Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 39
Filter
1.
Cell Rep ; 41(5): 111573, 2022 Nov 01.
Article in English | MEDLINE | ID: covidwho-2113996

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of coronavirus disease 2019 (COVID-19), can induce a plethora of neurological complications in some patients. However, it is still under debate whether SARS-CoV-2 directly infects the brain or whether CNS sequelae result from systemic inflammatory responses triggered in the periphery. By using high-resolution microscopy, we investigated whether SARS-CoV-2 reaches the brain and how viral neurotropism can be modulated by aging in a non-human primate model of COVID-19. Seven days after infection, SARS-CoV-2 was detected in the olfactory cortex and interconnected regions and was accompanied by robust neuroinflammation and neuronal damage exacerbated in aged, diabetic animals. Our study provides an initial framework for identifying the molecular and cellular mechanisms underlying SARS-CoV-2 neurological complications, which will be essential to reducing both the short- and long-term burden of COVID-19.


Subject(s)
COVID-19 , Nervous System Diseases , Animals , SARS-CoV-2 , Neuroinflammatory Diseases , Neurons , Primates
2.
Cell Rep ; 39(5): 110754, 2022 05 03.
Article in English | MEDLINE | ID: covidwho-2113939

ABSTRACT

Rapid spread of SARS-CoV-2 variants C.1.2 and B.1.621 (Mu variant) in Africa and the Americas, respectively, as well as a high number of mutations in the viral spike proteins raised concerns that these variants might pose an elevated threat to human health. Here, we show that C.1.2 and B.1.621 spike proteins mediate increased entry into certain cell lines but do not exhibit increased ACE2 binding. Further, we demonstrate that C.1.2 and B.1.621 are resistant to neutralization by bamlanivimab but remain sensitive to inhibition by antibody cocktails used for COVID-19 therapy. Finally, we show that C.1.2 and B.1.621 partially escape neutralization by antibodies induced upon infection and vaccination, with escape of vaccine-induced antibodies being as potent as that measured for B.1.351 (Beta variant), which is known to be highly neutralization resistant. Collectively, C.1.2 and B.1.621 partially evade control by vaccine-induced antibodies, suggesting that close monitoring of these variants is warranted.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Monoclonal, Humanized , Antibodies, Neutralizing , Antibodies, Viral , COVID-19 Vaccines , Humans , Spike Glycoprotein, Coronavirus , Vaccination
3.
Cell Rep ; : 111729, 2022 Nov 10.
Article in English | MEDLINE | ID: covidwho-2104503

ABSTRACT

Since the initial emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.1, several Omicron sublineages have emerged, leading to BA.5 as the current dominant sublineage. Here, we report the neutralization of different Omicron sublineages by human sera collected from individuals who had distinct mRNA vaccination and/or BA.1 infection. Four-dose-vaccine sera neutralize the original USA-WA1/2020, Omicron BA.1, BA.2, BA.2.12.1, BA.3, and BA.4/5 viruses with geometric mean titers (GMTs) of 1,554, 357, 236, 236, 165, and 95, respectively; two-dose-vaccine-plus-BA.1-infection sera exhibit GMTs of 2,114, 1,705, 730, 961, 813, and 274, respectively; and three-dose-vaccine-plus-BA.1-infection sera show GMTs of 2,962, 2,038, 983, 1,190, 1,019, and 297, respectively. Thus, the four-dose vaccine elicits the lowest neutralization against BA.5; the two-dose vaccine plus BA.1 infection elicits significantly higher GMTs against Omicron sublineages than the four-dose-vaccine; and the three-dose vaccine plus BA.1 infection elicits slightly higher GMTs (statistically insignificant) than the two-dose vaccine plus BA.1 infection. Finally, the BA.2.75 is more susceptible than BA.5 to four-dose-vaccine-elicited neutralization and three-dose-vaccine-plus-BA.1-infection-elicited neutralization.

4.
Cell Rep ; 41(4): 111540, 2022 10 25.
Article in English | MEDLINE | ID: covidwho-2104500

ABSTRACT

The cellular fate after infection with human coronaviruses (HCoVs) is typically death. Previous data suggest, however, that the transcriptional state of an individual cell may sometimes allow additional outcomes of infection. Here, to probe the range of interactions a permissive cell type can have with a HCoV, we perform a CRISPR activation screen with HCoV-229E. The screen identified the transcription factor ZBTB7A, which strongly promotes cell survival after infection. Rather than suppressing viral infection, ZBTB7A upregulation allows the virus to induce a persistent infection and homeostatic state with the cell. We also find that control of oxidative stress is a primary driver of cellular survival during HCoV-229E infection. These data illustrate that, in addition to the nature of the infecting virus and the type of cell that it encounters, the cellular gene expression profile prior to infection can affect the eventual fate.


