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1.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-317754

ABSTRACT

Background: The pathogenesis of SARS-CoV-2 remains to be defined. Elucidating SARS-CoV-2 cellular localization within cells and its cytopathic effects requires definition. We performed a comparative ultrastructural study of SARS-CoV-2 infection of Vero-6 cells and lung from COVID-19 patients. Main findings: SARS-CoV-2 induces rapid ultrastructural changes and death in Vero cells. Ultrastructural changes in SARS-CoV-2 infection differ from those in SARS-CoV-1. Type II pneumocytes in lung tissue showed prominent altered morphological features with numerous vacuoles and swollen mitochondria with presence of abundant lipid droplets. The accumulation of lipid droplets was the most striking finding we observed in cultured cells and in infected pneumocytes. Virus particles were also found associated with lipo-lysosomes suggesting that they can play an important step in virus assembly. Interpretation: The cytopathology of SARS-CoV-2 appears to be different to that caused by SARS-CoV-1. Our findings highlight important open topics which may represent future targets to contrast the pathogenicity of SARS-CoV-2.

2.
Cells ; 11(1)2021 12 24.
Article in English | MEDLINE | ID: covidwho-1580994

ABSTRACT

The ongoing pandemic of coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), needs better treatment options both at antiviral and anti-inflammatory levels. It has been demonstrated that the aminothiol cysteamine, an already human applied drug, and its disulfide product of oxidation, cystamine, have anti-infective properties targeting viruses, bacteria, and parasites. To determine whether these compounds exert antiviral effects against SARS-CoV-2, we used different in vitro viral infected cell-based assays. Moreover, since cysteamine has also immune-modulatory activity, we investigated its ability to modulate SARS-CoV-2-specific immune response in vitro in blood samples from COVID-19 patients. We found that cysteamine and cystamine decreased SARS-CoV-2-induced cytopathic effects (CPE) in Vero E6 cells. Interestingly, the antiviral action was independent of the treatment time respect to SARS-CoV-2 infection. Moreover, cysteamine and cystamine significantly decreased viral production in Vero E6 and Calu-3 cells. Finally, cysteamine and cystamine have an anti-inflammatory effect, as they significantly decrease the SARS-CoV-2 specific IFN-γ production in vitro in blood samples from COVID-19 patients. Overall, our findings suggest that cysteamine and cystamine exert direct antiviral actions against SARS-CoV-2 and have in vitro immunomodulatory effects, thus providing a rational to test these compounds as a novel therapy for COVID-19.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Cysteamine/pharmacology , Drug Repositioning/methods , SARS-CoV-2/drug effects , Aged , Animals , COVID-19/virology , Cell Line, Tumor , Chlorocebus aethiops , Cystamine/pharmacology , Cystine Depleting Agents/pharmacology , Female , Humans , Male , Middle Aged , RNA, Viral/genetics , RNA, Viral/metabolism , SARS-CoV-2/genetics , SARS-CoV-2/physiology , Vero Cells , Virus Replication/drug effects , Virus Replication/genetics
3.
J Transl Med ; 19(1): 501, 2021 12 07.
Article in English | MEDLINE | ID: covidwho-1560461

ABSTRACT

BACKGROUND: Omics data, driven by rapid advances in laboratory techniques, have been generated very quickly during the COVID-19 pandemic. Our aim is to use omics data to highlight the involvement of specific pathways, as well as that of cell types and organs, in the pathophysiology of COVID-19, and to highlight their links with clinical phenotypes of SARS-CoV-2 infection. METHODS: The analysis was based on the domain model, where for domain it is intended a conceptual repository, useful to summarize multiple biological pathways involved at different levels. The relevant domains considered in the analysis were: virus, pathways and phenotypes. An interdisciplinary expert working group was defined for each domain, to carry out an independent literature scoping review. RESULTS: The analysis revealed that dysregulated pathways of innate immune responses, (i.e., complement activation, inflammatory responses, neutrophil activation and degranulation, platelet degranulation) can affect COVID-19 progression and outcomes. These results are consistent with several clinical studies. CONCLUSIONS: Multi-omics approach may help to further investigate unknown aspects of the disease. However, the disease mechanisms are too complex to be explained by a single molecular signature and it is necessary to consider an integrated approach to identify hallmarks of severity.


