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1.
Cell Rep ; 38(12): 110558, 2022 03 22.
Article in English | MEDLINE | ID: covidwho-1797096

ABSTRACT

Mutations in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike receptor-binding domain (RBD) may alter viral host tropism and affect the activities of neutralizing antibodies. Here, we investigated 153 RBD mutants and 11 globally circulating variants of concern (VOCs) and variants of interest (VOIs) (including Omicron) for their antigenic changes and cross-species tropism in cells expressing 18 ACE2 orthologs. Several RBD mutations strengthened viral infectivity in cells expressing ACE2 orthologs of non-human animals, particularly those less susceptible to the ancestral strain. The mutations surrounding amino acids (aas) 439-448 and aa 484 are more likely to cause neutralization resistance. Strikingly, enhanced cross-species infection potential in the mouse and ferret, instead of the neutralization-escape scores of the mutations, account for the positive correlation with the cumulative prevalence of mutations in humans. These findings present insights for potential drivers of circulating SARS-CoV-2 variants and provide informative parameters for tracking and forecasting spreading mutations.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Ferrets , Humans , Membrane Glycoproteins/metabolism , Mice , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus , Tropism , Viral Envelope Proteins
2.
Nat Microbiol ; 7(4): 524-529, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1773981

ABSTRACT

SARS-CoV-2 variant Lambda was dominant in several South American countries, including Chile. To ascertain the efficacy of local vaccination efforts, we used pseudotyped viruses to characterize the neutralization capacity of antibodies elicited by CoronaVac (n = 53) and BNT162b2 (n = 56) in healthcare workers from Clínica Santa María and the Faculty of Medicine at Universidad de Chile, as well as in convalescent plasma from individuals infected during the first wave visiting the Hospital Clínico at Pontificia Universidad Católica (n = 30). We observed that BNT162b2 elicits higher neutralizing antibody titres than CoronaVac, with differences ranging from 7.4-fold for the ancestral spike (Wuhan-Hu-1) to 8.2-fold for the Lambda spike and 13-fold for the Delta spike. Compared with the ancestral virus, neutralization against D614G, Alpha, Gamma, Lambda and Delta variants was reduced by between 0.93- and 4.22-fold for CoronaVac, 1.04- and 2.38-fold for BNT162b2, and 1.26- and 2.67-fold for convalescent plasma. Comparative analyses among the spike structures of the different variants suggest that mutations in the spike protein from the Lambda variant, including the 246-252 deletion in an antigenic supersite at the N-terminal domain loop and L452Q/F490S within the receptor-binding domain, may account for immune escape. Interestingly, analyses using pseudotyped and whole viruses showed increased entry rates into HEK293T-ACE2 cells, but reduced replication rates in Vero-E6 cells for the Lambda variant when compared with the Alpha, Gamma and Delta variants. Our data show that inactivated virus and messenger RNA vaccines elicit different levels of neutralizing antibodies with different potency to neutralize SARS-CoV-2 variants, including the variant of interest Lambda.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Neutralizing/metabolism , COVID-19/therapy , Chile , HEK293 Cells , Humans , Immunization, Passive , Membrane Glycoproteins/metabolism , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Viral Envelope Proteins/metabolism
3.
Sci Rep ; 12(1): 5496, 2022 Mar 31.
Article in English | MEDLINE | ID: covidwho-1768853

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is accompanied by chronic neurological sequelae such as cognitive decline and mood disorder, but the underlying mechanisms have not yet been elucidated. We explored the possibility that the brain-infiltrating SARS-CoV-2 spike protein contributes to the development of neurological symptoms observed in COVID-19 patients in this study. Our behavioral study showed that administration of SARS-CoV-2 spike protein S1 subunit (S1 protein) to mouse hippocampus induced cognitive deficit and anxiety-like behavior in vivo. These neurological symptoms were accompanied by neuronal cell death in the dorsal and ventral hippocampus as well as glial cell activation. Interestingly, the S1 protein did not directly induce hippocampal cell death in vitro. Rather, it exerted neurotoxicity via glial cell activation, partially through interleukin-1ß induction. In conclusion, our data suggest a novel pathogenic mechanism for the COVID-19-associated neurological symptoms that involves glia activation and non-cell autonomous hippocampal neuronal death by the brain-infiltrating S1 protein.


