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1.
J Am Soc Nephrol ; 33(7): 1293-1307, 2022 07.
Article in English | MEDLINE | ID: covidwho-1799028

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) uses full-length angiotensin converting enzyme 2 (ACE2) as a main receptor to enter target cells. The goal of this study was to demonstrate the preclinical efficacy of a novel soluble ACE2 protein with increased duration of action and binding capacity in a lethal mouse model of COVID-19. METHODS: A human soluble ACE2 variant fused with an albumin binding domain (ABD) was linked via a dimerization motif hinge-like 4-cysteine dodecapeptide (DDC) to improve binding capacity to SARS-CoV-2. This novel soluble ACE2 protein (ACE2-1-618-DDC-ABD) was then administered intranasally and intraperitoneally to mice before intranasal inoculation of SARS-CoV-2 and then for two additional days post viral inoculation. RESULTS: Untreated animals became severely ill, and all had to be humanely euthanized by day 6 or 7 and had pulmonary alveolar hemorrhage with mononuclear infiltrates. In contrast, all but one mouse infected with a lethal dose of SARS-CoV-2 that received ACE2-1-618-DDC-ABD survived. In the animals inoculated with SARS-CoV-2 that were untreated, viral titers were high in the lungs and brain, but viral titers were absent in the kidneys. Some untreated animals, however, had variable degrees of kidney proximal tubular injury as shown by attenuation of the proximal tubular brush border and increased NGAL and TUNEL staining. Viral titers in the lung and brain were reduced or nondetectable in mice that received ACE2-1-618-DDC-ABD, and the animals developed only moderate disease as assessed by a near-normal clinical score, minimal weight loss, and improved lung and kidney injury. CONCLUSIONS: This study demonstrates the preclinical efficacy of a novel soluble ACE2 protein, termed ACE2-1-618-DDC-ABD, in a lethal mouse model of SARS-CoV-2 infection that develops severe lung injury and variable degrees of moderate kidney proximal tubular injury.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Angiotensin-Converting Enzyme 2/therapeutic use , Animals , COVID-19/therapy , Kidney/virology , Lung/virology , Mice , SARS-CoV-2
2.
mBio ; : e0375121, 2022 Feb 08.
Article in English | MEDLINE | ID: covidwho-1741580

ABSTRACT

The widespread coronavirus disease 2019 (COVID-19) is caused by infection with the novel coronavirus SARS-CoV-2. Currently, we have limited understanding of which cells become infected with SARS-CoV-2 in human tissues and where viral RNA localizes on the subcellular level. Here, we present a platform for preparing autopsy tissue for visualizing SARS-CoV-2 RNA using RNA fluorescence in situ hybridization (FISH) with amplification by hybridization chain reaction. We developed probe sets that target different regions of SARS-CoV-2 (including ORF1a and N), as well as probe sets that specifically target SARS-CoV-2 subgenomic mRNAs. We validated these probe sets in cell culture and tissues (lung, lymph node, and placenta) from infected patients. Using this technology, we observe distinct subcellular localization patterns of the ORF1a and N regions. In human lung tissue, we performed multiplexed RNA FISH HCR for SARS-CoV-2 and cell-type-specific marker genes. We found viral RNA in cells containing the alveolar type 2 (AT2) cell marker gene (SFTPC) and the alveolar macrophage marker gene (MARCO) but did not identify viral RNA in cells containing the alveolar type 1 (AT1) cell marker gene (AGER). Moreover, we observed distinct subcellular localization patterns of viral RNA in AT2 cells and alveolar macrophages. In sum, we demonstrate the use of RNA FISH HCR for visualizing different RNA species from SARS-CoV-2 in cell lines and FFPE (formalin fixation and paraffin embedding) autopsy specimens. We anticipate that this platform could be broadly useful for studying SARS-CoV-2 pathology in tissues, as well as extended for other applications, including investigating the viral life cycle, viral diagnostics, and drug screening. IMPORTANCE Here, we developed an in situ RNA detection assay for RNA generated by the SARS-CoV-2 virus. We found viral RNA in lung, lymph node, and placenta samples from pathology specimens from COVID patients. Using high-magnification microscopy, we can visualize the subcellular distribution of these RNA in single cells.

3.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-315485

ABSTRACT

Purpose: To explore the role of chronic liver disease (CLD) in COVID-19. Methods: : A total of 1,439 consecutively hospitalized patients with COVID-19 from one large medical center in the United States from March 16, 2020 to April 23, 2020 were retrospectively identified. Clinical characteristics and outcomes were compared between patients with and without CLD. Postmortem examination of liver in 8 critically ill COVID-19 patients was performed. Results: : There was no significant difference in the incidence of CLD between critical and non-critical groups (4.1% vs 2.9%, p=0.259), or COVID-19 related liver injury between patients with and without CLD (65.7% vs 49.7%, p=0.065). Postmortem examination of liver demonstrated mild liver injury associated central vein outflow obstruction and minimal to moderate portal lymphocytic infiltrate without evidence of CLD. Conclusion: Patients with CLD were not associated with a higher risk of liver injury or critical/fatal outcomes. CLD was not a significant comorbid condition for COVID-19.

4.
Sci Rep ; 11(1): 11734, 2021 06 03.
Article in English | MEDLINE | ID: covidwho-1258596

ABSTRACT

To explore the role of chronic liver disease (CLD) in COVID-19. A total of 1439 consecutively hospitalized patients with COVID-19 from one large medical center in the United States from March 16, 2020 to April 23, 2020 were retrospectively identified. Clinical characteristics and outcomes were compared between patients with and without CLD. Postmortem examination of liver in 8 critically ill COVID-19 patients was performed. There was no significant difference in the incidence of CLD between critical and non-critical groups (4.1% vs 2.9%, p = 0.259), or COVID-19 related liver injury between patients with and without CLD (65.7% vs 49.7%, p = 0.065). Postmortem examination of liver demonstrated mild liver injury associated central vein outflow obstruction and minimal to moderate portal lymphocytic infiltrate without evidence of CLD. Patients with CLD were not associated with a higher risk of liver injury or critical/fatal outcomes. CLD was not a significant comorbid condition for COVID-19.


Subject(s)
COVID-19/epidemiology , Liver Diseases/epidemiology , Acute Lung Injury/epidemiology , Acute Lung Injury/pathology , Aged , COVID-19/mortality , Chronic Disease , Comorbidity , Female , Humans , Liver Diseases/pathology , Liver Function Tests , Male , Middle Aged , Proportional Hazards Models , United States/epidemiology
5.
Br J Haematol ; 194(1): 44-52, 2021 07.
Article in English | MEDLINE | ID: covidwho-1247138

ABSTRACT

The inflammatory response to SARS/CoV-2 (COVID-19) infection may contribute to the risk of thromboembolic complications. α-Defensins, antimicrobial peptides released from activated neutrophils, are anti-fibrinolytic and prothrombotic in vitro and in mouse models. In this prospective study of 176 patients with COVID-19 infection, we found that plasma levels of α-defensins were elevated, tracked with disease progression/mortality or resolution and with plasma levels of interleukin-6 (IL-6) and D-dimers. Immunohistochemistry revealed intense deposition of α-defensins in lung vasculature and thrombi. IL-6 stimulated the release of α-defensins from neutrophils, thereby accelerating coagulation and inhibiting fibrinolysis in human blood, imitating the coagulation pattern in COVID-19 patients. The procoagulant effect of IL-6 was inhibited by colchicine, which blocks neutrophil degranulation. These studies describe a link between inflammation and the risk of thromboembolism, and they identify a potential new approach to mitigate this risk in patients with COVID-19 and potentially in other inflammatory prothrombotic conditions.


Subject(s)
COVID-19/metabolism , Inflammation/metabolism , Thromboembolism/prevention & control , alpha-Defensins/blood , Adult , Aged , Animals , Blood Coagulation/drug effects , COVID-19/complications , COVID-19/diagnosis , COVID-19/virology , Case-Control Studies , Colchicine/pharmacology , Female , Fibrin Fibrinogen Degradation Products/analysis , Humans , Inflammation/complications , Interleukin-6/blood , Interleukin-6/pharmacology , Male , Mice , Middle Aged , Models, Animal , Neutrophils/drug effects , Prospective Studies , Risk Factors , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Severity of Illness Index , Thromboembolism/etiology , Thrombosis/etiology , Thrombosis/metabolism , Tubulin Modulators/pharmacology , alpha-Defensins/pharmacology
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