Subject(s)
COVID-19 , Humans , Immunity, Innate , Pandemics , SARS-CoV-2
4.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-296091

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is highly contagious and causes lymphocytopenia, but the underlying mechanisms are poorly understood. We demonstrate here that heterotypic cell-in-cell structures with lymphocytes inside multinucleate syncytia are prevalent in the lung tissues of coronavirus disease 2019 (COVID-19) patients. These unique cellular structures are a direct result of SARS-CoV-2 infection, as the expression of the SARS-CoV-2 spike glycoprotein is sufficient to induce a rapid (approximately 45.1 nm/sec) membrane fusion to produce syncytium, which could readily internalize multiple lines of lymphocytes to form typical cell-in-cell structures, remarkably leading to the death of internalized cells. This membrane fusion is dictated by a bi-arginine motif within the polybasic S1/S2 cleavage site, which is frequently present in the surface glycoprotein of most highly contagious viruses. Moreover, candidate anti-viral drugs could efficiently inhibit spike glycoprotein processing, membrane fusion, and cell-in-cell formation. Together, we delineate a molecular and cellular rationale for SARS-CoV-2 pathogenesis and identify novel targets for COVID-19 therapy.

5.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-293601

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is highly contagious and causes lymphocytopenia, but the underlying mechanisms are poorly understood. We demonstrate here that heterotypic cell-in-cell structures with lymphocytes inside multinucleate syncytia are prevalent in the lung tissues of coronavirus disease 2019 (COVID-19) patients. These unique cellular structures are a direct result of SARS-CoV-2 infection, as the expression of the SARS-CoV-2 spike glycoprotein is sufficient to induce a rapid (approximately 45.1 nm/sec) membrane fusion to produce syncytium, which could readily internalize multiple lines of lymphocytes to form typical cell-in-cell structures, remarkably leading to the death of internalized cells. This membrane fusion is dictated by a bi-arginine motif within the polybasic S1/S2 cleavage site, which is frequently present in the surface glycoprotein of most highly contagious viruses. Moreover, candidate anti-viral drugs could efficiently inhibit spike glycoprotein processing, membrane fusion, and cell-in-cell formation. Together, we delineate a molecular and cellular rationale for SARS-CoV-2 pathogenesis and identify novel targets for COVID-19 therapy.

6.
Sci Transl Med ; 14(627): eabj1996, 2022 Jan 12.
Article in English | MEDLINE | ID: covidwho-1483986

ABSTRACT

Safe and effective vaccines against coronavirus disease 2019 (COVID-19) are essential for ending the ongoing pandemic. Although impressive progress has been made with several COVID-19 vaccines already approved, it is clear that those developed so far cannot meet the global vaccine demand alone. We describe a COVID-19 vaccine based on a replication-defective gorilla adenovirus expressing the stabilized prefusion severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein named GRAd-COV2. We assessed the safety and immunogenicity of a single-dose regimen of this vaccine in healthy younger and older adults to select the appropriate dose for each age group. For this purpose, a phase 1, dose-escalation, open-labeled trial was conducted including 90 healthy participants (45 aged 18 to 55 years old and 45 aged 65 to 85 years old) who received a single intramuscular administration of GRAd-COV2 at three escalating doses. Local and systemic adverse reactions were mostly mild or moderate and of short duration, and no serious adverse events were reported. Four weeks after vaccination, seroconversion to spike protein and receptor binding domain was achieved in 43 of 44 young volunteers and in 45 of 45 older participants. Consistently, neutralizing antibodies were detected in 42 of 44 younger-age and 45 of 45 older-age volunteers. In addition, GRAd-COV2 induced a robust and T helper 1 cell (TH1)­skewed T cell response against the spike protein in 89 of 90 participants from both age groups. Overall, the safety and immunogenicity data from the phase 1 trial support the further development of this vaccine.


