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1.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-332033

ABSTRACT

The SARS-CoV-2 Omicron variant has been partitioned into four sub-lineages designated BA.1, BA.1.1, BA.2 and BA.3, with BA.2 becoming dominant worldwide recently by outcompeting BA.1 and BA.1.1. We and others have reported the striking antibody evasion of BA.1 and BA.2, but side-by-side comparison of susceptibility of all the major Omicron sub-lineages to vaccine-elicited or monoclonal antibody (mAb)-mediated neutralization are urgently needed. Using VSV-based pseudovirus, we found that sera from individuals vaccinated by two doses of inactivated whole-virion vaccines (BBIBP-CorV) showed very weak to no neutralization activity, while a homologous inactivated vaccine booster or a heterologous booster with protein subunit vaccine (ZF2001) markedly improved the neutralization titers against all Omicron variants. The comparison between sub-lineages indicated that BA.1.1, BA.2 and BA.3 had comparable or even greater antibody resistance than BA.1. We further evaluated the neutralization profile of a panel of 20 mAbs, including 10 already authorized or approved, against these Omicron sub-lineages as well as viruses with different Omicron spike single or combined mutations. Most mAbs lost their neutralizing activity completely or substantially, while some demonstrated distinct neutralization patterns among Omicron sub-lineages, reflecting their antigenic difference. Taken together, our results suggest all four Omicron sub-lineages threaten the efficacies of current vaccines and antibody therapeutics, highlighting the importance of vaccine boosters to combat the emerging SARS-CoV-2 variants.

2.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-308930

ABSTRACT

Measuring traffic performance is critical for public agencies who manage traffic and individuals who plan trips, especially when special events happen. The COVID-19 pandemic has significantly influenced almost every aspect of daily life, including urban traffic patterns. Thus, it is important to measure the impact of COVID-19 on transportation to further guide agencies and residents to properly respond to changes in traffic patterns. However, most existing traffic performance metrics incorporate only a single traffic parameter and measure only the performance of individual corridors. To overcome these challenges, in this study, a Traffic Performance Score (TPS) is proposed that incorporates multiple parameters for measuring network-wide traffic performance. An interactive web-based TPS platform that provides real-time and historical spatial-temporal traffic performance analysis is developed by the STAR Lab at the University of Washington. Based on data from this platform, this study analyzes the impact of COVID-19 on different road segments and the traffic network as a whole. Considering this pandemic has greatly reshaped social and economic operations, this study also evaluates how COVID-19 is changing the urban mobility from both travel demand and driving behavior perspectives.

3.
Emerg Microbes Infect ; 11(1): 477-481, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-1625890

ABSTRACT

The massive and rapid transmission of SARS-CoV-2 has led to the emergence of several viral variants of concern (VOCs), with the most recent one, B.1.1.529 (Omicron), which accumulated a large number of spike mutations, raising the specter that this newly identified variant may escape from the currently available vaccines and therapeutic antibodies. Using VSV-based pseudovirus, we found that Omicron variant is markedly resistant to neutralization of sera from convalescents or individuals vaccinated by two doses of inactivated whole-virion vaccines (BBIBP-CorV). However, a homologous inactivated vaccine booster or a heterologous booster with protein subunit vaccine (ZF2001) significantly increased neutralization titers to both WT and Omicron variant. Moreover, at day 14 post the third dose, neutralizing antibody titer reduction for Omicron was less than that for convalescents or individuals who had only two doses of the vaccine, indicating that a homologous or heterologous booster can reduce the Omicron escape from neutralizing. In addition, we tested a panel of 17 SARS-CoV-2 monoclonal antibodies (mAbs). Omicron resists seven of eight authorized/approved mAbs, as well as most of the other mAbs targeting distinct epitopes on RBD and NTD. Taken together, our results suggest the urgency to push forward the booster vaccination to combat the emerging SARS-CoV-2 variants.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19 Vaccines/immunology , COVID-19/prevention & control , Immunization, Secondary , SARS-CoV-2/immunology , Vaccines, Inactivated/immunology , Antibodies, Monoclonal/immunology , COVID-19 Vaccines/administration & dosage , Epitopes/immunology , Humans , Neutralization Tests , Spike Glycoprotein, Coronavirus/immunology , Vaccination , Vaccines, Inactivated/administration & dosage
5.
Emerg Microbes Infect ; 11(1): 147-157, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-1537457

