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1.
PLoS Comput Biol ; 17(11): e1009560, 2021 11.
Article in English | MEDLINE | ID: covidwho-1523396

ABSTRACT

Severe acute respiratory coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, is of zoonotic origin. Evolutionary analyses assessing whether coronaviruses similar to SARS-CoV-2 infected ancestral species of modern-day animal hosts could be useful in identifying additional reservoirs of potentially dangerous coronaviruses. We reasoned that if a clade of species has been repeatedly exposed to a virus, then their proteins relevant for viral entry may exhibit adaptations that affect host susceptibility or response. We perform comparative analyses across the mammalian phylogeny of angiotensin-converting enzyme 2 (ACE2), the cellular receptor for SARS-CoV-2, in order to uncover evidence for selection acting at its binding interface with the SARS-CoV-2 spike protein. We uncover that in rodents there is evidence for adaptive amino acid substitutions at positions comprising the ACE2-spike interaction interface, whereas the variation within ACE2 proteins in primates and some other mammalian clades is not consistent with evolutionary adaptations. We also analyze aminopeptidase N (APN), the receptor for the human coronavirus 229E, a virus that causes the common cold, and find evidence for adaptation in primates. Altogether, our results suggest that the rodent and primate lineages may have had ancient exposures to viruses similar to SARS-CoV-2 and HCoV-229E, respectively.


Subject(s)
COVID-19/genetics , COVID-19/virology , Coronavirus Infections/genetics , Coronavirus Infections/virology , SARS-CoV-2/genetics , Adaptation, Physiological/genetics , Amino Acid Substitution , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/physiology , Animals , CD13 Antigens/genetics , CD13 Antigens/physiology , Common Cold/genetics , Common Cold/virology , Computational Biology , Coronavirus 229E, Human/genetics , Coronavirus 229E, Human/physiology , Evolution, Molecular , Genomics , Host Microbial Interactions/genetics , Host Microbial Interactions/physiology , Host Specificity/genetics , Host Specificity/physiology , Humans , Mammals/genetics , Mammals/virology , Phylogeny , Protein Interaction Domains and Motifs/genetics , Receptors, Virus/genetics , Receptors, Virus/physiology , SARS-CoV-2/physiology , Selection, Genetic , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/physiology , Virus Internalization
2.
J Clin Invest ; 131(14)2021 07 15.
Article in English | MEDLINE | ID: covidwho-1311200

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic is among the most important public health crises of our generation. Despite the promise of prevention offered by effective vaccines, patients with severe COVID-19 will continue to populate hospitals and intensive care units for the foreseeable future. The most common clinical presentation of severe COVID-19 is hypoxemia and respiratory failure, typical of the acute respiratory distress syndrome (ARDS). Whether the clinical features and pathobiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia differ from those of pneumonia secondary to other pathogens is unclear. This uncertainty has created variability in the application of historically proven therapies for ARDS to patients with COVID-19. We review the available literature and find many similarities between patients with ARDS from pneumonia attributable to SARS-CoV-2 versus other respiratory pathogens. A notable exception is the long duration of illness among patients with COVID-19, which could result from its unique pathobiology. Available data support the use of care pathways and therapies proven effective for patients with ARDS, while pointing to unique features that might be therapeutically targeted for patients with severe SARS-CoV-2 pneumonia.


Subject(s)
COVID-19/etiology , Pneumonia, Viral/etiology , Respiratory Distress Syndrome/etiology , SARS-CoV-2 , Angiotensin-Converting Enzyme 2/physiology , Autopsy , COVID-19/epidemiology , COVID-19/pathology , Cytokines/biosynthesis , Humans , Lung/immunology , Lung/pathology , Lung/virology , Macrophages, Alveolar/immunology , Macrophages, Alveolar/virology , Models, Biological , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Receptors, Virus/physiology , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/pathology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , Severity of Illness Index
3.
Cells ; 10(6)2021 06 08.
Article in English | MEDLINE | ID: covidwho-1264419

ABSTRACT

In late 2019, the betacoronavirus SARS-CoV-2 was identified as the viral agent responsible for the coronavirus disease 2019 (COVID-19) pandemic. Coronaviruses Spike proteins are responsible for their ability to interact with host membrane receptors and different proteins have been identified as SARS-CoV-2 interactors, among which Angiotensin-converting enzyme 2 (ACE2), and Basigin2/EMMPRIN/CD147 (CD147). CD147 plays an important role in human immunodeficiency virus type 1, hepatitis C virus, hepatitis B virus, Kaposi's sarcoma-associated herpesvirus, and severe acute respiratory syndrome coronavirus infections. In particular, SARS-CoV recognizes the CD147 receptor expressed on the surface of host cells by its nucleocapsid protein binding to cyclophilin A (CyPA), a ligand for CD147. However, the involvement of CD147 in SARS-CoV-2 infection is still debated. Interference with both the function (blocking antibody) and the expression (knock down) of CD147 showed that this receptor partakes in SARS-CoV-2 infection and provided additional clues on the underlying mechanism: CD147 binding to CyPA does not play a role; CD147 regulates ACE2 levels and both receptors are affected by virus infection. Altogether, these findings suggest that CD147 is involved in SARS-CoV-2 tropism and represents a possible therapeutic target to challenge COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/physiology , Basigin/physiology , SARS-CoV-2/physiology , Virus Internalization , A549 Cells , Angiotensin-Converting Enzyme 2/metabolism , Animals , Basigin/antagonists & inhibitors , Basigin/genetics , COVID-19/pathology , COVID-19/prevention & control , COVID-19/virology , Caco-2 Cells , Cell Line , Chlorocebus aethiops , Hep G2 Cells , Host-Pathogen Interactions , Humans , Molecular Targeted Therapy , RNA Interference/physiology , RNA, Small Interfering/pharmacology , RNA, Small Interfering/therapeutic use , Receptors, Virus/metabolism , Receptors, Virus/physiology , SARS-CoV-2/metabolism , Vero Cells , Viral Tropism/physiology
4.
Ann N Y Acad Sci ; 1486(1): 15-38, 2021 02.
Article in English | MEDLINE | ID: covidwho-1263857