Subject(s)
Adenovirus Vaccines , COVID-19 , Adenoviridae , Aged , Animals , COVID-19 Vaccines , Gorilla gorilla , Humans , SARS-CoV-2
7.
Cells ; 10(9)2021 08 31.
Article in English | MEDLINE | ID: covidwho-1390541

ABSTRACT

COVID-19 presents with a wide range of clinical neurological manifestations. It has been recognized that SARS-CoV-2 infection affects both the central and peripheral nervous system, leading to smell and taste disturbances; acute ischemic and hemorrhagic cerebrovascular disease; encephalopathies and seizures; and causes most surviving patients to have long lasting neurological symptoms. Despite this, typical neuropathological features associated with the infection have still not been identified. Studies of post-mortem examinations of the cerebral cortex are obtained with difficulty due to laboratory safety concerns. In addition, they represent cases with different neurological symptoms, age or comorbidities, thus a larger number of brain autoptic data from multiple institutions would be crucial. Histopathological findings described here are aimed to increase the current knowledge on neuropathology of COVID-19 patients. We report post-mortem neuropathological findings of ten COVID-19 patients. A wide range of neuropathological lesions were seen. The cerebral cortex of all patients showed vascular changes, hyperemia of the meninges and perivascular inflammation in the cerebral parenchyma with hypoxic neuronal injury. Perivascular lymphocytic inflammation of predominantly CD8-positive T cells mixed with CD68-positive macrophages, targeting the disrupted vascular wall in the cerebral cortex, cerebellum and pons were seen. Our findings support recent reports highlighting a role of microvascular injury in COVID-19 neurological manifestations.


Subject(s)
COVID-19/pathology , Cerebral Cortex/pathology , Aged , Aged, 80 and over , Autopsy , Brain/pathology , Brain/virology , Brain Diseases/pathology , Brain Diseases/virology , CD8-Positive T-Lymphocytes/pathology , Cerebral Cortex/virology , Female , Humans , Inflammation , Macrophages/pathology , Male , Microvessels/pathology , Microvessels/virology , Middle Aged , Nervous System Diseases/pathology , Nervous System Diseases/virology , SARS-CoV-2/pathogenicity
8.
Viruses ; 13(7)2021 07 06.
Article in English | MEDLINE | ID: covidwho-1302499

ABSTRACT

Complex systems are inherently multilevel and multiscale systems. The infectious disease system is considered a complex system resulting from the interaction between three sub-systems (host, pathogen, and environment) organized into a hierarchical structure, ranging from the cellular to the macro-ecosystem level, with multiscales. Therefore, to describe infectious disease phenomena that change through time and space and at different scales, we built a model framework where infectious disease must be considered the set of biological responses of human hosts to pathogens, with biological pathways shared with other pathologies in an ecological interaction context. In this paper, we aimed to design a framework for building a disease model for COVID-19 based on current literature evidence. The model was set up by identifying the molecular pathophysiology related to the COVID-19 phenotypes, collecting the mechanistic knowledge scattered across scientific literature and bioinformatic databases, and integrating it using a logical/conceptual model systems biology. The model framework building process began from the results of a domain-based literature review regarding a multiomics approach to COVID-19. This evidence allowed us to define a framework of COVID-19 conceptual model and to report all concepts in a multilevel and multiscale structure. The same interdisciplinary working groups that carried out the scoping review were involved. The conclusive result is a conceptual method to design multiscale models of infectious diseases. The methodology, applied in this paper, is a set of partially ordered research and development activities that result in a COVID-19 multiscale model.

9.
Cells ; 10(5)2021 05 04.
Article in English | MEDLINE | ID: covidwho-1223957

ABSTRACT

Liver injury in COVID-19 patients has progressively emerged, even in those without a history of liver disease, yet the mechanism of liver pathogenicity is still controversial. COVID-19 is frequently associated with increased serum ferritin levels, and hyperferritinemia was shown to correlate with illness severity. The liver is the major site for iron storage, and conditions of iron overload have been established to have a pathogenic role in development of liver diseases. We presented here six patients who developed severe COVID-19, with biochemical evidence of liver failure. Three cases were survived patients, who underwent liver biopsy; the other three were deceased patients, who were autopsied. None of the patients suffered underlying liver pathologies. Histopathological and ultrastructural analyses were performed. The most striking finding we demonstrated in all patients was iron accumulation into hepatocytes, associated with degenerative changes. Abundant ferritin particles were found enclosed in siderosomes, and large aggregates of hemosiderin were found, often in close contact with damaged mitochondria. Iron-caused oxidative stress may be responsible for mitochondria metabolic dysfunction. In agreement with this, association between mitochondria and lipid droplets was also found. Overall, our data suggest that hepatic iron overload could be the pathogenic trigger of liver injury associated to COVID-19.