Subject(s)
COVID-19 , Cognitive Dysfunction , Animals , Antibodies, Viral/metabolism , Anxiety , Cell Death , Cognition , Cognitive Dysfunction/etiology , Hippocampus/metabolism , Humans , Membrane Glycoproteins/metabolism , Mice , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism , Viral Envelope Proteins/metabolism
4.
Protein Eng Des Sel ; 352022 02 17.
Article in English | MEDLINE | ID: covidwho-1758841

ABSTRACT

Stabilizing antigenic proteins as vaccine immunogens or diagnostic reagents is a stringent case of protein engineering and design as the exterior surface must maintain recognition by receptor(s) and antigen-specific antibodies at multiple distinct epitopes. This is a challenge, as stability enhancing mutations must be focused on the protein core, whereas successful computational stabilization algorithms typically select mutations at solvent-facing positions. In this study, we report the stabilization of SARS-CoV-2 Wuhan Hu-1 Spike receptor binding domain using a combination of deep mutational scanning and computational design, including the FuncLib algorithm. Our most successful design encodes I358F, Y365W, T430I, and I513L receptor binding domain mutations, maintains recognition by the receptor ACE2 and a panel of different anti-receptor binding domain monoclonal antibodies, is between 1 and 2°C more thermally stable than the original receptor binding domain using a thermal shift assay, and is less proteolytically sensitive to chymotrypsin and thermolysin than the original receptor binding domain. Our approach could be applied to the computational stabilization of a wide range of proteins without requiring detailed knowledge of active sites or binding epitopes. We envision that this strategy may be particularly powerful for cases when there are multiple or unknown binding sites.


Subject(s)
SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Binding Sites , Membrane Glycoproteins/metabolism , Mutation , Protein Domains , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics
5.
J Phys Chem B ; 126(12): 2353-2360, 2022 Mar 31.
Article in English | MEDLINE | ID: covidwho-1751666

ABSTRACT

Variants of the SARS-CoV-2 virus continue to remain a threat 2 years from the beginning of the pandemic. As more variants arise, and the B.1.1.529 (Omicron) variant threatens to create another wave of infections, a method is needed to predict the binding affinity of the spike protein quickly and accurately with human angiotensin-converting enzyme II (ACE2). We present an accurate and convenient energy minimization/molecular mechanics Poisson-Boltzmann surface area methodology previously used with engineered ACE2 therapeutics to predict the binding affinity of the Omicron variant. Without any additional data from the variants discovered after the publication of our first model, the methodology can accurately predict the binding of the spike/ACE2 variant complexes. From this methodology, we predicted that the Omicron variant spike has a Kd of ∼22.69 nM (which is very close to the experimental Kd of 20.63 nM published during the review process of the current report) and that spike protein of the new "Stealth" Omicron variant (BA.2) will display a Kd of ∼12.9 nM with the wild-type ACE2 protein. This methodology can be used with as-yet discovered variants, allowing for quick determinations regarding the variant's infectivity versus either the wild-type virus or its variants.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Angiotensins , Humans , Membrane Glycoproteins/metabolism , Peptidyl-Dipeptidase A/metabolism , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Viral Envelope Proteins
6.
Viruses ; 14(3)2022 03 13.
Article in English | MEDLINE | ID: covidwho-1742726

ABSTRACT

The prolonged duration of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic has resulted in the continuous emergence of variants of concern (VOC, e.g., Omicron) and variants of interest (VOI, e.g., Lambda). These variants have challenged the protective efficacy of current COVID-19 vaccines, thus calling for the development of novel therapeutics against SARS-CoV-2 and its VOCs. Here, we constructed a novel fusion inhibitor-based recombinant protein, denoted as 5-Helix, consisting of three heptad repeat 1 (HR1) and two heptad repeat 2 (HR2) fragments. The 5-Helix interacted with the HR2 domain of the viral S2 subunit, the most conserved region in spike (S) protein, to block homologous six-helix bundle (6-HB) formation between viral HR1 and HR2 domains and, hence, viral S-mediated cell-cell fusion. The 5-Helix potently inhibited infection by pseudotyped SARS-CoV-2 and its VOCs, including Delta and Omicron variants. The 5-Helix also inhibited infection by authentic SARS-CoV-2 wild-type (nCoV-SH01) strain and its Delta variant. Collectively, our findings suggest that 5-Helix can be further developed as either a therapeutic or prophylactic to treat and prevent infection by SARS-CoV-2 and its variants.