ABSTRACT

Exposure to air pollutants has been previously associated with respiratory viral infections, including influenza, measles, mumps, rhinovirus, and respiratory syncytial virus. Epidemiological studies have also suggested that air pollution exposure is associated with increased cases of SARS-CoV-2 infection and COVID-19-associated mortality, although the molecular mechanisms by which pollutant exposure affects viral infection and pathogenesis of COVID-19 remain unknown. In this review, we suggest potential molecular mechanisms that could account for this association. We have focused on the potential effect of exposure to nitrogen dioxide (NO2 ), ozone (O3 ), and particulate matter (PM) since there are studies investigating how exposure to these pollutants affects the life cycle of other viruses. We have concluded that pollutant exposure may affect different stages of the viral life cycle, including inhibition of mucociliary clearance, alteration of viral receptors and proteases required for entry, changes to antiviral interferon production and viral replication, changes in viral assembly mediated by autophagy, prevention of uptake by macrophages, and promotion of viral spread by increasing epithelial permeability. We believe that exposure to pollutants skews adaptive immune responses toward bacterial/allergic immune responses, as opposed to antiviral responses. Exposure to air pollutants could also predispose exposed populations toward developing COIVD-19-associated immunopathology, enhancing virus-induced tissue inflammation and damage.


Subject(s)
Air Pollution/adverse effects , COVID-19/etiology , Pandemics , SARS-CoV-2 , Adaptive Immunity , Air Pollutants/adverse effects , COVID-19/immunology , COVID-19/virology , Host Microbial Interactions , Humans , Immunity, Innate , Models, Biological , Particulate Matter/adverse effects , Receptors, Virus/physiology , Respiratory System/physiopathology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , Toll-Like Receptors/physiology , Virus Internalization , Virus Replication
5.
Blood ; 138(4): 344-349, 2021 07 29.
Article in English | MEDLINE | ID: covidwho-1255893

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with the hypercoagulable state. Tissue factor (TF) is the primary cellular initiator of coagulation. Most of the TF expressed on cell surfaces remains cryptic. Sphingomyelin (SM) is responsible for maintaining TF in the encrypted state, and hydrolysis of SM by acid sphingomyelinase (ASMase) increases TF activity. ASMase was shown to play a role in virus infection biology. In the present study, we investigated the role of ASMase in SARS-CoV-2 infection-induced TF procoagulant activity. Infection of human monocyte-derived macrophages (MDMs) with SARS-CoV-2 spike protein pseudovirus (SARS-CoV-2-SP-PV) markedly increased TF procoagulant activity at the cell surface and released TF+ extracellular vesicles. The pseudovirus infection did not increase either TF protein expression or phosphatidylserine externalization. SARS-CoV-2-SP-PV infection induced the translocation of ASMase to the outer leaflet of the plasma membrane, which led to the hydrolysis of SM in the membrane. Pharmacologic inhibitors or genetic silencing of ASMase attenuated SARS-CoV-2-SP-PV-induced increased TF activity. Inhibition of the SARS-CoV-2 receptor, angiotensin-converting enzyme-2, attenuated SARS-CoV-2-SP-PV-induced increased TF activity. Overall, our data suggest that SARS-CoV-2 infection activates the coagulation by decrypting TF through activation of ASMase. Our data suggest that the US Food and Drug Administration-approved functional inhibitors of ASMase may help treat hypercoagulability in patients with COVID-19.


Subject(s)
COVID-19/blood , Macrophages/virology , Membrane Proteins/physiology , SARS-CoV-2 , Sphingomyelin Phosphodiesterase/physiology , Spike Glycoprotein, Coronavirus/physiology , Thrombophilia/etiology , Thromboplastin/physiology , Angiotensin-Converting Enzyme 2/physiology , COVID-19/complications , Cell-Derived Microparticles , Enzyme Activation , Humans , Hydrolysis , Macrophages/enzymology , Molecular Targeted Therapy , Plasmids , Protein Transport , RNA Interference , RNA, Small Interfering/genetics , Receptors, Virus/physiology , Sphingomyelin Phosphodiesterase/antagonists & inhibitors , Sphingomyelins/physiology , Thrombophilia/blood , Thrombophilia/drug therapy , Thrombophilia/enzymology
6.
Mol Neurobiol ; 58(9): 4535-4563, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1252224

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a devastating viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The incidence and mortality of COVID-19 patients have been increasing at an alarming rate. The mortality is much higher in older individuals, especially the ones suffering from respiratory distress, cardiac abnormalities, renal diseases, diabetes, and hypertension. Existing evidence demonstrated that SARS-CoV-2 makes its entry into human cells through angiotensin-converting enzyme 2 (ACE-2) followed by the uptake of virions through cathepsin L or transmembrane protease serine 2 (TMPRSS2). SARS-CoV-2-mediated abnormalities in particular cardiovascular and neurological ones and the damaged coagulation systems require extensive research to develop better therapeutic modalities. As SARS-CoV-2 uses its S-protein to enter into the host cells of several organs, the S-protein of the virus is considered as the ideal target to develop a potential vaccine. In this review, we have attempted to highlight the landmark discoveries that lead to the development of various vaccines that are currently under different stages of clinical progression. Besides, a brief account of various drug candidates that are being tested to mitigate the burden of COVID-19 was also covered. Further, in a dedicated section, the impact of SARS-CoV-2 infection on neuronal inflammation and neuronal disorders was discussed. In summary, it is expected that the content covered in this article help to understand the pathophysiology of COVID-19 and the impact on neuronal complications induced by SARS-CoV-2 infection while providing an update on the vaccine development.