ABSTRACT

The repeated emergence of highly pathogenic human coronaviruses as well as their evolving variants highlight the need to develop potent and broad-spectrum antiviral therapeutics and vaccines. By screening monoclonal antibodies (mAbs) isolated from COVID-19-convalescent patients, we found one mAb, 2-36, with cross-neutralizing activity against SARS-CoV. We solved the cryo-EM structure of 2-36 in complex with SARS-CoV-2 or SARS-CoV spike, revealing a highly conserved epitope in the receptor-binding domain (RBD). Antibody 2-36 neutralized not only all current circulating SARS-CoV-2 variants and SARS-COV, but also a panel of bat and pangolin sarbecoviruses that can use human angiotensin-converting enzyme 2 (ACE2) as a receptor. We selected 2-36-escape viruses in vitro and confirmed that K378 T in SARS-CoV-2 RBD led to viral resistance. Taken together, 2-36 represents a strategic reserve drug candidate for the prevention and treatment of possible diseases caused by pre-emergent SARS-related coronaviruses. Its epitope defines a promising target for the development of a pan-sarbecovirus vaccine.


Subject(s)
Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , SARS-CoV-2/immunology , Animals , Broadly Neutralizing Antibodies/immunology , COVID-19 , Chlorocebus aethiops , Cryoelectron Microscopy , Epitopes/immunology , HEK293 Cells , Humans , Neutralization Tests , Protein Interaction Domains and Motifs , Protein Structure, Tertiary , Vero Cells
6.
Cell Rep ; 37(6): 109920, 2021 11 09.
Article in English | MEDLINE | ID: covidwho-1530684

ABSTRACT

It is urgent to develop disease models to dissect mechanisms regulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we derive airway organoids from human pluripotent stem cells (hPSC-AOs). The hPSC-AOs, particularly ciliated-like cells, are permissive to SARS-CoV-2 infection. Using this platform, we perform a high content screen and identify GW6471, which blocks SARS-CoV-2 infection. GW6471 can also block infection of the B.1.351 SARS-CoV-2 variant. RNA sequencing (RNA-seq) analysis suggests that GW6471 blocks SARS-CoV-2 infection at least in part by inhibiting hypoxia inducible factor 1 subunit alpha (HIF1α), which is further validated by chemical inhibitor and genetic perturbation targeting HIF1α. Metabolic profiling identifies decreased rates of glycolysis upon GW6471 treatment, consistent with transcriptome profiling. Finally, xanthohumol, 5-(tetradecyloxy)-2-furoic acid, and ND-646, three compounds that suppress fatty acid biosynthesis, also block SARS-CoV-2 infection. Together, a high content screen coupled with transcriptome and metabolic profiling reveals a key role of the HIF1α-glycolysis axis in mediating SARS-CoV-2 infection of human airway epithelium.


Subject(s)
COVID-19/metabolism , Glycolysis/physiology , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Lung/metabolism , Organoids/metabolism , Animals , Cell Line , Chlorocebus aethiops , Epithelial Cells/metabolism , HEK293 Cells , Humans , Pluripotent Stem Cells/metabolism , SARS-CoV-2/pathogenicity , Transcriptome/physiology , Vero Cells
7.
PubMed; 2020.
Preprint in English | PubMed | ID: ppcovidwho-292815