Subject(s)
COVID-19 , Viral Envelope Proteins , COVID-19 Vaccines , Humans , Membrane Glycoproteins/metabolism , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Viral Envelope Proteins/metabolism
7.
Molecules ; 27(6)2022 Mar 14.
Article in English | MEDLINE | ID: covidwho-1742557

ABSTRACT

The S protein of SARS-CoV-2 is a crucial structural and functional component for virus entry. Due to the constant mutation of the virus, there are very limited ways to prevent and control COVID-19. This experiment used a macroscopic SDS-PAGE method and proved that the S protein of wild-type SARS-CoV-2 virus, especially the S1 subunit, is very sensitive to alkaline serine protease with acidic pI (ASPNJ), NJ represents Neanthes japonica (Izuka) from which ASP is purified). ASPNJ cleaves proteins when the carbonyl group of the peptide bond is contributed by arginine or lysine. ASPNJ can degrade the S protein very quickly and effectively in vitro with relative selectivity. It can be inferred that the S, S1 and RBD of SARS-CoV-2 variants can also be easily degraded by ASPNJ. This rapid and strong degradation of the S protein by ASPNJ may become a potential new treatment strategy.


Subject(s)
COVID-19 , Serine Proteases , Humans , Membrane Glycoproteins/metabolism , SARS-CoV-2 , Serine Proteases/genetics , Viral Envelope Proteins/metabolism
8.
FASEB J ; 36(3): e22234, 2022 03.
Article in English | MEDLINE | ID: covidwho-1702985

ABSTRACT

The transmembrane protease angiotensin converting enzyme 2 (ACE2) is a protective regulator within the renin angiotensin system and additionally represents the cellular receptor for SARS-CoV. The release of soluble ACE2 (sACE2) from the cell surface is hence believed to be a crucial part of its (patho)physiological functions, as both, ACE2 protease activity and SARS-CoV binding ability, are transferred from the cell membrane to body fluids. Yet, the molecular sources of sACE2 are still not completely investigated. In this study, we show different sources and prerequisites for the release of sACE2 from the cell membrane. By using inhibitors as well as CRISPR/Cas9-derived cells, we demonstrated that, in addition to the metalloprotease ADAM17, also ADAM10 is an important novel shedding protease of ACE2. Moreover, we observed that ACE2 can also be released in extracellular vesicles. The degree of either ADAM10- or ADAM17-mediated ACE2 shedding is dependent on stimulatory conditions and on the expression level of the pro-inflammatory ADAM17 regulator iRhom2. Finally, by using structural analysis and in vitro verification, we determined for the first time that the susceptibility to ADAM10- and ADAM17-mediated shedding is mediated by the collectrin-like part of ACE2. Overall, our findings give novel insights into sACE2 release by several independent molecular mechanisms.


Subject(s)
ADAM10 Protein/metabolism , ADAM17 Protein/metabolism , Amyloid Precursor Protein Secretases/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Extracellular Vesicles/metabolism , Membrane Glycoproteins/metabolism , Membrane Proteins/metabolism , SARS Virus/metabolism , ADAM10 Protein/genetics , ADAM17 Protein/genetics , Amyloid Precursor Protein Secretases/genetics , Angiotensin-Converting Enzyme 2/genetics , Clustered Regularly Interspaced Short Palindromic Repeats , Extracellular Vesicles/genetics , HEK293 Cells , Humans , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Membrane Glycoproteins/genetics , Membrane Proteins/genetics , SARS Virus/genetics , SARS-CoV-2
9.
Nat Cell Biol ; 24(1): 24-34, 2022 01.
Article in English | MEDLINE | ID: covidwho-1625709