Subject(s)
COVID-19 Vaccines , COVID-19/complications , Inflammation/etiology , Neurodevelopmental Disorders/etiology , SARS-CoV-2/pathogenicity , Angiotensin-Converting Enzyme 2/physiology , Animals , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/physiopathology , COVID-19/prevention & control , COVID-19/therapy , COVID-19 Vaccines/adverse effects , Cell Line , Comorbidity , Cytokine Release Syndrome/etiology , Female , Hormesis , Humans , Immunization, Passive , Infectious Disease Transmission, Vertical , Mice , Models, Neurological , Murine hepatitis virus/pathogenicity , Nervous System/virology , Nervous System Diseases/epidemiology , Nervous System Diseases/etiology , Organ Specificity , Organoids , Pregnancy , Pregnancy Complications, Infectious/virology , Receptors, Virus/physiology , SARS-CoV-2/genetics , SARS-CoV-2/physiology , Serine Endopeptidases/physiology , Spike Glycoprotein, Coronavirus/physiology
7.
IUBMB Life ; 73(6): 843-854, 2021 06.
Article in English | MEDLINE | ID: covidwho-1219298

ABSTRACT

The 78 kDa glucose-regulated protein (GRP78) is an endoplasmic reticulum (ER)-resident molecular chaperone. GRP78 is a member of the 70 kDa heat shock family of proteins involved in correcting and clearing misfolded proteins in the ER. In response to cellular stress, GRP78 escapes from the ER and moves to the plasma membrane where it (a) functions as a receptor for many ligands, and (b) behaves as an autoantigen for autoantibodies that contribute to human disease and cancer. Cell surface GRP78 (csGRP78) associates with the major histocompatibility complex class I (MHC-I), and is the port of entry for several viruses, including the predictive binding of the novel SARS-CoV-2. Furthermore, csGRP78 is found in association with partners as diverse as the teratocarcinoma-derived growth factor 1 (Cripto), the melanocortin-4 receptor (MC4R) and the DnaJ-like protein MTJ-1. CsGRP78 also serves as a receptor for a large variety of ligands including activated α2 -macroglobulin (α2 M*), plasminogen kringle 5 (K5), microplasminogen, the voltage-dependent anion channel (VDAC), tissue factor (TF), and the prostate apoptosis response-4 protein (Par-4). In this review, we discuss the mechanisms involved in the translocation of GRP78 from the ER to the cell surface, and the role of secreted GRP78 and its autoantibodies in cancer and neurological disorders.


Subject(s)
Autoimmune Diseases of the Nervous System/immunology , COVID-19/transmission , Heat-Shock Proteins/physiology , Neoplasm Proteins/physiology , Nerve Tissue Proteins/physiology , Receptors, Cell Surface/physiology , Receptors, Virus/physiology , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Autoantibodies/immunology , Autoantigens/immunology , Autoimmune Diseases of the Nervous System/metabolism , Cell Survival , Endoplasmic Reticulum Stress/physiology , Exosomes , GPI-Linked Proteins/metabolism , Heat-Shock Proteins/chemistry , Heat-Shock Proteins/immunology , Humans , Ligands , Neoplasm Invasiveness , Neoplasm Proteins/immunology , Nerve Tissue Proteins/immunology , Protein Domains , Protein Transport , Signal Transduction , Tumor Microenvironment , Unfolded Protein Response/physiology , Virus Internalization
8.
Sci Signal ; 14(665)2021 01 12.
Article in English | MEDLINE | ID: covidwho-1066811

ABSTRACT

The spike protein of SARS-CoV-2 binds the angiotensin-converting enzyme 2 (ACE2) on the host cell surface and subsequently enters host cells through receptor-mediated endocytosis. Additional cell receptors may be directly or indirectly involved, including integrins. The cytoplasmic tails of ACE2 and integrins contain several predicted short linear motifs (SLiMs) that may facilitate internalization of the virus as well as its subsequent propagation through processes such as autophagy. Here, we measured the binding affinity of predicted interactions between SLiMs in the cytoplasmic tails of ACE2 and integrin ß3 with proteins that mediate endocytic trafficking and autophagy. We validated that a class I PDZ-binding motif mediated binding of ACE2 to the scaffolding proteins SNX27, NHERF3, and SHANK, and that a binding site for the clathrin adaptor AP2 µ2 in ACE2 overlaps with a phospho-dependent binding site for the SH2 domains of Src family tyrosine kinases. Furthermore, we validated that an LC3-interacting region (LIR) in integrin ß3 bound to the ATG8 domains of the autophagy receptors MAP1LC3 and GABARAP in a manner enhanced by LIR-adjacent phosphorylation. Our results provide molecular links between cell receptors and mediators of endocytosis and autophagy that may facilitate viral entry and propagation.