Subject(s)
COVID-19/diagnosis , Iron Overload/etiology , Liver Failure/etiology , Liver/pathology , Severity of Illness Index , Adult , Aged , Antiviral Agents , Biopsy , COVID-19/complications , COVID-19/mortality , COVID-19/therapy , Female , Ferritins/analysis , Hepatocytes/cytology , Hepatocytes/pathology , Humans , Iron/analysis , Iron/metabolism , Iron Overload/mortality , Iron Overload/pathology , Iron Overload/therapy , Liver/cytology , Liver/metabolism , Liver Failure/mortality , Liver Failure/pathology , Liver Failure/therapy , Liver Function Tests , Male , Middle Aged , Mitochondria/pathology , Positive-Pressure Respiration , SARS-CoV-2/isolation & purification
10.
J Immunol ; 206(10): 2420-2429, 2021 05 15.
Article in English | MEDLINE | ID: covidwho-1215526

ABSTRACT

We have recently shown that type 2 transglutaminase (TG2) plays a key role in the host's inflammatory response during bacterial infections. In this study, we investigated whether the enzyme is involved in the regulation of the STING pathway, which is the main signaling activated in the presence of both self- and pathogen DNA in the cytoplasm, leading to type I IFN (IFN I) production. In this study, we demonstrated that TG2 negatively regulates STING signaling by impairing IRF3 phosphorylation in bone marrow-derived macrophages, isolated from wild-type and TG2 knockout mice. In the absence of TG2, we found an increase in the IFN-ß production and in the downstream JAK/STAT pathway activation. Interestingly, proteomic analysis revealed that TG2 interacts with TBK1, affecting its interactome composition. Indeed, TG2 ablation facilitates the TBK1-IRF3 interaction, thus indicating that the enzyme plays a negative regulatory effect on IRF3 recruitment in the STING/TBK1 complex. In keeping with these findings, we observed an increase in the IFNß production in bronchoalveolar lavage fluids from COVID-19-positive dead patients paralleled by a dramatic decrease of the TG2 expression in the lung pneumocytes. Taken together, these results suggest that TG2 plays a negative regulation on the IFN-ß production associated with the innate immunity response to the cytosolic presence of both self- and pathogen DNA.


Subject(s)
COVID-19/immunology , GTP-Binding Proteins/immunology , Immunity, Innate , Interferon Regulatory Factor-3/immunology , Membrane Proteins/immunology , SARS-CoV-2/immunology , Signal Transduction/immunology , Transglutaminases/immunology , Animals , COVID-19/genetics , COVID-19/pathology , GTP-Binding Proteins/genetics , Humans , Interferon Regulatory Factor-3/genetics , Interferon-beta/genetics , Interferon-beta/immunology , Membrane Proteins/genetics , Mice , Mice, Knockout , Signal Transduction/genetics , Transglutaminases/genetics
11.
Cell Death Differ ; 28(9): 2765-2777, 2021 09.
Article in English | MEDLINE | ID: covidwho-1195611

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is highly contagious and causes lymphocytopenia, but the underlying mechanisms are poorly understood. We demonstrate here that heterotypic cell-in-cell structures with lymphocytes inside multinucleate syncytia are prevalent in the lung tissues of coronavirus disease 2019 (COVID-19) patients. These unique cellular structures are a direct result of SARS-CoV-2 infection, as the expression of the SARS-CoV-2 spike glycoprotein is sufficient to induce a rapid (~45.1 nm/s) membrane fusion to produce syncytium, which could readily internalize multiple lines of lymphocytes to form typical cell-in-cell structures, remarkably leading to the death of internalized cells. This membrane fusion is dictated by a bi-arginine motif within the polybasic S1/S2 cleavage site, which is frequently present in the surface glycoprotein of most highly contagious viruses. Moreover, candidate anti-viral drugs could efficiently inhibit spike glycoprotein processing, membrane fusion, and cell-in-cell formation. Together, we delineate a molecular and cellular rationale for SARS-CoV-2 pathogenesis and identify novel targets for COVID-19 therapy.