ABSTRACT

SARS-CoV-2 infection of human cells is initiated by the binding of the viral Spike protein to its cell-surface receptor ACE2. We conducted a targeted CRISPRi screen to uncover druggable pathways controlling Spike protein binding to human cells. Here we show that the protein BRD2 is required for ACE2 transcription in human lung epithelial cells and cardiomyocytes, and BRD2 inhibitors currently evaluated in clinical trials potently block endogenous ACE2 expression and SARS-CoV-2 infection of human cells, including those of human nasal epithelia. Moreover, pharmacological BRD2 inhibition with the drug ABBV-744 inhibited SARS-CoV-2 replication in Syrian hamsters. We also found that BRD2 controls transcription of several other genes induced upon SARS-CoV-2 infection, including the interferon response, which in turn regulates the antiviral response. Together, our results pinpoint BRD2 as a potent and essential regulator of the host response to SARS-CoV-2 infection and highlight the potential of BRD2 as a therapeutic target for COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/pharmacology , Epithelial Cells/virology , SARS-CoV-2/metabolism , Transcription Factors/drug effects , Angiotensin-Converting Enzyme 2/drug effects , COVID-19/drug therapy , COVID-19/metabolism , COVID-19/virology , Cell Line , Epithelial Cells/metabolism , Humans , Membrane Glycoproteins/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , Transcription Factors/metabolism
10.
PLoS One ; 17(1): e0260897, 2022.
Article in English | MEDLINE | ID: covidwho-1613343

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can manifest with varying disease severity and mortality. Genetic predisposition influences the clinical course of infectious diseases. We investigated whether genetic polymorphisms in candidate genes ACE2, TIRAP, and factor X are associated with clinical outcomes in COVID-19. METHODS: We conducted a single-centre retrospective cohort study. All patients who visited the emergency department with SARS-CoV-2 infection proven by polymerase chain reaction were included. Single nucleotide polymorphisms in ACE2 (rs2285666), TIRAP (rs8177374) and factor X (rs3211783) were assessed. The outcomes were mortality, respiratory failure and venous thromboembolism. Respiratory failure was defined as the necessity of >5 litres/minute oxygen, high flow nasal oxygen suppletion or mechanical ventilation. RESULTS: Between March and April 2020, 116 patients (35% female, median age 65 [inter quartile range 55-75] years) were included and treated according to the then applicable guidelines. Sixteen patients (14%) died, 44 patients (38%) had respiratory failure of whom 23 required endotracheal intubation for mechanical ventilation, and 20 patients (17%) developed venous thromboembolism. The percentage of TIRAP polymorphism carriers in the survivor group was 28% as compared to 0% in the non-survivor group (p = 0.01, Bonferroni corrected p = 0.02). Genotype distribution of ACE2 and factor X did not differ between survivors and non-survivors. CONCLUSION: This study shows that carriage of TIRAP polymorphism rs8177374 could be associated with a significantly lower mortality in COVID-19. This TIRAP polymorphism may be an important predictor in the outcome of COVID-19.


Subject(s)
COVID-19/genetics , COVID-19/mortality , Membrane Glycoproteins/genetics , Receptors, Interleukin-1/genetics , Aged , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/epidemiology , Cohort Studies , Factor X/genetics , Factor X/metabolism , Female , Genetic Predisposition to Disease/genetics , Genotype , Humans , Male , Membrane Glycoproteins/metabolism , Middle Aged , Netherlands/epidemiology , Polymorphism, Single Nucleotide/genetics , Receptors, Interleukin-1/metabolism , Retrospective Studies , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Severity of Illness Index , Treatment Outcome
12.
Nat Commun ; 12(1): 4502, 2021 07 23.
Article in English | MEDLINE | ID: covidwho-1550282