Subject(s)
Angiotensin-Converting Enzyme 2/physiology , COVID-19/virology , Integrin beta3/physiology , Receptors, Virus/physiology , SARS-CoV-2/physiology , SARS-CoV-2/pathogenicity , Virus Internalization , Amino Acid Sequence , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/genetics , Autophagy/physiology , Endocytosis/physiology , Host Microbial Interactions/genetics , Host Microbial Interactions/physiology , Humans , Integrin beta3/chemistry , Integrin beta3/genetics , Models, Molecular , Pandemics , Peptide Fragments/chemistry , Peptide Fragments/genetics , Peptide Fragments/physiology , Phosphorylation , Protein Binding , Protein Interaction Domains and Motifs , Protein Sorting Signals/genetics , Protein Sorting Signals/physiology , Receptors, Virus/chemistry , Receptors, Virus/genetics , SARS-CoV-2/genetics
9.
Epidemiol Prev ; 44(5-6 Suppl 2): 169-182, 2020.
Article in English | MEDLINE | ID: covidwho-1068137

ABSTRACT

As the Coronavirus situation (COVID-19) continues to evolve, many questions concerning the factors relating to the diffusion and severity of the disease remain unanswered.Whilst opinions regarding the weight of evidence for these risk factors, and the studies published so far are often inconclusive or offer contrasting results, the role of comorbidities in the risk of serious adverse outcomes in patients affected with COVID-19 appears to be evident since the outset. Hypertension, diabetes, and obesity are under discussion as important factors affecting the severity of disease. Air pollution has been considered to play a role in the diffusion of the virus, in the propagation of the contagion, in the severity of symptoms, and in the poor prognosis. Accumulating evidence supports the hypothesis that environmental particulate matter (PM) can trigger inflammatory responses at molecular, cellular, and organ levels, sustaining respiratory, cardiovascular, and dysmetabolic diseases.To better understand the intricate relationships among pre-existing conditions, PM, and viral infection, we examined the response at the molecular level of T47D human breast adenocarcinoma cells exposed to different fractions of PM. T47D cells express several receptors, including the aryl hydrocarbon receptor (AhR), and ACE2, the main - but not the only - receptor for SARS-CoV-2 entry.PM samples were collected in an urban background site located in the Northern area of the City of Bologna (Emilia-Romagna Region, Northern Italy) during winter 2013. T47D cells were exposed to organic or aqueous (inorganic) extracts at the final concentration of 8 m3 for a 4-hour duration. Both the concentration and the exposure time were chosen to resemble an average outdoor exposure. RNA was extracted from cells, purified and hybridised on 66k microarray slides from Agilent.The lists of differentially expressed genes in PM organic extracts were evaluated by using Metacore, and an enrichment analysis was performed to identify pathways maps, process networks, and disease by biomarkers altered after T47D treatment.The analysis of the modulated genes gave evidence for the involvement of PM in dysmetabolic diseases, including diabetes and obesity, and hypertension through the activation of the aryl hydrocarbon receptor (AhR) canonical pathway.On the basis of current knowledge, existing data, and exploratory experimental evidence, we tease out the likely molecular interplay that can ultimately tip the disease outcome into severity. Looking beyond ACE2, several additional key markers are identified. Disruption of these targets worsens pre-existing conditions and/or exacerbates the adverse effects induced by SARS-CoV-2 infection. Whilst appropriately designed, epidemiological studies are very much needed to investigate these associations based on our hypothesis of investigation, by reviewing recent experimental and epidemiological evidence, here we speculate and provide new insights on the possible role of environmental pollution in the exacerbation of effects by SARS-CoV-2 and other respiratory viruses. This work is intended to assist in the development of appropriate investigative approaches to protect public health.


Subject(s)
Air Pollution/adverse effects , COVID-19/epidemiology , Particulate Matter/adverse effects , SARS-CoV-2/physiology , Angiotensin-Converting Enzyme 2/physiology , COVID-19/etiology , Cell Line, Tumor , Comorbidity , Coronaviridae/physiology , Cytochrome P-450 CYP1A1/physiology , Diabetes Mellitus/epidemiology , Diabetes Mellitus/genetics , Diabetes Mellitus/metabolism , Disease Susceptibility , Gene Expression Profiling , Gene Expression Regulation/drug effects , Humans , Hypertension/epidemiology , Hypertension/genetics , Hypertension/metabolism , Inflammation/epidemiology , Inflammation/genetics , Inflammation/metabolism , Italy , Obesity/epidemiology , Obesity/genetics , Obesity/metabolism , Particulate Matter/pharmacology , Receptors, Aryl Hydrocarbon/physiology , Receptors, Virus/physiology , Risk , SARS-CoV-2/ultrastructure , Signal Transduction
10.
J Mol Neurosci ; 71(11): 2192-2209, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1037256