ABSTRACT

Biotin-labeled molecular probes, comprising specific regions of the SARS-CoV-2 spike, would be helpful in the isolation and characterization of antibodies targeting this recently emerged pathogen. To develop such probes, we designed constructs incorporating an N-terminal purification tag, a site-specific protease-cleavage site, the probe region of interest, and a C-terminal sequence targeted by biotin ligase. Probe regions included full-length spike ectodomain as well as various subregions, and we also designed mutants to eliminate recognition of the ACE2 receptor. Yields of biotin-labeled probes from transient transfection ranged from ~0.5 mg/L for the complete ectodomain to >5 mg/L for several subregions. Probes were characterized for antigenicity and ACE2 recognition, and the structure of the spike ectodomain probe was determined by cryo-electron microscopy. We also characterized antibody-binding specificities and cell-sorting capabilities of the biotinylated probes. Altogether, structure-based design coupled to efficient purification and biotinylation processes can thus enable streamlined development of SARS-CoV-2 spike-ectodomain probes. Funding: Support for this work was provided by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID). Support for this work was also provided by COVID-19 Fast Grants, the Jack Ma Foundation, the Self Graduate Fellowship Program, and NIH grants DP5OD023118, R21AI143407, and R21AI144408. Some of this work was performed at the Columbia University Cryo-EM Center at the Zuckerman Institute, and some at the Simons Electron Microscopy Center (SEMC) and National Center for Cryo-EM Access and Training (NCCAT) located at the New York Structural Biology Center, supported by grants from the Simons Foundation (SF349247), NYSTAR, and the NIH National Institute of General Medical Sciences (GM103310). Conflict of Interest: The authors declare that they have no conflict of interest. Ethical Approval: Peripheral blood mononuclear cells (PBMCs) for B cell sorting were obtained from a convalescent SARS-CoV-2 patient (collected 75 days post symptom onset under an IRB approved clinical trial protocol, VRC 200 - ClinicalTrials.gov Identifier: NCT00067054) and a healthy control donor from the NIH blood bank pre-SARS-CoV-2 pandemic.

8.
Non-conventional in English | [Unspecified Source], Grey literature | ID: grc-750489

ABSTRACT

SARS-CoV-2 has emerged as a global pathogen, sparking urgent vaccine development efforts with the trimeric spike. However, the inability of antibodies like CR3022, which binds a cryptic spike epitope with nanomolar affinity, to neutralize virus, suggests a spike-based means of neutralization escape. Here, we show the SARS-CoV-2 spike to have 10% the unfolding enthalpy of a globular protein at physiological pH, where it is recognized by antibodies like CR3022, and up to 10-times more unfolding enthalpy at endosomal pH, where it sheds such antibodies, suggesting that the spike evades potentially neutralizing antibody through a pH-dependent mechanism of conformational masking. To understand the compatibility of this mechanism with ACE2-receptor interactions, we carried out binding measurements and determined cryo-EM structures of the spike recognizing up to three ACE2 molecules at both physiological and endosomal pH. In the absence of ACE2, cryo-EM analyses indicated lower pH to reduce conformational heterogeneity. Single-receptor binding domain (RBD)-up conformations dominated at pH 5.5, resolving into a locked all-down conformation at lower pH through lowering of RBD and refolding of a pH-dependent switch. Notably, the emerging Asp614Gly strain partially destabilizes the switch that locks RBD down, thereby enhancing functional interactions with ACE2 while reducing evasion by conformational masking.

9.
Cell Rep ; 37(5): 109928, 2021 11 02.
Article in English | MEDLINE | ID: covidwho-1466096

ABSTRACT

Antibodies that potently neutralize SARS-CoV-2 target mainly the receptor-binding domain or the N-terminal domain (NTD). Over a dozen potently neutralizing NTD-directed antibodies have been studied structurally, and all target a single antigenic supersite in NTD (site 1). Here, we report the cryo-EM structure of a potent NTD-directed neutralizing antibody 5-7, which recognizes a site distinct from other potently neutralizing antibodies, inserting a binding loop into an exposed hydrophobic pocket between the two sheets of the NTD ß sandwich. Interestingly, this pocket was previously identified as the binding site for hydrophobic molecules, including heme metabolites, but we observe that their presence does not substantially impede 5-7 recognition. Mirroring its distinctive binding, antibody 5-7 retains neutralization potency with many variants of concern (VOCs). Overall, we reveal that a hydrophobic pocket in NTD proposed for immune evasion can be used by the immune system for recognition.

