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1.
Sci Immunol ; 8(85): eadg0033, 2023 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-37506197

RESUMO

Type I interferons (IFN-I) are critical mediators of innate control of viral infections but also drive the recruitment of inflammatory cells to sites of infection, a key feature of severe coronavirus disease 2019. Here, IFN-I signaling was modulated in rhesus macaques (RMs) before and during acute SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection using a mutated IFN-α2 (IFN-modulator; IFNmod), which has previously been shown to reduce the binding and signaling of endogenous IFN-I. IFNmod treatment in uninfected RMs was observed to induce a modest up-regulation of only antiviral IFN-stimulated genes (ISGs); however, in SARS-CoV-2-infected RMs, IFNmod reduced both antiviral and inflammatory ISGs. IFNmod treatment resulted in a potent reduction in SARS-CoV-2 viral loads both in vitro in Calu-3 cells and in vivo in bronchoalveolar lavage (BAL), upper airways, lung, and hilar lymph nodes of RMs. Furthermore, in SARS-CoV-2-infected RMs, IFNmod treatment potently reduced inflammatory cytokines, chemokines, and CD163+ MRC1- inflammatory macrophages in BAL and expression of Siglec-1 on circulating monocytes. In the lung, IFNmod also reduced pathogenesis and attenuated pathways of inflammasome activation and stress response during acute SARS-CoV-2 infection. Using an intervention targeting both IFN-α and IFN-ß pathways, this study shows that, whereas early IFN-I restrains SARS-CoV-2 replication, uncontrolled IFN-I signaling critically contributes to SARS-CoV-2 inflammation and pathogenesis in the moderate disease model of RMs.


Assuntos
COVID-19 , Interferon Tipo I , Animais , Interferon Tipo I/farmacologia , SARS-CoV-2 , Macaca mulatta , Replicação Viral , Antivirais/farmacologia , Antivirais/uso terapêutico , Inflamação/tratamento farmacológico
2.
J Biomol Tech ; 32(3): 134-136, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-35027871

RESUMO

At this writing, over 100 million people have tested positive for Corona Virus Disease-19 (COVID-19), and the global death toll from this disease has reached nearly 3 million. Despite the many tests currently available, we have not yet achieved the testing capacity needed to limit the spread of the virus and mitigate suffering worldwide. We have developed the One Hour COVID Test to address this challenge. Our test leverages an easy-to-use, commercially available oral swab kit for sample collection paired with a novel RNA processing protocol and a simple colorimetric assay that requires minimal equipment. The test can be easily scaled via automation and takes 1 h from sample collection to result.


Assuntos
COVID-19 , Colorimetria , Teste para COVID-19 , Humanos , Técnicas de Diagnóstico Molecular , Técnicas de Amplificação de Ácido Nucleico , Tempo de Protrombina , RNA Viral/genética , SARS-CoV-2 , Sensibilidade e Especificidade
3.
Proc Natl Acad Sci U S A ; 115(42): E9944-E9952, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30275336

RESUMO

Dysfunctional endothelium causes more disease than any other cell type. Systemically administered RNA delivery to nonliver tissues remains challenging, in large part because there is no high-throughput method to identify nanoparticles that deliver functional mRNA to cells in vivo. Here we report a system capable of simultaneously quantifying how >100 lipid nanoparticles (LNPs) deliver mRNA that is translated into functional protein. Using this system (named FIND), we measured how >250 LNPs delivered mRNA to multiple cell types in vivo and identified 7C2 and 7C3, two LNPs that efficiently deliver siRNA, single-guide RNA (sgRNA), and mRNA to endothelial cells. The 7C3 delivered Cas9 mRNA and sgRNA to splenic endothelial cells as efficiently as hepatocytes, distinguishing it from LNPs that deliver Cas9 mRNA and sgRNA to hepatocytes more than other cell types. These data demonstrate that FIND can identify nanoparticles with novel tropisms in vivo.


Assuntos
Sistemas CRISPR-Cas , Células Endoteliais/metabolismo , Edição de Genes , Técnicas de Transferência de Genes , Lipídeos/química , Nanopartículas/administração & dosagem , RNA Guia de Cinetoplastídeos/genética , RNA Mensageiro/genética , Animais , Células Cultivadas , Células Endoteliais/citologia , Células HEK293 , Hepatócitos/citologia , Hepatócitos/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , RNA Guia de Cinetoplastídeos/química , RNA Mensageiro/química
4.
Nano Lett ; 18(3): 2148-2157, 2018 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-29489381

RESUMO

Endothelial cells and macrophages play active roles in disease and as a result are important targets for nucleic acid therapies. While thousands of chemically distinct lipid nanoparticles (LNPs) can be synthesized to deliver nucleic acids, studying more than a few LNPs in vivo is challenging. As a result, it is difficult to understand how nanoparticles target these cells in vivo. Using high throughput LNP barcoding, we quantified how well LNPs delivered DNA barcodes to endothelial cells and macrophages in vitro, as well as endothelial cells and macrophages isolated from the lung, heart, and bone marrow in vivo. We focused on two fundamental questions in drug delivery. First, does in vitro LNP delivery predict in vivo LNP delivery? By comparing how 281 LNPs delivered barcodes to endothelial cells and macrophages in vitro and in vivo, we found in vitro delivery did not predict in vivo delivery. Second, does LNP delivery change within the microenvironment of a tissue? We quantified how 85 LNPs delivered barcodes to eight splenic cell populations, and found that cell types derived from myeloid progenitors tended to be targeted by similar LNPs, relative to cell types derived from lymphoid progenitors. These data demonstrate that barcoded LNPs can elucidate fundamental questions about in vivo nanoparticle delivery.


Assuntos
Sistemas de Liberação de Medicamentos , Lipídeos/química , Nanopartículas/química , Ácidos Nucleicos/administração & dosagem , Animais , Linhagem Celular , Células Cultivadas , Células Endoteliais/metabolismo , Feminino , Humanos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Nanotecnologia , Ácidos Nucleicos/farmacocinética
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