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic is an issue of global significance that has taken the lives of many across the world. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for its pathogenesis. The pulmonary manifestations of COVID-19 have been well described in the literature. Initially, it was thought to be limited to the respiratory system; however, we now recognize that COVID-19 also affects several other organs, including the nervous system. Two similar human coronaviruses (CoV) that cause severe acute respiratory syndrome (SARS-CoV-1) and Middle East respiratory syndrome (MERS-CoV) are also known to cause disease in the nervous system. The neurological manifestations of SARS-CoV-2 infection are growing rapidly, as evidenced by several reports. There are several mechanisms responsible for such manifestations in the nervous system. For instance, post-infectious immune-mediated processes, direct virus infection of the central nervous system (CNS), and virus-induced hyperinflammatory and hypercoagulable states are commonly involved. Guillain-Barré syndrome (GBS) and its variants, dysfunction of taste and smell, and muscle injury are numerous examples of COVID-19 PNS (peripheral nervous system) disease. Likewise, hemorrhagic and ischemic stroke, encephalitis, meningitis, encephalopathy acute disseminated encephalomyelitis, endothelialitis, and venous sinus thrombosis are some instances of COVID-19 CNS disease. Due to multifactorial and complicated pathogenic mechanisms, COVID-19 poses a large-scale threat to the whole nervous system. A complete understanding of SARS-CoV-2 neurological impairments is still lacking, but our knowledge base is rapidly expanding. Therefore, we anticipate that this comprehensive review will provide valuable insights and facilitate the work of neuroscientists in unfolding different neurological dimensions of COVID-19 and other CoV associated abnormalities.


Subject(s)
COVID-19/complications , Nervous System Diseases/etiology , Pandemics , SARS-CoV-2/pathogenicity , Adolescent , Adult , Angiotensin-Converting Enzyme 2/physiology , Asymptomatic Infections , Autoimmune Diseases of the Nervous System/etiology , Blood-Brain Barrier , COVID-19/immunology , COVID-19/physiopathology , Cerebrovascular Disorders/etiology , Child , Communicable Diseases, Emerging , Coronavirus Infections/complications , Humans , Hypoxia/etiology , Hypoxia/physiopathology , Nervous System/virology , Nervous System Diseases/immunology , Nervous System Diseases/physiopathology , Organ Specificity , Receptors, Virus/physiology , Severe Acute Respiratory Syndrome/complications , Synapses/virology , Viral Tropism , Young Adult
11.
Sci Signal ; 14(665)2021 01 12.
Article in English | MEDLINE | ID: covidwho-1029425

ABSTRACT

The first reported receptor for SARS-CoV-2 on host cells was the angiotensin-converting enzyme 2 (ACE2). However, the viral spike protein also has an RGD motif, suggesting that cell surface integrins may be co-receptors. We examined the sequences of ACE2 and integrins with the Eukaryotic Linear Motif (ELM) resource and identified candidate short linear motifs (SLiMs) in their short, unstructured, cytosolic tails with potential roles in endocytosis, membrane dynamics, autophagy, cytoskeleton, and cell signaling. These SLiM candidates are highly conserved in vertebrates and may interact with the µ2 subunit of the endocytosis-associated AP2 adaptor complex, as well as with various protein domains (namely, I-BAR, LC3, PDZ, PTB, and SH2) found in human signaling and regulatory proteins. Several motifs overlap in the tail sequences, suggesting that they may act as molecular switches, such as in response to tyrosine phosphorylation status. Candidate LC3-interacting region (LIR) motifs are present in the tails of integrin ß3 and ACE2, suggesting that these proteins could directly recruit autophagy components. Our findings identify several molecular links and testable hypotheses that could uncover mechanisms of SARS-CoV-2 attachment, entry, and replication against which it may be possible to develop host-directed therapies that dampen viral infection and disease progression. Several of these SLiMs have now been validated to mediate the predicted peptide interactions.


Subject(s)
COVID-19/virology , Host Microbial Interactions/physiology , SARS-CoV-2/physiology , SARS-CoV-2/pathogenicity , Virus Internalization , Amino Acid Sequence , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/physiology , Animals , COVID-19/therapy , Conserved Sequence , Host Microbial Interactions/genetics , Humans , Integrins/chemistry , Integrins/genetics , Integrins/physiology , Intrinsically Disordered Proteins/chemistry , Intrinsically Disordered Proteins/genetics , Intrinsically Disordered Proteins/physiology , Models, Biological , Models, Molecular , Oligopeptides/chemistry , Oligopeptides/genetics , Oligopeptides/physiology , Protein Interaction Domains and Motifs/genetics , Protein Interaction Domains and Motifs/physiology , Protein Sorting Signals/genetics , Protein Sorting Signals/physiology , Receptors, Virus/chemistry , Receptors, Virus/genetics , Receptors, Virus/physiology , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/physiology
12.
Radiat Res ; 195(1): 1-24, 2021 01 01.
Article in English | MEDLINE | ID: covidwho-1021760

ABSTRACT

As the multi-systemic components of COVID-19 emerge, parallel etiologies can be drawn between SARS-CoV-2 infection and radiation injuries. While some SARS-CoV-2-infected individuals present as asymptomatic, others exhibit mild symptoms that may include fever, cough, chills, and unusual symptoms like loss of taste and smell and reddening in the extremities (e.g., "COVID toes," suggestive of microvessel damage). Still others alarm healthcare providers with extreme and rapid onset of high-risk indicators of mortality that include acute respiratory distress syndrome (ARDS), multi-organ hypercoagulation, hypoxia and cardiovascular damage. Researchers are quickly refocusing their science to address this enigmatic virus that seems to unveil itself in new ways without discrimination. As investigators begin to identify early markers of disease, identification of common threads with other pathologies may provide some clues. Interestingly, years of research in the field of radiation biology documents the complex multiorgan nature of another disease state that occurs after exposure to high doses of radiation: the acute radiation syndrome (ARS). Inflammation is a key common player in COVID-19 and ARS, and drives the multi-system damage that dramatically alters biological homeostasis. Both conditions initiate a cytokine storm, with similar pro-inflammatory molecules increased and other anti-inflammatory molecules decreased. These changes manifest in a variety of ways, with a demonstrably higher health impact in patients having underlying medical conditions. The potentially dramatic human impact of ARS has guided the science that has identified many biomarkers of radiation exposure, established medical management strategies for ARS, and led to the development of medical countermeasures for use in the event of a radiation public health emergency. These efforts can now be leveraged to help elucidate mechanisms of action of COVID-19 injuries. Furthermore, this intersection between COVID-19 and ARS may point to approaches that could accelerate the discovery of treatments for both.