ABSTRACT

Cells in many tissues, such as bone, muscle, and placenta, fuse into syncytia to acquire new functions and transcriptional programs. While it is known that fused cells are specialized, it is unclear whether cell-fusion itself contributes to programmatic-changes that generate the new cellular state. Here, we address this by employing a fusogen-mediated, cell-fusion system to create syncytia from undifferentiated cells. RNA-Seq analysis reveals VSV-G-induced cell fusion precedes transcriptional changes. To gain mechanistic insights, we measure the plasma membrane surface area after cell-fusion and observe it diminishes through increases in endocytosis. Consequently, glucose transporters internalize, and cytoplasmic glucose and ATP transiently decrease. This reduced energetic state activates AMPK, which inhibits YAP1, causing transcriptional-reprogramming and cell-cycle arrest. Impairing either endocytosis or AMPK activity prevents YAP1 inhibition and cell-cycle arrest after fusion. Together, these data demonstrate plasma membrane diminishment upon cell-fusion causes transient nutrient stress that may promote transcriptional-reprogramming independent from extrinsic cues.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Cell Membrane/metabolism , Cell Nucleus/metabolism , Membrane Glycoproteins/metabolism , Transcription Factors/metabolism , Transcription, Genetic/genetics , Viral Envelope Proteins/metabolism , AMP-Activated Protein Kinases/genetics , AMP-Activated Protein Kinases/metabolism , Adaptor Proteins, Signal Transducing/genetics , Animals , Biological Transport , Cell Fusion , Cell Line , Cell Line, Tumor , Cells, Cultured , Giant Cells/metabolism , HEK293 Cells , Humans , Membrane Glycoproteins/genetics , Mice , RNA-Seq/methods , Signal Transduction/genetics , Transcription Factors/genetics , Viral Envelope Proteins/genetics
13.
Biochem Biophys Res Commun ; 586: 137-142, 2022 01 01.
Article in English | MEDLINE | ID: covidwho-1520712

ABSTRACT

Nuclear pore complexes (NPC) regulate molecular traffics on nuclear envelope, which plays crucial roles during cell fate specification and diseases. The viral accessory protein NSP9 of SARS-CoV-2 is reported to interact with nucleoporin 62 (NUP62), a structural component of the NPC, but its biological impact on the host cell remain obscure. Here, we established new cell line models with ectopic NSP9 expression and determined the subcellular destination and biological functions of NSP9. Confocal imaging identified NSP9 to be largely localized in close proximity to the endoplasmic reticulum. In agreement with the subcellular distribution of NSP9, association of NSP9 with NUP62 was observed in cytoplasm. Furthermore, the overexpression of NSP9 correlated with a reduction of NUP62 expression on the nuclear envelope, suggesting that attenuating NUP62 expression might have contributed to defective NPC formation. Importantly, the loss of NUP62 impaired translocation of p65, a subunit of NF-κB, upon TNF-α stimulation. Concordantly, NSP9 over-expression blocked p65 nuclear transport. Taken together, these data shed light on the molecular mechanisms underlying the modulation of host cells during SARS-CoV-2 infection.


Subject(s)
COVID-19/metabolism , COVID-19/virology , Host Microbial Interactions/physiology , Membrane Glycoproteins/metabolism , Nuclear Pore Complex Proteins/metabolism , RNA-Binding Proteins/metabolism , SARS-CoV-2/metabolism , Viral Nonstructural Proteins/metabolism , Active Transport, Cell Nucleus , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum/virology , Gene Knockdown Techniques , HeLa Cells , Humans , Membrane Glycoproteins/antagonists & inhibitors , Membrane Glycoproteins/genetics , Models, Biological , Nuclear Envelope/metabolism , Nuclear Envelope/virology , Nuclear Pore Complex Proteins/antagonists & inhibitors , Nuclear Pore Complex Proteins/genetics , RNA-Binding Proteins/genetics , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Transcription Factor RelA/metabolism , Viral Nonstructural Proteins/genetics
14.
Viruses ; 13(10)2021 09 26.
Article in English | MEDLINE | ID: covidwho-1485180