Subject(s)
COVID-19/virology , Giant Cells/virology , Lymphocytes/virology , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/metabolism , COVID-19/pathology , Cell Line , Cell Line, Tumor , Giant Cells/pathology , HEK293 Cells , HeLa Cells , Humans , Jurkat Cells , K562 Cells , Lymphocytes/pathology , Virus Internalization , Virus Replication/genetics
12.
Int J Mol Sci ; 22(8)2021 Apr 15.
Article in English | MEDLINE | ID: covidwho-1186970

ABSTRACT

The family of coronaviruses (CoVs) uses the autophagy machinery of host cells to promote their growth and replication; thus, this process stands out as a potential target to combat COVID-19. Considering the different roles of autophagy during viral infection, including SARS-CoV-2 infection, in this review, we discuss several clinically used drugs that have effects at different stages of autophagy. Among them, we mention (1) lysosomotropic agents, which can prevent CoVs infection by alkalinizing the acid pH in the endolysosomal system, such as chloroquine and hydroxychloroquine, azithromycin, artemisinins, two-pore channel modulators and imatinib; (2) protease inhibitors that can inhibit the proteolytic cleavage of the spike CoVs protein, which is necessary for viral entry into host cells, such as camostat mesylate, lopinavir, umifenovir and teicoplanin and (3) modulators of PI3K/AKT/mTOR signaling pathways, such as rapamycin, heparin, glucocorticoids, angiotensin-converting enzyme inhibitors (IECAs) and cannabidiol. Thus, this review aims to highlight and discuss autophagy-related drugs for COVID-19, from in vitro to in vivo studies. We identified specific compounds that may modulate autophagy and exhibit antiviral properties. We hope that research initiatives and efforts will identify novel or "off-label" drugs that can be used to effectively treat patients infected with SARS-CoV-2, reducing the risk of mortality.


Subject(s)
Autophagy/drug effects , COVID-19/drug therapy , Molecular Targeted Therapy , Humans , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Signal Transduction , Virus Replication/drug effects , Virus Replication/physiology
13.
Antiviral Res ; 190: 105064, 2021 06.
Article in English | MEDLINE | ID: covidwho-1157118

ABSTRACT

COVID-19 is currently a highly pressing health threat and therapeutic strategies to mitigate the infection impact are urgently needed. Characterization of the SARS-CoV-2 interactome in infected cells may represent a powerful tool to identify cellular proteins hijacked by viruses for their life cycle and develop host-oriented antiviral therapeutics. Here we report the proteomic characterization of host proteins interacting with SARS-CoV-2 Nucleoprotein in infected Vero E6 cells. We identified 24 high-confidence proteins mainly playing a role in RNA metabolism and translation, including RNA helicases and scaffold proteins involved in the formation of stress granules, cytoplasmic aggregates of messenger ribonucleoproteins that accumulate as a result of stress-induced translation arrest. Analysis of stress granules upon SARS-CoV-2 infection showed that these structures are not induced in infected cells, neither eIF2α phosphorylation, an upstream event leading to stress-induced translation inhibition. Notably, we found that G3BP1, a stress granule component that associates with the Nucleoprotein, is required for efficient SARS-CoV-2 replication. Moreover, we showed that the Nucleoprotein-interacting RNA helicase DDX3X colocalizes with viral RNA foci and its inhibition by small molecules or small interfering RNAs significantly reduces viral replication. Altogether, these results indicate that SARS-CoV-2 subverts the stress granule machinery and exploits G3BP1 and DDX3X for its replication cycle, offering groundwork for future development of host-directed therapies.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/metabolism , DEAD-box RNA Helicases/metabolism , Animals , COVID-19/virology , Cell Line , Chlorocebus aethiops , DNA Helicases , Eukaryotic Initiation Factor-2/metabolism , Host-Pathogen Interactions , Humans , Poly-ADP-Ribose Binding Proteins/genetics , Poly-ADP-Ribose Binding Proteins/metabolism , Proteomics/methods , RNA Helicases , RNA Recognition Motif Proteins/metabolism , RNA, Small Interfering/metabolism , RNA, Viral/metabolism , SARS-CoV-2/metabolism , Vero Cells , Virus Replication/physiology
14.
Cell Death Dis ; 12(3): 263, 2021 03 12.
Article in English | MEDLINE | ID: covidwho-1132058

ABSTRACT

The pathogenesis of SARS-CoV-2 remains to be completely understood, and detailed SARS-CoV-2 cellular cytopathic effects requires definition. We performed a comparative ultrastructural study of SARS-CoV-1 and SARS-CoV-2 infection in Vero E6 cells and in lungs from deceased COVID-19 patients. SARS-CoV-2 induces rapid death associated with profound ultrastructural changes in Vero cells. Type II pneumocytes in lung tissue showed prominent altered features with numerous vacuoles and swollen mitochondria with presence of abundant lipid droplets. The accumulation of lipids was the most striking finding we observed in SARS-CoV-2 infected cells, both in vitro and in the lungs of patients, suggesting that lipids can be involved in SARS-CoV-2 pathogenesis. Considering that in most cases, COVID-19 patients show alteration of blood cholesterol and lipoprotein homeostasis, our findings highlight a peculiar important topic that can suggest new approaches for pharmacological treatment to contrast the pathogenicity of SARS-CoV-2.


