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1.
Proc Natl Acad Sci U S A ; 119(35): e2200960119, 2022 08 30.
Article in English | MEDLINE | ID: covidwho-1991765

ABSTRACT

Although increasing evidence confirms neuropsychiatric manifestations associated mainly with severe COVID-19 infection, long-term neuropsychiatric dysfunction (recently characterized as part of "long COVID-19" syndrome) has been frequently observed after mild infection. We show the spectrum of cerebral impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, ranging from long-term alterations in mildly infected individuals (orbitofrontal cortical atrophy, neurocognitive impairment, excessive fatigue and anxiety symptoms) to severe acute damage confirmed in brain tissue samples extracted from the orbitofrontal region (via endonasal transethmoidal access) from individuals who died of COVID-19. In an independent cohort of 26 individuals who died of COVID-19, we used histopathological signs of brain damage as a guide for possible SARS-CoV-2 brain infection and found that among the 5 individuals who exhibited those signs, all of them had genetic material of the virus in the brain. Brain tissue samples from these five patients also exhibited foci of SARS-CoV-2 infection and replication, particularly in astrocytes. Supporting the hypothesis of astrocyte infection, neural stem cell-derived human astrocytes in vitro are susceptible to SARS-CoV-2 infection through a noncanonical mechanism that involves spike-NRP1 interaction. SARS-CoV-2-infected astrocytes manifested changes in energy metabolism and in key proteins and metabolites used to fuel neurons, as well as in the biogenesis of neurotransmitters. Moreover, human astrocyte infection elicits a secretory phenotype that reduces neuronal viability. Our data support the model in which SARS-CoV-2 reaches the brain, infects astrocytes, and consequently, leads to neuronal death or dysfunction. These deregulated processes could contribute to the structural and functional alterations seen in the brains of COVID-19 patients.


Subject(s)
Brain , COVID-19 , Central Nervous System Viral Diseases , SARS-CoV-2 , Astrocytes/pathology , Astrocytes/virology , Brain/pathology , Brain/virology , COVID-19/complications , COVID-19/pathology , Central Nervous System Viral Diseases/etiology , Central Nervous System Viral Diseases/pathology , Humans
2.
Front Cell Infect Microbiol ; 12: 849017, 2022.
Article in English | MEDLINE | ID: covidwho-1952255

ABSTRACT

SARS-CoV-2 is an emerging virus from the Coronaviridae family and is responsible for the ongoing COVID-19 pandemic. In this work, we explored the previously reported SARS-CoV-2 structural membrane protein (M) interaction with human Proliferating Cell Nuclear Antigen (PCNA). The M protein is responsible for maintaining virion shape, and PCNA is a marker of DNA damage which is essential for DNA replication and repair. We validated the M-PCNA interaction through immunoprecipitation, immunofluorescence co-localization, and PLA (Proximity Ligation Assay). In cells infected with SARS-CoV-2 or transfected with M protein, using immunofluorescence and cell fractioning, we documented a reallocation of PCNA from the nucleus to the cytoplasm and the increase of PCNA and γH2AX (another DNA damage marker) expression. We also observed an increase in PCNA and γH2AX expression in the lung of a COVID-19 patient by immunohistochemistry. In addition, the inhibition of PCNA translocation by PCNA I1 and Verdinexor led to a reduction of plaque formation in an in vitro assay. We, therefore, propose that the transport of PCNA to the cytoplasm and its association with M could be a virus strategy to manipulate cell functions and may be considered a target for COVID-19 therapy.


Subject(s)
COVID-19 , Coronavirus M Proteins , Proliferating Cell Nuclear Antigen , COVID-19/drug therapy , Coronavirus M Proteins/metabolism , Humans , Proliferating Cell Nuclear Antigen/metabolism , SARS-CoV-2
3.
Arq Bras Oftalmol ; 2022 Mar 21.
Article in English | MEDLINE | ID: covidwho-1761094

ABSTRACT

Coronavirus disease (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Its main form of transmission is through respiratory droplets. Case reports have described the presence of this virus in biological materials such as blood, feces, urine, and tears, which generate hypotheses about other means thereby the disease is transmitted. In this report, we describe a case of SARS-CoV-2 identified on the eye surface of an asymptomatic health-care professional. The nasopharyngeal reverse transcription polymerase chain reaction test, using a sample collected on the same day, and the serological test, performed 3 months later, did not reveal any evidence of SARS-CoV-2 infection. These results alert on the possibility of a false-positive reverse transcription polymerase chain reaction result for the ocular surface or the presence of the virus in the conjunctival mucosa in individuals without infection.

4.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-297097

ABSTRACT

SARS-CoV-2 is an emerging virus from the Coronaviridae family and is responsible for the ongoing COVID-19 pandemic. In this work, we explored the previously reported SARS-CoV-2 structural membrane protein (M) interaction with human Proliferating Cell Nuclear Antigen (PCNA). The M protein is responsible for maintaining virion shape, and PCNA is a marker of DNA damage which is essential for DNA replication and repair. We validated the M PCNA interaction through immunoprecipitation, immunofluorescence co-localization, and a PLA assay. In cells infected with SARS-CoV-2 or transfected with M protein, using immunofluorescence and cell fractioning, we documented a reallocation of PCNA from the nucleus to the cytoplasm and the increase of PCNA and γH2AX (another DNA damage marker) expression. We also observed an increase of PCNA and γH2AX expression in the lung of a COVID-19 patient by immunohistochemistry. In addition, the inhibition of PCNA translocation by PCNA I1 and Verdinexor led to a reduction of plaque formation in an in vitro assay. We, therefore, propose that the transport of PCNA to the cytoplasm and its association with M could be a virus strategy to manipulate cell functions and may be considered a target for COVID-19 therapy.

6.
Gut Microbes ; 13(1): 1-9, 2021.
Article in English | MEDLINE | ID: covidwho-1069185

ABSTRACT

Microbiota-derived molecules called short-chain fatty acids (SCFAs) play a key role in the maintenance of the intestinal barrier and regulation of immune response during infectious conditions. Recent reports indicate that SARS-CoV-2 infection changes microbiota and SCFAs production. However, the relevance of this effect is unknown. In this study, we used human intestinal biopsies and intestinal epithelial cells to investigate the impact of SCFAs in the infection by SARS-CoV-2. SCFAs did not change the entry or replication of SARS-CoV-2 in intestinal cells. These metabolites had no effect on intestinal cells' permeability and presented only minor effects on the production of anti-viral and inflammatory mediators. Together our findings indicate that the changes in microbiota composition of patients with COVID-19 and, particularly, of SCFAs do not interfere with the SARS-CoV-2 infection in the intestine.


Subject(s)
COVID-19/virology , Fatty Acids, Volatile/metabolism , Gastrointestinal Microbiome , Intestinal Mucosa/virology , Adult , Aged , Caco-2 Cells , Colon/virology , Epithelial Cells/virology , Female , Humans , In Vitro Techniques , Male , Middle Aged , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , Viral Load , Virus Internalization , Young Adult
7.
Cell Metab ; 32(3): 437-446.e5, 2020 09 01.
Article in English | MEDLINE | ID: covidwho-670096

ABSTRACT

COVID-19 can result in severe lung injury. It remained to be determined why diabetic individuals with uncontrolled glucose levels are more prone to develop the severe form of COVID-19. The molecular mechanism underlying SARS-CoV-2 infection and what determines the onset of the cytokine storm found in severe COVID-19 patients are unknown. Monocytes and macrophages are the most enriched immune cell types in the lungs of COVID-19 patients and appear to have a central role in the pathogenicity of the disease. These cells adapt their metabolism upon infection and become highly glycolytic, which facilitates SARS-CoV-2 replication. The infection triggers mitochondrial ROS production, which induces stabilization of hypoxia-inducible factor-1α (HIF-1α) and consequently promotes glycolysis. HIF-1α-induced changes in monocyte metabolism by SARS-CoV-2 infection directly inhibit T cell response and reduce epithelial cell survival. Targeting HIF-1ɑ may have great therapeutic potential for the development of novel drugs to treat COVID-19.


Subject(s)
Betacoronavirus/physiology , Blood Glucose/metabolism , Coronavirus Infections/complications , Diabetes Complications/complications , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Monocytes/metabolism , Pneumonia, Viral/complications , Adult , COVID-19 , Cell Line , Coronavirus Infections/metabolism , Diabetes Complications/metabolism , Diabetes Mellitus/metabolism , Female , Glycolysis , Humans , Inflammation/complications , Inflammation/metabolism , Male , Middle Aged , Monocytes/virology , Pandemics , Pneumonia, Viral/metabolism , Reactive Oxygen Species/metabolism , SARS-CoV-2 , Signal Transduction
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