10.
J Minim Invasive Gynecol ; 28(5): 942, 2021 05.
Article in English | MEDLINE | ID: covidwho-1454311

ABSTRACT

STUDY OBJECTIVE: To demonstrate intra- and postoperative steps in a successful management of a complicated vesico-[utero]/cervicovaginal fistula. DESIGN: Stepwise demonstration of the technique with narrated video footage. SETTING: A urogenital fistula in developed countries mostly occurs after gynecologic surgeries but rarely from obstetric complications. The main treatment of a urogenital fistula is either transvaginal or transabdominal surgical repair. We present a case of a 36-year-old woman, gravida 3 para 3-0-0-3, who developed a complicated large vesico-[utero]/cervicovaginal fistula after an emergent repeat cesarean section. Robotic repair was performed 2 months after the injury using the modified O'Connor method. Blood loss was minimal, and the patient was discharged from the hospital 1 day postoperatively. Follow-up showed complete healing of the fistula with no urine leakage, frequency of urination, or dyspareunia. The patient resumed normal bladder function and menstrual period up to 4 months after the repair procedure. INTERVENTIONS: The basic surgical principle of urogenital fistula repair is demonstrated: (1) development of vesicovaginal spaces by dissection of the bladder from the uterus and the vagina, (2) meticulous hemostasis, (3) adequate freshened of the fistula edges, (4) tension-free and watertight closure of the bladder. We also demonstrate some other techniques that have developed though our own practice: (1) facilitating bladder distention by temporarily blocking the fistula, (2) placement of a ureteral catheter to protect the ureters, (3) interposition with omental flap, (4) single layer through and through closure of a cystotomy with 2-0 V-Loc suture (Covidien, Irvington, NJ). CONCLUSION: Complicated urogenital fistulas may be repaired successfully using minimally invasive surgery using robotic assistance, enabling less blood loss, faster recovery, shorter hospital stay, and fewer complications, etc.


Subject(s)
Fistula , Robotic Surgical Procedures , Vesicovaginal Fistula , Adult , Cesarean Section , Female , Humans , Pregnancy , Robotic Surgical Procedures/adverse effects , Urinary Bladder/surgery , Uterus , Vesicovaginal Fistula/etiology , Vesicovaginal Fistula/surgery
11.
Nature ; 597(7878): 703-708, 2021 09.
Article in English | MEDLINE | ID: covidwho-1442788

ABSTRACT

SARS-CoV-2 infections have surged across the globe in recent months, concomitant with considerable viral evolution1-3. Extensive mutations in the spike protein may threaten the efficacy of vaccines and therapeutic monoclonal antibodies4. Two signature spike mutations of concern are E484K, which has a crucial role in the loss of neutralizing activity of antibodies, and N501Y, a driver of rapid worldwide transmission of the B.1.1.7 lineage. Here we report the emergence of the variant lineage B.1.526 (also known as the Iota variant5), which contains E484K, and its rise to dominance in New York City in early 2021. This variant is partially or completely resistant to two therapeutic monoclonal antibodies that are in clinical use and is less susceptible to neutralization by plasma from individuals who had recovered from SARS-CoV-2 infection or serum from vaccinated individuals, posing a modest antigenic challenge. The presence of the B.1.526 lineage has now been reported in all 50 states in the United States and in many other countries. B.1.526 rapidly replaced earlier lineages in New York, with an estimated transmission advantage of 35%. These transmission dynamics, together with the relative antibody resistance of its E484K sub-lineage, are likely to have contributed to the sharp rise and rapid spread of B.1.526. Although SARS-CoV-2 B.1.526 initially outpaced B.1.1.7 in the region, its growth subsequently slowed concurrently with the rise of B.1.1.7 and ensuing variants.