Subject(s)
COVID-19 , Lipid Droplets , Lipid Metabolism , Lung , SARS-CoV-2/metabolism , Animals , COVID-19/metabolism , COVID-19/pathology , Chlorocebus aethiops , Cytopathogenic Effect, Viral , Humans , Lipid Droplets/ultrastructure , Lipid Droplets/virology , Lung/metabolism , Lung/ultrastructure , Lung/virology , SARS Virus/metabolism , SARS Virus/ultrastructure , SARS-CoV-2/ultrastructure , Severe Acute Respiratory Syndrome/metabolism , Severe Acute Respiratory Syndrome/pathology , Vero Cells
15.
Cardiovasc Res ; 117(6): 1557-1566, 2021 05 25.
Article in English | MEDLINE | ID: covidwho-1127334

ABSTRACT

AIMS: Patients with severe respiratory syndrome caused by SARS-CoV-2 undergo cardiac complications due to hyper-inflammatory conditions. Although the presence of the virus has been detected in the myocardium of infected patients, and infection of induced pluripotent cell-derived cardiomyocytes has been demonstrated, the reported expression of Angiotensin-Converting Enzyme-2 (ACE2) in cardiac stromal cells suggests that SARS-CoV-2 may determine cardiac injury by sustaining productive infection and increasing inflammation. METHODS AND RESULTS: We analysed expression of ACE2 receptor in primary human cardiac stromal cells derived from cardiospheres, using proteomics and transcriptomics before exposing them to SARS-CoV-2 in vitro. Using conventional and high sensitivity PCR methods, we measured virus release in the cellular supernatants and monitored the intracellular viral bioprocessing. We performed high-resolution imaging to show the sites of intracellular viral production and demonstrated the presence of viral particles in the cells with electron microscopy. We finally used RT-qPCR assays to detect genes linked to innate immunity and fibrotic pathways coherently regulated in cells after exposure to the virus. CONCLUSIONS: Our findings indicate that cardiac stromal cells are susceptible to SARS-CoV-2 infection and produce variable viral yields depending on the extent of cellular ACE2 receptor expression. Interestingly, these cells also evolved towards hyper-inflammatory/pro-fibrotic phenotypes independently of ACE2 levels. Thus, SARS-CoV-2 infection of myocardial stromal cells could be involved in cardiac injury and explain the high number of complications observed in severe cases of COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/virology , Heart Diseases/virology , Myocardium/enzymology , Receptors, Virus/metabolism , SARS-CoV-2/pathogenicity , Stromal Cells/virology , Virion/pathogenicity , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/genetics , Animals , COVID-19/complications , Chlorocebus aethiops , Female , Fibrosis , Heart Diseases/enzymology , Heart Diseases/pathology , Host-Pathogen Interactions , Humans , Inflammation Mediators/metabolism , Male , Middle Aged , Myocardium/ultrastructure , Phenotype , Receptors, Virus/genetics , SARS-CoV-2/ultrastructure , Spheroids, Cellular , Stromal Cells/enzymology , Stromal Cells/ultrastructure , Vero Cells , Virion/ultrastructure
16.
J Infect Dis ; 222(11): 1807-1815, 2020 11 09.
Article in English | MEDLINE | ID: covidwho-919293