ABSTRACT

Nascent HIV-1 particles incorporate the viral envelope glycoprotein and multiple host transmembrane proteins during assembly at the plasma membrane. At least some of these host transmembrane proteins on the surface of virions are reported as pro-viral factors that enhance virus attachment to target cells or facilitate trans-infection of CD4+ T cells via interactions with non-T cells. In addition to the pro-viral factors, anti-viral transmembrane proteins are incorporated into progeny virions. These virion-incorporated transmembrane proteins inhibit HIV-1 entry at the point of attachment and fusion. In infected polarized CD4+ T cells, HIV-1 Gag localizes to a rear-end protrusion known as the uropod. Regardless of cell polarization, Gag colocalizes with and promotes the virion incorporation of a subset of uropod-directed host transmembrane proteins, including CD162, CD43, and CD44. Until recently, the functions of these virion-incorporated proteins had not been clear. Here, we review the recent findings about the roles played by virion-incorporated CD162, CD43, and CD44 in HIV-1 spread to CD4+ T cells.


Subject(s)
HIV Infections/metabolism , Hyaluronan Receptors/metabolism , Leukosialin/metabolism , Membrane Glycoproteins/metabolism , Cell Membrane/metabolism , HIV Infections/genetics , HIV-1/genetics , HIV-1/metabolism , HIV-1/pathogenicity , Host-Pathogen Interactions , Humans , Hyaluronan Receptors/genetics , Leukosialin/genetics , Membrane Glycoproteins/genetics , Membrane Proteins/metabolism , T-Lymphocytes/metabolism , T-Lymphocytes/virology , Virion/metabolism , Virus Assembly , Virus Attachment , gag Gene Products, Human Immunodeficiency Virus/metabolism
15.
Nat Commun ; 12(1): 5739, 2021 10 19.
Article in English | MEDLINE | ID: covidwho-1475293

ABSTRACT

Protein aggregates associated with neurodegenerative diseases have the ability to transmit to unaffected cells, thereby templating their own aberrant conformation onto soluble homotypic proteins. Proteopathic seeds can be released into the extracellular space, secreted in association with extracellular vesicles (EV) or exchanged by direct cell-to-cell contact. The extent to which each of these pathways contribute to the prion-like spreading of protein misfolding is unclear. Exchange of cellular cargo by both direct cell contact or via EV depends on receptor-ligand interactions. We hypothesized that enabling these interactions through viral ligands enhances intercellular proteopathic seed transmission. Using different cellular models propagating prions or pathogenic Tau aggregates, we demonstrate that vesicular stomatitis virus glycoprotein and SARS-CoV-2 spike S increase aggregate induction by cell contact or ligand-decorated EV. Thus, receptor-ligand interactions are important determinants of intercellular aggregate dissemination. Our data raise the possibility that viral infections contribute to proteopathic seed spreading by facilitating intercellular cargo transfer.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Extracellular Vesicles/metabolism , Membrane Glycoproteins/metabolism , Protein Aggregation, Pathological/virology , Spike Glycoprotein, Coronavirus/metabolism , Viral Envelope Proteins/metabolism , Adult , Aged , Brain/pathology , Case-Control Studies , Cell Line , Endocytosis , Female , Humans , Intravital Microscopy , Male , Middle Aged , Prions/metabolism , Protein Aggregation, Pathological/pathology , Protein Folding , tau Proteins/metabolism
16.
Physiol Rev ; 101(4): 1457-1486, 2021 10 01.
Article in English | MEDLINE | ID: covidwho-1443666

ABSTRACT

This medical review addresses the hypothesis that CD38/NADase is at the center of a functional axis (i.e., intracellular Ca2+ mobilization/IFNγ response/reactive oxygen species burst) driven by severe acute respiratory syndrome coronavirus 2 infection, as already verified in respiratory syncytial virus pathology and CD38 activity in other cellular settings. Key features of the hypothesis are that 1) the substrates of CD38 (e.g., NAD+ and NADP+) are depleted by viral-induced metabolic changes; 2) the products of the enzymatic activity of CD38 [e.g., cyclic adenosine diphosphate-ribose (ADPR)/ADPR/nicotinic acid adenine dinucleotide phosphate] and related enzymes [e.g., poly(ADP-ribose)polymerase, Sirtuins, and ADP-ribosyl hydrolase] are involved in the anti-viral and proinflammatory response that favors the onset of lung immunopathology (e.g., cytokine storm and organ fibrosis); and 3) the pathological changes induced by this kinetic mechanism may be reduced by distinct modulators of the CD38/NAD+ axis (e.g., CD38 blockers, NAD+ suppliers, among others). This view is supported by arrays of associative basic and applied research data that are herein discussed and integrated with conclusions reported by others in the field of inflammatory, immune, tumor, and viral diseases.


Subject(s)
ADP-ribosyl Cyclase 1/metabolism , COVID-19/metabolism , Membrane Glycoproteins/metabolism , SARS-CoV-2 , ADP-ribosyl Cyclase 1/genetics , COVID-19/pathology , COVID-19/virology , Gene Expression Regulation, Enzymologic , Humans , Membrane Glycoproteins/genetics
17.
mBio ; 12(5): e0237121, 2021 10 26.
Article in English | MEDLINE | ID: covidwho-1440804

ABSTRACT

In 2019, a new pandemic virus belonging to the betacoronavirus family emerged, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This new coronavirus appeared in Wuhan, China, and is responsible for severe respiratory pneumonia in humans, namely, coronavirus disease 2019 (COVID-19). Having infected almost 200 million people worldwide and caused more than 4.1 million deaths as of today, this new disease has raised a significant number of questions about its molecular mechanism of replication and, in particular, how infectious viral particles are produced. Although viral entry is well characterized, the full assembly steps of SARS-CoV-2 have still not been fully described. Coronaviruses, including SARS-CoV-2, have four main structural proteins, namely, the spike glycoprotein (S), the membrane glycoprotein (M), the envelope protein (E), and the nucleocapsid protein (N). All these proteins have key roles in the process of coronavirus assembly and budding. In this review, we gathered the current knowledge about betacoronavirus structural proteins involved in viral particle assembly, membrane curvature and scission, and then egress in order to suggest and question a coherent model for SARS-CoV-2 particle production and release.


Subject(s)
Betacoronavirus/metabolism , SARS-CoV-2/metabolism , Membrane Glycoproteins/metabolism , Nucleocapsid Proteins/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Virus Assembly/physiology
18.
Physiol Rev ; 102(1): 339-341, 2022 01 01.
Article in English | MEDLINE | ID: covidwho-1398740

ABSTRACT

During the COVID-19 pandemic, efforts have been made worldwide to develop effective therapies to address the devastating immune-mediated effects of SARS-CoV-2. With the exception of monoclonal antibody-mediated therapeutics and preventive approaches such as mass immunization, most experimental or repurposed drugs have failed in large randomized clinical trials (https://www.who.int/publications/i/item/therapeutics-and-covid-19-living-guideline). The worldwide spread of SARS-CoV-2 virus revealed specific susceptibilities to the virus among the elderly and individuals with age-related syndromes. These populations were more likely to experience a hyperimmune response characterized by a treatment-resistant acute lung pathology accompanied by multiple organ failure. These observations underscore the interplay between the virus, the biology of aging, and outcomes observed in the most severe cases of SARS-CoV-2 infection. The ectoenzyme CD38 has been implicated in the process of "inflammaging" in aged tissues. In a current publication, Horenstein et al. present evidence to support the hypothesis that CD38 plays a central role in altered immunometabolism resulting from COVID-19 infection. The authors discuss a critical but underappreciated trifecta of CD38-mediated NAD+ metabolism, aging, and COVID-19 immune response and speculate that the CD38/NAD+ axis is a promising therapeutic target for this disease.


Subject(s)
ADP-ribosyl Cyclase 1/metabolism , COVID-19/physiopathology , Membrane Glycoproteins/metabolism , SARS-CoV-2 , ADP-ribosyl Cyclase 1/genetics , Aging , Gene Expression Regulation, Enzymologic , Humans , Membrane Glycoproteins/genetics , NAD/metabolism
19.
Front Immunol ; 12: 708149, 2021.
Article in English | MEDLINE | ID: covidwho-1337643

ABSTRACT

Microbial translocation (MT) and intestinal damage (ID) are poorly explored in COVID-19. Aims were to assess whether alteration of gut permeability and cell integrity characterize COVID-19 patients, whether it is more pronounced in severe infections and whether it influences the development of subsequent bloodstream infection (BSI). Furthermore, we looked at the potential predictive role of TM and ID markers on Intensive Care Unit (ICU) admission and in-hospital mortality. Over March-July 2020, 45 COVID-19 patients were enrolled. Markers of MT [LPB (Lipopolysacharide Binding Protein) and EndoCab IgM] and ID [I-FABP (Intestinal Fatty Acid Binding Protein)] were evaluated at COVID-19 diagnosis and after 7 days. As a control group, age- and gender-matched healthy donors (HDs) enrolled during the same study period were included. Median age was 66 (56-71) years. Twenty-one (46.6%) were admitted to ICU and mortality was 22% (10/45). Compared to HD, a high degree of MT and ID was observed. ICU patients had higher levels of MT, but not of ID, than non-ICU ones. Likewise, patients with BSI had lower EndoCab IgM than non-BSI. Interestingly, patients with high degree of MT and low ID were likely to be admitted to ICU (AUC 0.822). Patients with COVID-19 exhibited high level of MT, especially subjects admitted to ICU. COVID-19 is associated with gut permeability.


Subject(s)
COVID-19/metabolism , Intestinal Mucosa/metabolism , SARS-CoV-2/physiology , Acute-Phase Proteins/metabolism , Aged , Biomarkers/metabolism , COVID-19/diagnosis , COVID-19/mortality , COVID-19/pathology , Carrier Proteins/metabolism , Disease Progression , Fatty Acid-Binding Proteins/metabolism , Female , Humans , Intensive Care Units , Intestinal Mucosa/pathology , Male , Membrane Glycoproteins/metabolism , Middle Aged , Predictive Value of Tests , Prognosis , Survival Analysis , Tight Junctions/metabolism
20.
Int Immunopharmacol ; 99: 108020, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1330896

ABSTRACT

The spike protein of the SARS-CoV-2 virus is the foremost target for the designing of vaccines and therapeutic antibodies and also acts as a crucial antigen in the assessment of COVID-19 immune responses. The enveloped viruses; such as SARS-CoV-2, Human Immunodeficiency Virus-1 (HIV-1) and influenza, often hijack host-cell glycosylation pathways and influence pathobiology and immune selection. These glycan motifs can lead to either immune evasion or viral neutralization by the production of cross-reactive antibodies that can lead to antibody-dependent enhancement (ADE) of infection. Potential cross-protection from influenza vaccine has also been reported in COVID-19 infected individuals in several epidemiological studies recently; however, the scientific basis for these observations remains elusive. Herein, we show that the anti-SARS-CoV2 antibodies cross-reacts with the Hemagglutinin (HA) protein. This phenomenon is common to both the sera from convalescent SARS-CoV-2 donors and spike immunized mice, although these antibodies were unable to cross-neutralize, suggesting the presence of a non-neutralizing antibody response. Epitope mapping suggests that the cross-reactive antibodies are targeted towards glycan epitopes of the SARS-CoV-2 spike and HA. Overall, our findings address the cross-reactive responses, although non-neutralizing, elicited against RNA viruses and warrant further studies to investigate whether such non-neutralizing antibody responses can contribute to effector functions such as antibody-dependent cellular cytotoxicity (ADCC) or ADE.


Subject(s)
COVID-19/immunology , Cross Reactions/immunology , Hemagglutinin Glycoproteins, Influenza Virus/immunology , Spike Glycoprotein, Coronavirus/immunology , Animals , Antibodies, Neutralizing , Antigen-Antibody Reactions , Binding Sites, Antibody/immunology , Cell Culture Techniques , Chlorocebus aethiops , Dogs , Epitope Mapping , Epitopes/immunology , Glycosylation , Humans , Influenza Vaccines/immunology , Madin Darby Canine Kidney Cells , Membrane Glycoproteins/metabolism , Mice , Mice, Inbred C57BL , SARS-CoV-2/immunology , Vero Cells
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