Subject(s)
COVID-19/physiopathology , Pandemics , Radiation Injuries/physiopathology , SARS-CoV-2/pathogenicity , Acute Lung Injury/etiology , Acute Lung Injury/physiopathology , Angiotensin-Converting Enzyme 2/deficiency , Angiotensin-Converting Enzyme 2/physiology , Animals , Anti-Bacterial Agents/therapeutic use , Anti-Inflammatory Agents/therapeutic use , Antioxidants/therapeutic use , Biomarkers/blood , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/etiology , Blood Coagulation Disorders/physiopathology , COVID-19/drug therapy , COVID-19/epidemiology , COVID-19/immunology , Clinical Trials as Topic , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/physiopathology , Hematologic Diseases/etiology , Hematologic Diseases/physiopathology , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Inflammation/etiology , Inflammation/physiopathology , Intercellular Signaling Peptides and Proteins/therapeutic use , Mesenchymal Stem Cell Transplantation , Mice , Organ Specificity , Pyroptosis , Radiation Injuries/blood , Radiation Injuries/drug therapy , Radiation Injuries/immunology , Receptors, Virus/physiology , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/physiology , SARS-CoV-2/isolation & purification , Vascular Diseases/drug therapy , Vascular Diseases/etiology , Vascular Diseases/physiopathology
14.
Biomolecules ; 10(9)2020 09 11.
Article in English | MEDLINE | ID: covidwho-976280

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing a pandemic of coronavirus disease 2019 (COVID-19). The worldwide transmission of COVID-19 from human to human is spreading like wildfire, affecting almost every country in the world. In the past 100 years, the globe did not face a microbial pandemic similar in scale to COVID-19. Taken together, both previous outbreaks of other members of the coronavirus family (severe acute respiratory syndrome (SARS-CoV) and middle east respiratory syndrome (MERS-CoV)) did not produce even 1% of the global harm already inflicted by COVID-19. There are also four other CoVs capable of infecting humans (HCoVs), which circulate continuously in the human population, but their phenotypes are generally mild, and these HCoVs received relatively little attention. These dramatic differences between infection with HCoVs, SARS-CoV, MERS-CoV, and SARS-CoV-2 raise many questions, such as: Why is COVID-19 transmitted so quickly? Is it due to some specific features of the viral structure? Are there some specific human (host) factors? Are there some environmental factors? The aim of this review is to collect and concisely summarize the possible and logical answers to these questions.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/transmission , Coronavirus/pathogenicity , Pandemics , Pneumonia, Viral/transmission , Age Factors , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus/genetics , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/epidemiology , Coronavirus Infections/veterinary , Coronavirus Infections/virology , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/physiopathology , Disease Outbreaks , Disease Reservoirs/virology , Female , Global Health , Host Specificity , Host-Pathogen Interactions , Humans , Male , Middle East Respiratory Syndrome Coronavirus/pathogenicity , Organ Specificity , Peptide Hydrolases/physiology , Peptidyl-Dipeptidase A/physiology , Pneumonia, Viral/complications , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , Receptors, Virus/physiology , Risk Factors , SARS Virus/pathogenicity , SARS-CoV-2 , Severe Acute Respiratory Syndrome/epidemiology , Viral Proteins/physiology , Viral Tropism , Virulence , Virus Internalization
15.
Med Hypotheses ; 143: 109886, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-912466

ABSTRACT

Coronavirus disease 2019 (COVID-19) is an infectious disease with fast spreading all over the world caused by the SARS-CoV-2 virus which can culminate in a severe acute respiratory syndrome by the injury caused in the lungs. However, other organs can be also damaged. SARS-CoV-2 enter into the host cells using the angiotensin-converting enzyme 2 (ACE2) as receptor, like its ancestor SARS-CoV. ACE2 is then downregulated in lung tissues with augmented serum levels of ACE2 in SARS-CoV-2 patients. Interestingly, ACE2+ organs reveal the symptomatic repercussions, which are signals of the infection such as dry cough, shortness of breath, heart failure, liver and kidney damage, anosmia or hyposmia, and diarrhea. ACE2 exerts a chief role in the renin-angiotensin system (RAS) by converting angiotensin II to angiotensin-(1-7) that activates Mas receptor, inhibits ACE1, and modulates bradykinin (BK) receptor sensitivity, especially the BK type 2 receptor (BKB2R). ACE2 also hydrolizes des-Arg9-bradykinin (DABK), an active BK metabolite, agonist at BK type 1 receptors (BKB1R), which is upregulated by inflammation. In this opinion article, we conjecture a dialogue by the figure of Sérgio Ferreira which brought together basic science of classical pharmacology and clinical repercussions in COVID-19, then we propose that in the course of SARS-CoV-2 infection: i) downregulation of ACE2 impairs the angiotensin II and DABK inactivation; ii) BK and its metabolite DABK seems to be in elevated levels in tissues by interferences in kallikrein/kinin system; iii) BK1 receptor contributes to the outbreak and maintenance of the inflammatory response; iv) kallikrein/kinin system crosstalks to RAS and coagulation system, linking inflammation to thrombosis and organ injury. We hypothesize that targeting the kallikrein/kinin system and BKB1R pathway may be beneficial in SARS-CoV-2 infection, especially on early stages. This route of inference should be experimentally verified by SARS-CoV-2 infected mice.


