, contribute to COVID-19 pathology. Cytometric and transcriptomic profiling revealed a distinct Treg phenotype in severe COVID-19 patients, with an increase in Treg proportions and intracellular levels of the lineage-defining transcription factor FoxP3, correlating with poor outcomes. These Tregs showed a distinct transcriptional signature, with overexpression of several suppressive effectors, but also proinflammatory molecules like interleukin (IL)-32, and a striking similarity to tumor-infiltrating Tregs that suppress antitumor responses. Most marked during acute severe disease, these traits persisted somewhat in convalescent patients. A screen for candidate agents revealed that IL-6 and IL-18 may individually contribute different facets of these COVID-19-linked perturbations. These results suggest that Tregs may play nefarious roles in COVID-19, by suppressing antiviral T cell responses during the severe phase of the disease, and by a direct proinflammatory role.


Subject(s)
COVID-19/etiology , T-Lymphocytes, Regulatory/physiology , Adult , Aged , CD4-Positive T-Lymphocytes/virology , Female , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Gene Expression Profiling , Gene Expression Regulation , Humans , Inflammation/metabolism , Inflammation/virology , Interleukin-18/genetics , Interleukin-18/metabolism , Interleukin-2 Receptor alpha Subunit/genetics , Interleukin-2 Receptor alpha Subunit/metabolism , Interleukin-6/genetics , Interleukin-6/metabolism , Lymphocytes, Tumor-Infiltrating/physiology , Male , Middle Aged , Severity of Illness Index , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/virology , Transcription Factors/genetics , Transcription Factors/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL