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1.
JACC Basic Transl Sci ; 7(5): 425-441, 2022 May.
Article in English | MEDLINE | ID: covidwho-1819515

ABSTRACT

To gain insights into the mechanisms driving cardiovascular complications in COVID-19, we performed a case-control plasma proteomics study in COVID-19 patients. Our results identify the senescence-associated secretory phenotype, a marker of biological aging, as the dominant process associated with disease severity and cardiac involvement. FSTL3, an indicator of senescence-promoting Activin/TGFß signaling, and ADAMTS13, the von Willebrand Factor-cleaving protease whose loss-of-function causes microvascular thrombosis, were among the proteins most strongly associated with myocardial stress and injury. Findings were validated in a larger COVID-19 patient cohort and the hamster COVID-19 model, providing new insights into the pathophysiology of COVID-19 cardiovascular complications with therapeutic implications.

2.
PLoS Pathog ; 18(4): e1009990, 2022 04.
Article in English | MEDLINE | ID: covidwho-1785209

ABSTRACT

Syrian golden hamsters exhibit features of severe disease after SARS-CoV-2 WA1/2020 challenge and are therefore useful models of COVID-19 pathogenesis and prevention with vaccines. Recent studies have shown that SARS-CoV-2 infection stimulates type I interferon, myeloid, and inflammatory signatures similar to human disease and that weight loss can be prevented with vaccines. However, the impact of vaccination on transcriptional programs associated with COVID-19 pathogenesis and protective adaptive immune responses is unknown. Here we show that SARS-CoV-2 WA1/2020 challenge in hamsters stimulates myeloid and inflammatory programs as well as signatures of complement and thrombosis associated with human COVID-19. Notably, immunization with Ad26.COV2.S, an adenovirus serotype 26 vector (Ad26)-based vaccine expressing a stabilized SARS-CoV-2 spike protein, prevents the upregulation of these pathways, such that the mRNA expression profiles of vaccinated hamsters are comparable to uninfected animals. Using proteomics profiling, we validated these findings in rhesus macaques challenged with SARS-CoV-2 WA1/2020 or SARS-CoV-2 B.1.351. Finally, we show that Ad26.COV2.S vaccination induces T and B cell signatures that correlate with binding and neutralizing antibody responses weeks following vaccination. These data provide insights into the molecular mechanisms of Ad26.COV2.S protection against severe COVID-19 in animal models.


Subject(s)
COVID-19 , Thrombosis , Ad26COVS1 , Animals , Antibodies, Neutralizing , COVID-19 Vaccines , Cricetinae , Humans , Inflammation , Macaca mulatta , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Up-Regulation
3.
Sci Transl Med ; 14(638): eabm4996, 2022 03 30.
Article in English | MEDLINE | ID: covidwho-1705843

ABSTRACT

Ad26.COV2.S has demonstrated durability and clinical efficacy against symptomatic COVID-19 in humans. In this study, we report the correlates of durability of humoral and cellular immune responses in 20 rhesus macaques immunized with single-shot Ad26.COV2.S and the immunogenicity of a booster shot at 8 to 10 months after the initial immunization. Ad26.COV2.S elicited durable binding and neutralizing antibodies as well as memory B cells and long-lived bone marrow plasma cells. Innate immune responses and bone marrow plasma cell responses correlated with durable antibody responses. After Ad26.COV2.S boost immunization, binding and neutralizing antibody responses against multiple SARS-CoV-2 variants increased 31- to 69-fold and 23- to 43-fold, respectively, compared with preboost concentrations. Antigen-specific B cell and T cell responses also increased substantially after the boost immunization. Boosting with a modified Ad26.COV2.S.351 vaccine expressing the SARS-CoV-2 spike protein from the beta variant led to largely comparable responses with slightly higher beta- and omicron-specific humoral immune responses. These data demonstrate that a late boost with Ad26.COV2.S or Ad26.COV2.S.351 resulted in a marked increase in humoral and cellular immune responses that were highly cross-reactive across multiple SARS-CoV-2 variants in rhesus macaques.


Subject(s)
Ad26COVS1 , COVID-19 , Immunity, Humoral , Immunization, Secondary , SARS-CoV-2 , Ad26COVS1/immunology , Animals , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , Macaca mulatta , Spike Glycoprotein, Coronavirus
4.
J Virol ; 95(14): e0040421, 2021 06 24.
Article in English | MEDLINE | ID: covidwho-1501539

ABSTRACT

Emerging SARS-CoV-2 variants of concern that overcome natural and vaccine-induced immunity threaten to exacerbate the COVID-19 pandemic. Increasing evidence suggests that neutralizing antibody (NAb) responses are a primary mechanism of protection against infection. However, little is known about the extent and mechanisms by which natural immunity acquired during the early COVID-19 pandemic confers cross-neutralization of emerging variants. In this study, we investigated cross-neutralization of the B.1.1.7 and B.1.351 SARS-CoV-2 variants in a well-characterized cohort of early pandemic convalescent subjects. We observed modestly decreased cross-neutralization of B.1.1.7 but a substantial 4.8-fold reduction in cross-neutralization of B.1.351. Correlates of cross-neutralization included receptor binding domain (RBD) and N-terminal domain (NTD) binding antibodies, homologous NAb titers, and membrane-directed T cell responses. These data shed light on the cross-neutralization of emerging variants by early pandemic convalescent immune responses. IMPORTANCE Widespread immunity to SARS-CoV-2 will be necessary to end the COVID-19 pandemic. NAb responses are a critical component of immunity that can be stimulated by natural infection as well as vaccines. However, SARS-CoV-2 variants are emerging that contain mutations in the spike gene that promote evasion from NAb responses. These variants may therefore delay control of the COVID-19 pandemic. We studied whether NAb responses from early COVID-19 convalescent patients are effective against the two SARS-CoV-2 variants, B.1.1.7 and B.1.351. We observed that the B.1.351 variant demonstrates significantly reduced susceptibility to early pandemic NAb responses. We additionally characterized virological, immunological, and clinical features that correlate with cross-neutralization. These studies increase our understanding of emerging SARS-CoV-2 variants.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/epidemiology , COVID-19/immunology , Pandemics , SARS-CoV-2/immunology , Adult , Cross Reactions , Humans , Male
5.
Res Sq ; 2021 Jun 08.
Article in English | MEDLINE | ID: covidwho-1270320