Subject(s)
COVID-19/virology , SARS-CoV-2/growth & development , SARS-CoV-2/isolation & purification , Antibodies, Neutralizing/immunology , Humans , Mutation , New York/epidemiology , Phylogeny , Phylogeography , Prevalence , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , United States/epidemiology
12.
Cell Rep ; 37(1): 109771, 2021 10 05.
Article in English | MEDLINE | ID: covidwho-1439919

ABSTRACT

Understanding mechanisms of protective antibody recognition can inform vaccine and therapeutic strategies against SARS-CoV-2. We report a monoclonal antibody, 910-30, targeting the SARS-CoV-2 receptor-binding site for ACE2 as a member of a public antibody response encoded by IGHV3-53/IGHV3-66 genes. Sequence and structural analyses of 910-30 and related antibodies explore how class recognition features correlate with SARS-CoV-2 neutralization. Cryo-EM structures of 910-30 bound to the SARS-CoV-2 spike trimer reveal binding interactions and its ability to disassemble spike. Despite heavy-chain sequence similarity, biophysical analyses of IGHV3-53/3-66-encoded antibodies highlight the importance of native heavy:light pairings for ACE2-binding competition and SARS-CoV-2 neutralization. We develop paired heavy:light class sequence signatures and determine antibody precursor prevalence to be ∼1 in 44,000 human B cells, consistent with public antibody identification in several convalescent COVID-19 patients. These class signatures reveal genetic, structural, and functional immune features that are helpful in accelerating antibody-based medical interventions for SARS-CoV-2.


Subject(s)
Angiotensin-Converting Enzyme 2/immunology , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/immunology , COVID-19/immunology , COVID-19/virology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Aged , Angiotensin-Converting Enzyme 2/chemistry , Animals , Antibodies, Monoclonal/genetics , Antibodies, Monoclonal/ultrastructure , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Antibody Formation , B-Lymphocytes/immunology , Binding Sites , Chlorocebus aethiops , Cryoelectron Microscopy , HEK293 Cells , Humans , Immunoglobulin Heavy Chains/chemistry , Immunoglobulin Heavy Chains/genetics , Immunoglobulin Heavy Chains/immunology , Immunoglobulin Heavy Chains/ultrastructure , Immunoglobulin Light Chains/chemistry , Immunoglobulin Light Chains/genetics , Immunoglobulin Light Chains/immunology , Immunoglobulin Light Chains/ultrastructure , Male , Protein Binding , Protein Interaction Domains and Motifs , SARS-CoV-2/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Vero Cells
13.
AIChE J ; 67(12): e17440, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1427045

ABSTRACT

Antiviral monoclonal antibody (mAb) discovery enables the development of antibody-based antiviral therapeutics. Traditional antiviral mAb discovery relies on affinity between antibody and a viral antigen to discover potent neutralizing antibodies, but these approaches are inefficient because many high affinity mAbs have no neutralizing activity. We sought to determine whether screening for anti-SARS-CoV-2 mAbs at reduced pH could provide more efficient neutralizing antibody discovery. We mined the antibody response of a convalescent COVID-19 patient at both physiological pH (7.4) and reduced pH (4.5), revealing that SARS-CoV-2 neutralizing antibodies were preferentially enriched in pH 4.5 yeast display sorts. Structural analysis revealed that a potent new antibody called LP5 targets the SARS-CoV-2 N-terminal domain supersite via a unique binding recognition mode. Our data combine with evidence from prior studies to support antibody screening at pH 4.5 to accelerate antiviral neutralizing antibody discovery.