ABSTRACT

BACKGROUND: Descriptions of the pathological features of coronavirus disease-2019 (COVID-19) caused by the novel zoonotic pathogen severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emanate from tissue biopsies, case reports, and small postmortem studies restricted to the lung and specific organs. Whole-body autopsy studies of COVID-19 patients have been sparse. METHODS: To further define the pathology caused by SARS-CoV-2 across all body organs, we performed autopsies on 22 patients with COVID-19 (18 with comorbidities and 4 without comorbidities) who died at the National Institute for Infectious Diseases Lazzaro Spallanzani-IRCCS Hospital, Rome, Italy. Tissues from the lung, heart, liver, kidney, spleen, and bone marrow (but not the brain) were examined. Only lung tissues were subject to transmission electron microscopy. RESULTS: COVID-19 caused multisystem pathology. Pulmonary and cardiovascular involvement were dominant pathological features. Extrapulmonary manifestations included hepatic, kidney, splenic, and bone marrow involvement, and microvascular injury and thrombosis were also detected. These findings were similar in patients with or without preexisting medical comorbidities. CONCLUSIONS: SARS-CoV-2 infection causes multisystem disease and significant pathology in most organs in patients with and without comorbidities.


Subject(s)
COVID-19/pathology , Adult , Aged , Aged, 80 and over , Autopsy/methods , Bone Marrow/pathology , COVID-19/epidemiology , COVID-19/virology , Comorbidity , Female , Humans , Italy/epidemiology , Kidney/pathology , Liver/pathology , Lung/pathology , Male , Middle Aged , Spleen/pathology , Thrombosis/pathology , Vascular Diseases/pathology , Vascular Diseases/virology
17.
Oncoimmunology ; 9(1): 1807836, 2020 08 25.
Article in English | MEDLINE | ID: covidwho-741761

ABSTRACT

Over the past 16 years, three coronaviruses (CoVs), severe acute respiratory syndrome CoV (SARS-CoV) in 2002, Middle East respiratory syndrome CoV (MERS-CoV) in 2012 and 2015, and SARS-CoV-2 in 2020, have been causing severe and fatal human epidemics. The unpredictability of coronavirus disease-19 (COVID-19) poses a major burden on health care and economic systems across the world. This is caused by the paucity of in-depth knowledge of the risk factors for severe COVID-19, insufficient diagnostic tools for the detection of SARS-CoV-2, as well as the absence of specific and effective drug treatments. While protective humoral and cellular immune responses are usually mounted against these betacoronaviruses, immune responses to SARS-CoV2 sometimes derail towards inflammatory tissue damage, leading to rapid admissions to intensive care units. The lack of knowledge on mechanisms that tilt the balance between these two opposite outcomes poses major threats to many ongoing clinical trials dealing with immunostimulatory or immunoregulatory therapeutics. This review will discuss innate and cognate immune responses underlying protective or deleterious immune reactions against these pathogenic coronaviruses.


Subject(s)
COVID-19/immunology , Host Microbial Interactions/immunology , SARS-CoV-2/immunology , COVID-19/diagnosis , COVID-19/virology , Humans , Immunity, Cellular , Immunity, Humoral , Middle East Respiratory Syndrome Coronavirus/immunology , Protective Factors , Risk Factors , SARS Virus/immunology , Severity of Illness Index
18.
Cell Death Dis ; 11(8): 656, 2020 08 19.
Article in English | MEDLINE | ID: covidwho-725491

ABSTRACT

The current epidemic of coronavirus disease-19 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) calls for the development of inhibitors of viral replication. Here, we performed a bioinformatic analysis of published and purported SARS-CoV-2 antivirals including imatinib mesylate that we found to suppress SARS-CoV-2 replication on Vero E6 cells and that, according to the published literature on other coronaviruses is likely to act on-target, as a tyrosine kinase inhibitor. We identified a cluster of SARS-CoV-2 antivirals with characteristics of lysosomotropic agents, meaning that they are lipophilic weak bases capable of penetrating into cells. These agents include cepharentine, chloroquine, chlorpromazine, clemastine, cloperastine, emetine, hydroxychloroquine, haloperidol, ML240, PB28, ponatinib, siramesine, and zotatifin (eFT226) all of which are likely to inhibit SARS-CoV-2 replication by non-specific (off-target) effects, meaning that they probably do not act on their 'official' pharmacological targets, but rather interfere with viral replication through non-specific effects on acidophilic organelles including autophagosomes, endosomes, and lysosomes. Imatinib mesylate did not fall into this cluster. In conclusion, we propose a tentative classification of SARS-CoV-2 antivirals into specific (on-target) versus non-specific (off-target) agents based on their physicochemical characteristics.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/metabolism , Drug Evaluation, Preclinical/methods , Pneumonia, Viral/metabolism , Virus Replication/drug effects , Animals , Antiviral Agents/pharmacology , COVID-19 , Cell Death/drug effects , Chlorocebus aethiops , Coronavirus Infections/virology , Hydroxychloroquine/pharmacology , Imatinib Mesylate/pharmacology , Lysosomes/drug effects , Pandemics , Pneumonia, Viral/virology , Protein Kinase Inhibitors/pharmacology , RNA, Viral/drug effects , SARS-CoV-2 , Vero Cells , Viral Load/drug effects
19.
J Transl Med ; 18(1): 233, 2020 06 10.
Article in English | MEDLINE | ID: covidwho-592324