ABSTRACT

Cardiovascular complications are common in COVID-19 and strongly associated with disease severity and mortality. However, the mechanisms driving cardiac injury and failure in COVID-19 are largely unknown. We performed plasma proteomics on 80 COVID-19 patients and controls, grouped according to disease severity and cardiac involvement. Findings were validated in 305 independent COVID-19 patients and investigated in an animal model. Here we show that senescence-associated secretory proteins, markers of biological aging, strongly associate with disease severity and cardiac involvement even in age-matched cohorts. FSTL3, an indicator of Activin/TGFß signaling, was the most significantly upregulated protein associated with the heart failure biomarker, NTproBNP (ß = 0.4;p adj =4.6x10 - 7 ), while ADAMTS13, a vWF-cleaving protease whose loss-of-function causes microvascular thrombosis, was the most downregulated protein associated with myocardial injury (ß=-0.4;p adj =8x10 - 7 ). Mendelian randomization supported a causal role for ADAMTS13 in myocardial injury. These data provide important new insights into the pathophysiology of COVID-19 cardiovascular complications with therapeutic implications.

6.
J Virol ; 95(14): e0040421, 2021 06 24.
Article in English | MEDLINE | ID: covidwho-1203944

ABSTRACT

Emerging SARS-CoV-2 variants of concern that overcome natural and vaccine-induced immunity threaten to exacerbate the COVID-19 pandemic. Increasing evidence suggests that neutralizing antibody (NAb) responses are a primary mechanism of protection against infection. However, little is known about the extent and mechanisms by which natural immunity acquired during the early COVID-19 pandemic confers cross-neutralization of emerging variants. In this study, we investigated cross-neutralization of the B.1.1.7 and B.1.351 SARS-CoV-2 variants in a well-characterized cohort of early pandemic convalescent subjects. We observed modestly decreased cross-neutralization of B.1.1.7 but a substantial 4.8-fold reduction in cross-neutralization of B.1.351. Correlates of cross-neutralization included receptor binding domain (RBD) and N-terminal domain (NTD) binding antibodies, homologous NAb titers, and membrane-directed T cell responses. These data shed light on the cross-neutralization of emerging variants by early pandemic convalescent immune responses. IMPORTANCE Widespread immunity to SARS-CoV-2 will be necessary to end the COVID-19 pandemic. NAb responses are a critical component of immunity that can be stimulated by natural infection as well as vaccines. However, SARS-CoV-2 variants are emerging that contain mutations in the spike gene that promote evasion from NAb responses. These variants may therefore delay control of the COVID-19 pandemic. We studied whether NAb responses from early COVID-19 convalescent patients are effective against the two SARS-CoV-2 variants, B.1.1.7 and B.1.351. We observed that the B.1.351 variant demonstrates significantly reduced susceptibility to early pandemic NAb responses. We additionally characterized virological, immunological, and clinical features that correlate with cross-neutralization. These studies increase our understanding of emerging SARS-CoV-2 variants.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/epidemiology , COVID-19/immunology , Pandemics , SARS-CoV-2/immunology , Adult , Cross Reactions , Humans , Male
7.
Cell ; 183(5): 1354-1366.e13, 2020 11 25.
Article in English | MEDLINE | ID: covidwho-871817

ABSTRACT

The COVID-19 pandemic has led to extensive morbidity and mortality throughout the world. Clinical features that drive SARS-CoV-2 pathogenesis in humans include inflammation and thrombosis, but the mechanistic details underlying these processes remain to be determined. In this study, we demonstrate endothelial disruption and vascular thrombosis in histopathologic sections of lungs from both humans and rhesus macaques infected with SARS-CoV-2. To define key molecular pathways associated with SARS-CoV-2 pathogenesis in macaques, we performed transcriptomic analyses of bronchoalveolar lavage and peripheral blood and proteomic analyses of serum. We observed macrophage infiltrates in lung and upregulation of macrophage, complement, platelet activation, thrombosis, and proinflammatory markers, including C-reactive protein, MX1, IL-6, IL-1, IL-8, TNFα, and NF-κB. These results suggest a model in which critical interactions between inflammatory and thrombosis pathways lead to SARS-CoV-2-induced vascular disease. Our findings suggest potential therapeutic targets for COVID-19.


Subject(s)
COVID-19/complications , COVID-19/immunology , SARS-CoV-2/genetics , Thrombosis/complications , Vascular Diseases/complications , Aged, 80 and over , Animals , Bronchoalveolar Lavage , C-Reactive Protein/analysis , COVID-19/blood , COVID-19/pathology , Complement Activation , Cytokines/blood , Female , Humans , Inflammation/blood , Inflammation/immunology , Inflammation/virology , Lung/pathology , Macaca mulatta , Macrophages/immunology , Male , Platelet Activation , Thrombosis/blood , Thrombosis/pathology , Transcriptome , Vascular Diseases/blood , Vascular Diseases/pathology
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