Subject(s)
Betacoronavirus , Coronavirus Infections/drug therapy , Coronavirus Infections/physiopathology , Kallikrein-Kinin System/physiology , Models, Biological , Pneumonia, Viral/drug therapy , Pneumonia, Viral/physiopathology , Angiotensin-Converting Enzyme 2 , Animals , COVID-19 , Coronavirus Infections/etiology , Humans , Kallikrein-Kinin System/drug effects , Mice , Pandemics , Peptidyl-Dipeptidase A/physiology , Pneumonia, Viral/etiology , Receptors, Virus/physiology , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/physiology , SARS-CoV-2 , Virus Internalization/drug effects
16.
Med Hypotheses ; 146: 110378, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-912500

ABSTRACT

In December 2019, in China, a disease derived from a new beta coronavirus (SARS-CoV-2) was reported, which was termed coronavirus disease 2019 (COVID-19). Currently, it is known that endothelial cell dysfunction is a critical event in the infection by this virus. However, in a representative percentage of patients with COVID-19, neither cardiovascular disease nor diabetes mellitus, which could be linked with endothelial dysfunction, has been reported. Previous evidence has shown the presence of early endothelial dysfunction in healthy subjects but with a family history of type 2 diabetes (FH-DM2), where glucose metabolism, the synthesis of nitric oxide (NO), reactive oxygen species (ROS), as well as expression of genes involved with their synthesis are impaired. Besides, in subjects with an FH-DM2, the presence of hyperinsulinemia and high glucose levels are common events that could favor the infection of endothelial cells by the coronavirus. Interestingly, both events have been reported in patients with COVID-19, in whom hyperinsulinemia increases the surface expression of ACE2 through a diminution of ADAMTS17 activity; whereas hyperglycemia induces higher expression of ACE2 in different tissues, including microvascular endothelial cells from the pancreatic islets, favoring chronic hyperglycemia and affecting the release of insulin. Therefore, we hypothesized that an FH-DM2 should be considered an important risk factor, since the individuals with this background develop an early endothelial dysfunction, which would increase the susceptibility and severity of infection and damage to the endothelium, in the patient infected with the SARS-CoV-2.


Subject(s)
COVID-19/etiology , COVID-19/pathology , Diabetes Mellitus, Type 2/complications , Endothelium, Vascular/pathology , Angiotensin-Converting Enzyme 2/physiology , COVID-19/physiopathology , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/physiopathology , Disease Susceptibility , Endothelium, Vascular/physiopathology , Host Microbial Interactions/physiology , Humans , Models, Biological , Pandemics , Receptors, Virus/physiology , Risk Factors , SARS-CoV-2/pathogenicity
17.
Med Hypotheses ; 146: 110371, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-912499

ABSTRACT

The universal phenomenon of blood clotting is well known to be protective in external cellular/ tissue injury. However, the emergence of unusual thrombotic presentations in COVID-19 patients is the real concern. Interaction of the spike glycoprotein with ACE2 receptor present in the host cell surface mediates the entry of SARS-CoV-2 causing COVID-19 infection. New clinical findings of SARS-CoV-2 pathogenesis are coming out every day, and one such mystery is the formation of mysterious blood clots in the various tissues and organs of COVID-19 patients, which needs critical attention. To address this issue, we hypothesis that, high ACE2 expression in the endothelium of blood vessels facilitates the high-affinity binding of SARS-CoV-2 using spike protein, causing infection and internal injury inside the vascular wall of blood vessels. This viral associated injury may directly/indirectly initiate activation of coagulation and clotting cascades forming internal blood clots. However, the presence of these clots is undesirable as they are responsible for thrombosis and need to be treated with anti-thrombotic intervention.


Subject(s)
COVID-19/complications , Models, Cardiovascular , Pandemics , SARS-CoV-2 , Thrombosis/etiology , Angiotensin-Converting Enzyme 2/physiology , Blood Coagulation/physiology , COVID-19/physiopathology , COVID-19/virology , Endothelium, Vascular/injuries , Endothelium, Vascular/physiopathology , Endothelium, Vascular/virology , Host Microbial Interactions/physiology , Humans , Receptors, Virus/physiology , Spike Glycoprotein, Coronavirus/physiology , Thrombosis/physiopathology , Thrombosis/virology
18.
Med Hypotheses ; 146: 110368, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-912498

ABSTRACT

Understanding how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highjacks epithelial cells and infiltrates the lung, as well as other organs and tissues, is essential for developing treatment strategies and vaccines against this highly contagious virus. Another major goal is to fully elucidate the mechanisms by which SARS-CoV- 2 bypasses the innate immune system and induces a cytokine storm, and its effects on mortality. Currently, SARS- CoV-2 is thought to evade innate antiviral immunity, undergo endocytosis, and fuse with the host cell membrane by exploiting ACE2 receptors and the protease TMMPRSS2, with cathepsin B/L as alternative protease, for entry into the epithelial cells of tissues vulnerable to developing coronavirus disease 2019 (COVID-19) symptoms. However, the incorporation of new and unique binding sites, i.e., O-linked glycans, and the preservation and augmentation of effective binding sites (N-linked glycans) on the outer membrane of SARS-CoV-2 may represent other strategies of infecting the human host. Here, I will rationalize the possibility that other host molecules-i.e., sugar molecules and the sialic acidsN-glycolylneuraminic acid, N-acetylneuraminic acid, and their derivates could be viable candidates for the use as virus receptors by SARS-CoV-2 and/or serve as determinants for the adherence on ACE2 of SARS-CoV-2.