ABSTRACT

BACKGROUND: Epidemiological, virological and pathogenetic characteristics of SARS-CoV-2 infection are under evaluation. A better understanding of the pathophysiology associated with COVID-19 is crucial to improve treatment modalities and to develop effective prevention strategies. Transcriptomic and proteomic data on the host response against SARS-CoV-2 still have anecdotic character; currently available data from other coronavirus infections are therefore a key source of information. METHODS: We investigated selected molecular aspects of three human coronavirus (HCoV) infections, namely SARS-CoV, MERS-CoV and HCoV-229E, through a network based-approach. A functional analysis of HCoV-host interactome was carried out in order to provide a theoretic host-pathogen interaction model for HCoV infections and in order to translate the results in prediction for SARS-CoV-2 pathogenesis. The 3D model of S-glycoprotein of SARS-CoV-2 was compared to the structure of the corresponding SARS-CoV, HCoV-229E and MERS-CoV S-glycoprotein. SARS-CoV, MERS-CoV, HCoV-229E and the host interactome were inferred through published protein-protein interactions (PPI) as well as gene co-expression, triggered by HCoV S-glycoprotein in host cells. RESULTS: Although the amino acid sequences of the S-glycoprotein were found to be different between the various HCoV, the structures showed high similarity, but the best 3D structural overlap shared by SARS-CoV and SARS-CoV-2, consistent with the shared ACE2 predicted receptor. The host interactome, linked to the S-glycoprotein of SARS-CoV and MERS-CoV, mainly highlighted innate immunity pathway components, such as Toll Like receptors, cytokines and chemokines. CONCLUSIONS: In this paper, we developed a network-based model with the aim to define molecular aspects of pathogenic phenotypes in HCoV infections. The resulting pattern may facilitate the process of structure-guided pharmaceutical and diagnostic research with the prospect to identify potential new biological targets.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/genetics , Coronavirus Infections/virology , Gene Regulatory Networks , Host-Pathogen Interactions , Models, Biological , Pneumonia, Viral/genetics , Pneumonia, Viral/virology , Protein Interaction Mapping , COVID-19 , Humans , Membrane Glycoproteins/metabolism , Pandemics , SARS-CoV-2 , Signal Transduction/genetics , Viral Envelope Proteins
20.
Cell Death Dis ; 11(6): 438, 2020 06 08.
Article in English | MEDLINE | ID: covidwho-591593

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the COVID-19 pandemic. Since its first report in December 2019, despite great efforts made in almost every country worldwide, this disease continues to spread globally, especially in most parts of Europe, Iran, and the United States. Here, we update the recent understanding in clinical characteristics, diagnosis strategies, as well as clinical management of COVID-19 in China as compared to Italy, with the purpose to integrate the China experience with the global efforts to outline references for prevention, basic research, treatment as well as final control of the disease. Being the first two countries we feel appropriate to evaluate the evolution of the disease as well as the early result of the treatment, in order to offer a different baseline to other countries. It is also interesting to compare two countries, with a very significant difference in population, where the morbidity and mortality has been so different, and unrelated to the size of the country.


Subject(s)
Betacoronavirus/genetics , Betacoronavirus/immunology , Coronavirus Infections/epidemiology , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/epidemiology , Pneumonia, Viral/prevention & control , Adolescent , Adult , Aged , Antimalarials/therapeutic use , Antiviral Agents/therapeutic use , Asymptomatic Diseases , COVID-19 , Child , Child, Preschool , China/epidemiology , Coronavirus Infections/diagnosis , Coronavirus Infections/physiopathology , Female , Humans , Immunologic Factors/therapeutic use , Infant , Infant, Newborn , Italy/epidemiology , Male , Middle Aged , Pneumonia, Viral/diagnosis , Pneumonia, Viral/physiopathology , SARS-CoV-2 , Young Adult
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