15.
Cell Host Microbe ; 28(6): 867-879.e5, 2020 12 09.
Article in English | MEDLINE | ID: covidwho-1385264

ABSTRACT

The SARS-CoV-2 spike employs mobile receptor-binding domains (RBDs) to engage the human ACE2 receptor and to facilitate virus entry, which can occur through low-pH-endosomal pathways. To understand how ACE2 binding and low pH affect spike conformation, we determined cryo-electron microscopy structures-at serological and endosomal pH-delineating spike recognition of up to three ACE2 molecules. RBDs freely adopted "up" conformations required for ACE2 interaction, primarily through RBD movement combined with smaller alterations in neighboring domains. In the absence of ACE2, single-RBD-up conformations dominated at pH 5.5, resolving into a solitary all-down conformation at lower pH. Notably, a pH-dependent refolding region (residues 824-858) at the spike-interdomain interface displayed dramatic structural rearrangements and mediated RBD positioning through coordinated movements of the entire trimer apex. These structures provide a foundation for understanding prefusion-spike mechanics governing endosomal entry; we suggest that the low pH all-down conformation potentially facilitates immune evasion from RBD-up binding antibody.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , Pandemics , Spike Glycoprotein, Coronavirus/ultrastructure , Amino Acid Sequence/genetics , Angiotensin-Converting Enzyme 2/ultrastructure , Antibodies, Neutralizing/genetics , Antibodies, Neutralizing/immunology , Binding Sites , COVID-19/pathology , COVID-19/virology , Cryoelectron Microscopy , Endosomes/ultrastructure , Humans , Hydrogen-Ion Concentration , Protein Binding , Protein Domains , Receptors, Virus/genetics , Receptors, Virus/ultrastructure , SARS-CoV-2/genetics , SARS-CoV-2/ultrastructure , Spike Glycoprotein, Coronavirus/genetics
16.
Nature ; 597(7878): 703-708, 2021 09.
Article in English | MEDLINE | ID: covidwho-1371602

ABSTRACT

SARS-CoV-2 infections have surged across the globe in recent months, concomitant with considerable viral evolution1-3. Extensive mutations in the spike protein may threaten the efficacy of vaccines and therapeutic monoclonal antibodies4. Two signature spike mutations of concern are E484K, which has a crucial role in the loss of neutralizing activity of antibodies, and N501Y, a driver of rapid worldwide transmission of the B.1.1.7 lineage. Here we report the emergence of the variant lineage B.1.526 (also known as the Iota variant5), which contains E484K, and its rise to dominance in New York City in early 2021. This variant is partially or completely resistant to two therapeutic monoclonal antibodies that are in clinical use and is less susceptible to neutralization by plasma from individuals who had recovered from SARS-CoV-2 infection or serum from vaccinated individuals, posing a modest antigenic challenge. The presence of the B.1.526 lineage has now been reported in all 50 states in the United States and in many other countries. B.1.526 rapidly replaced earlier lineages in New York, with an estimated transmission advantage of 35%. These transmission dynamics, together with the relative antibody resistance of its E484K sub-lineage, are likely to have contributed to the sharp rise and rapid spread of B.1.526. Although SARS-CoV-2 B.1.526 initially outpaced B.1.1.7 in the region, its growth subsequently slowed concurrently with the rise of B.1.1.7 and ensuing variants.


Subject(s)
COVID-19/virology , SARS-CoV-2/growth & development , SARS-CoV-2/isolation & purification , Antibodies, Neutralizing/immunology , Humans , Mutation , New York/epidemiology , Phylogeny , Phylogeography , Prevalence , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , United States/epidemiology
17.
Stem Cell Reports ; 16(9): 2274-2288, 2021 09 14.
Article in English | MEDLINE | ID: covidwho-1360129

ABSTRACT

Heart injury has been reported in up to 20% of COVID-19 patients, yet the cause of myocardial histopathology remains unknown. Here, using an established in vivo hamster model, we demonstrate that SARS-CoV-2 can be detected in cardiomyocytes of infected animals. Furthermore, we found damaged cardiomyocytes in hamsters and COVID-19 autopsy samples. To explore the mechanism, we show that both human pluripotent stem cell-derived cardiomyocytes (hPSC-derived CMs) and adult cardiomyocytes (CMs) can be productively infected by SARS-CoV-2, leading to secretion of the monocyte chemoattractant cytokine CCL2 and subsequent monocyte recruitment. Increased CCL2 expression and monocyte infiltration was also observed in the hearts of infected hamsters. Although infected CMs suffer damage, we find that the presence of macrophages significantly reduces SARS-CoV-2-infected CMs. Overall, our study provides direct evidence that SARS-CoV-2 infects CMs in vivo and suggests a mechanism of immune cell infiltration and histopathology in heart tissues of COVID-19 patients.


Subject(s)
COVID-19/pathology , Chemokine CCL2/metabolism , Heart Injuries/virology , Monocytes/immunology , Myocytes, Cardiac/metabolism , Animals , Cell Communication/physiology , Cell Line , Chlorocebus aethiops , Cricetinae , Disease Models, Animal , Humans , Macrophages/immunology , Male , Myocytes, Cardiac/virology , Pluripotent Stem Cells/cytology , Vero Cells
18.
SSRN; 2021.
Preprint in English | SSRN | ID: ppcovidwho-289566
19.
Structure ; 29(7): 655-663.e4, 2021 07 01.
Article in English | MEDLINE | ID: covidwho-1263379

ABSTRACT

Emerging SARS-CoV-2 strains, B.1.1.7 and B.1.351, from the UK and South Africa, respectively, show decreased neutralization by monoclonal antibodies and convalescent or vaccinee sera raised against the original wild-type virus, and are thus of clinical concern. However, the neutralization potency of two antibodies, 1-57 and 2-7, which target the receptor-binding domain (RBD) of the spike, was unaffected by these emerging strains. Here, we report cryo-EM structures of 1-57 and 2-7 in complex with spike, revealing each of these antibodies to utilize a distinct mechanism to bypass or accommodate RBD mutations. Notably, each antibody represented an immune response with recognition distinct from those of frequent antibody classes. Moreover, many epitope residues recognized by 1-57 and 2-7 were outside hotspots of evolutionary pressure for ACE2 binding and neutralizing antibody escape. We suggest the therapeutic use of antibodies, such as 1-57 and 2-7, which target less prevalent epitopes, could ameliorate issues of monoclonal antibody escape.


Subject(s)
Angiotensin-Converting Enzyme 2/chemistry , Antibodies, Monoclonal/chemistry , Antibodies, Neutralizing/chemistry , Antibodies, Viral/chemistry , Receptors, Virus/chemistry , SARS-CoV-2/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Monoclonal/genetics , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/metabolism , Antibodies, Neutralizing/genetics , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/metabolism , Antibodies, Viral/genetics , Antibodies, Viral/immunology , Antibodies, Viral/metabolism , Binding Sites , Cloning, Molecular , Cryoelectron Microscopy , Epitopes/chemistry , Epitopes/genetics , Epitopes/immunology , Epitopes/metabolism , Gene Expression , HEK293 Cells , Humans , Models, Molecular , Mutation , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Receptors, Virus/genetics , Receptors, Virus/immunology , Receptors, Virus/metabolism , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/immunology , Recombinant Proteins/metabolism , SARS-CoV-2/genetics , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism
20.
Sci Rep ; 11(1): 9803, 2021 05 07.
Article in English | MEDLINE | ID: covidwho-1262011

ABSTRACT

Angiotensin converting enzyme 2 (ACE2) is a key regulator of the renin-angiotensin system, but also the functional receptor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Based on structural similarity with other γ-secretase (γS) targets, we hypothesized that ACE2 may be affected by γS proteolytic activity. We found that after ectodomain shedding, ACE2 is targeted for intramembrane proteolysis by γS, releasing a soluble ACE2 C-terminal fragment. Consistently, chemical or genetic inhibition of γS results in the accumulation of a membrane-bound fragment of ectodomain-deficient ACE2. Although chemical inhibition of γS does not alter SARS-CoV-2 cell entry, these data point to a novel pathway for cellular ACE2 trafficking.


Subject(s)
Amyloid Precursor Protein Secretases/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Membrane Glycoproteins/metabolism , Presenilin-1/metabolism , Presenilin-2/metabolism , SARS-CoV-2/physiology , Amyloid Precursor Protein Secretases/genetics , Angiotensin-Converting Enzyme 2/genetics , Animals , COVID-19/genetics , Caco-2 Cells , Cell Line , Chlorocebus aethiops , Gene Knockout Techniques , HEK293 Cells , Humans , Membrane Glycoproteins/genetics , Mice , Presenilin-1/genetics , Presenilin-2/genetics , Proteolysis , Vero Cells , Virus Internalization
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