Subject(s)
COVID-19/physiopathology , COVID-19/virology , Receptors, Virus/physiology , SARS-CoV-2/physiology , Angiotensin-Converting Enzyme 2/physiology , COVID-19/immunology , Host Microbial Interactions/immunology , Host Microbial Interactions/physiology , Humans , Immune Evasion , Immunity, Innate , Models, Biological , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Sialic Acids/physiology , Virus Attachment , Virus Internalization
19.
PLoS One ; 15(10): e0240647, 2020.
Article in English | MEDLINE | ID: covidwho-895060

ABSTRACT

The World Health Organization declared the COVID-19 epidemic a public health emergency of international concern on March 11th, 2020, and the pandemic is rapidly spreading worldwide. COVID-19 is caused by a novel coronavirus SARS-CoV-2, which enters human target cells via angiotensin converting enzyme 2 (ACE2). We used a number of bioinformatics tools to computationally characterize ACE2 by determining its cell-specific expression in trachea, lung, and small intestine, derive its putative functions, and predict transcriptional regulation. The small intestine expressed higher levels of ACE2 mRNA than any other organ. By immunohistochemistry, duodenum, kidney and testis showed strong signals, whereas the signal was weak in the respiratory tract. Single cell RNA-Seq data from trachea indicated positive signals along the respiratory tract in key protective cell types including club, goblet, proliferating, and ciliary epithelial cells; while in lung the ratio of ACE2-expressing cells was low in all cell types (<2.6%), but was highest in vascular endothelial and goblet cells. Gene ontology analysis suggested that, besides its classical role in the renin-angiotensin system, ACE2 may be functionally associated with angiogenesis/blood vessel morphogenesis. Using a novel tool for the prediction of transcription factor binding sites we identified several putative binding sites within two tissue-specific promoters of the ACE2 gene as well as a new putative short form of ACE2. These include several interferon-stimulated response elements sites for STAT1, IRF8, and IRF9. Our results also confirmed that age and gender play no significant role in the regulation of ACE2 mRNA expression in the lung.


Subject(s)
Betacoronavirus/physiology , Computational Biology , Coronavirus Infections/virology , Pandemics , Peptidyl-Dipeptidase A/physiology , Pneumonia, Viral/virology , Receptors, Virus/physiology , Aging/metabolism , Angiotensin-Converting Enzyme 2 , Binding Sites , COVID-19 , Carrier Proteins/biosynthesis , Carrier Proteins/genetics , Female , Gene Expression Regulation, Enzymologic , Gene Ontology , Humans , Interferons/physiology , Lung/metabolism , Male , Metalloproteases/biosynthesis , Metalloproteases/genetics , Neovascularization, Physiologic/physiology , Organ Specificity , Peptidyl-Dipeptidase A/biosynthesis , Peptidyl-Dipeptidase A/genetics , Promoter Regions, Genetic , RNA, Messenger/biosynthesis , Receptors, Virus/biosynthesis , Receptors, Virus/genetics , Renin-Angiotensin System/physiology , SARS-CoV-2 , Sex Characteristics , Single-Cell Analysis , Transcription Factors/metabolism , Transcription Initiation Site , Virus Attachment
20.
J Thromb Haemost ; 19(1): 46-50, 2021 01.
Article in English | MEDLINE | ID: covidwho-894786

ABSTRACT

There is an urgent need to understand the underlying mechanisms contributing to thrombotic and inflammatory complications during COVID-19. Data from independent groups have identified that platelets are hyperreactive during COVID-19. Platelet hyperreactivity is accompanied by changes in platelet gene expression, and enhanced interactions between platelets and leukocytes. In some patients, SARS-CoV-2 mRNA has been detected in platelets. Together, this suggests that SARS-CoV-2 may interact with platelets. However, controversy remains on which receptors mediate SARS-CoV-2 platelet interactions. Most, but not all, transcriptomic and proteomic analyses fail to observe the putative SARS-CoV-2 receptor, angiotensin converting enzyme-2, or the cellular serine protease necessary for viral entry, TMPRSS2, on platelets and megakaryocytes. Interestingly, platelets express other known SARS-CoV-2 receptors, which induce similar patterns of activation to those observed when platelets are incubated with SARS-CoV-2. This article explores these findings and discusses ongoing areas of controversy and uncertainty with regard to SARS-CoV-2 platelet interactions.


Subject(s)
Angiotensin-Converting Enzyme 2/blood , Blood Platelets/virology , COVID-19/blood , COVID-19/virology , Receptors, Virus/blood , SARS-CoV-2/physiology , SARS-CoV-2/pathogenicity , Angiotensin-Converting Enzyme 2/physiology , COVID-19/complications , Host Microbial Interactions/genetics , Host Microbial Interactions/physiology , Humans , Megakaryocytes/virology , Models, Biological , Platelet Activation , RNA, Viral/blood , RNA, Viral/genetics , Receptors, Virus/physiology , SARS-CoV-2/genetics , Serine Endopeptidases/blood , Serine Endopeptidases/physiology , Thrombosis/blood , Thrombosis/etiology , Thrombosis/virology , Virus Internalization
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