Subject(s)
Coronavirus 229E, Human , Humans , Coronavirus 229E, Human/genetics , Cell Line, Tumor , DNA-Binding Proteins , Transcription Factors/genetics , Homeostasis
5.
Cell Rep ; 41(7): 111650, 2022 Nov 15.
Article in English | MEDLINE | ID: covidwho-2086004

ABSTRACT

As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concerns (VOCs) continue to emerge, cross-neutralizing antibody responses become key toward next-generation design of a more universal COVID-19 vaccine. By analyzing published data from the literature, we report here that the combination of germline genes IGHV2-5/IGLV2-14 represents a public antibody response to the receptor-binding domain (RBD) that potently cross-neutralizes a broad range of VOCs, including Omicron and its sub-lineages. Detailed molecular analysis shows that the complementarity-determining region H3 sequences of IGHV2-5/IGLV2-14-encoded RBD antibodies have a preferred length of 11 amino acids and a conserved HxIxxI motif. In addition, these antibodies have a strong allelic preference due to an allelic polymorphism at amino acid residue 54 of IGHV2-5, which is located at the paratope. These findings have important implications for understanding cross-neutralizing antibody responses to SARS-CoV-2 and its heterogenicity at the population level as well as the development of a universal COVID-19 vaccine.


Subject(s)
Antibodies, Viral , Broadly Neutralizing Antibodies , COVID-19 , Humans , Antibodies, Viral/immunology , Broadly Neutralizing Antibodies/immunology , COVID-19/immunology , COVID-19 Vaccines , Receptors, Virus/metabolism , SARS-CoV-2
6.
Cell Rep ; 41(5): 111528, 2022 Nov 01.
Article in English | MEDLINE | ID: covidwho-2060517

ABSTRACT

The emergence and global spread of the SARS-CoV-2 Omicron variants, which carry an unprecedented number of mutations, raise serious concerns due to the reduced efficacy of current vaccines and resistance to therapeutic antibodies. Here, we report the generation and characterization of two potent human monoclonal antibodies, NA8 and NE12, against the receptor-binding domain of the SARS-CoV-2 spike protein. NA8 interacts with a highly conserved region and has a breadth of neutralization with picomolar potency against the Beta variant and the Omicron BA.1 and BA.2 sublineages and nanomolar potency against BA.2.12.1 and BA.4. Combination of NA8 and NE12 retains potent neutralizing activity against the major SARS-CoV-2 variants of concern. Cryo-EM analysis provides the structural basis for the broad and complementary neutralizing activity of these two antibodies. We confirm the in vivo protective and therapeutic efficacies of NA8 and NE12 in the hamster model. These results show that broad and potent human antibodies can overcome the continuous immune escape of evolving SARS-CoV-2 variants.


Subject(s)
Antineoplastic Agents, Immunological , COVID-19 , Humans , SARS-CoV-2 , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal/genetics , Neutralization Tests , Antibodies, Viral/therapeutic use , Viral Envelope Proteins , Membrane Glycoproteins/genetics , Antibodies, Neutralizing/therapeutic use
7.
Cell Rep ; 41(3): 111512, 2022 10 18.
Article in English | MEDLINE | ID: covidwho-2060516

ABSTRACT

The SARS-CoV-2 Omicron variant evades most neutralizing vaccine-induced antibodies and is associated with lower antibody titers upon breakthrough infections than previous variants. However, the mechanism remains unclear. Here, we find using a geometric deep-learning model that Omicron's extensively mutated receptor binding site (RBS) features reduced antigenicity compared with previous variants. Mice immunization experiments with different recombinant receptor binding domain (RBD) variants confirm that the serological response to Omicron is drastically attenuated and less potent. Analyses of serum cross-reactivity and competitive ELISA reveal a reduction in antibody response across both variable and conserved RBD epitopes. Computational modeling confirms that the RBS has a potential for further antigenicity reduction while retaining efficient receptor binding. Finally, we find a similar trend of antigenicity reduction over decades for hCoV229E, a common cold coronavirus. Thus, our study explains the reduced antibody titers associated with Omicron infection and reveals a possible trajectory of future viral evolution.


Subject(s)
COVID-19 , Viral Vaccines , Mice , Animals , Spike Glycoprotein, Coronavirus , Neutralization Tests , Antibodies, Viral/chemistry , SARS-CoV-2 , Antibodies, Neutralizing/chemistry , Epitopes/chemistry
8.
Cell Rep ; 40(7): 111212, 2022 08 16.
Article in English | MEDLINE | ID: covidwho-2060513

ABSTRACT

Evolutionary changes in host-virus interactions can alter the course of infection, but the biophysical and regulatory constraints that shape interface evolution remain largely unexplored. Here, we focus on viral mimicry of host-like motifs that allow binding to host domains and modulation of cellular pathways. We observe that motifs from unrelated viruses preferentially target conserved, widely expressed, and highly connected host proteins, enriched with regulatory and essential functions. The interface residues within these host domains are more conserved and bind a larger number of cellular proteins than similar motif-binding domains that are not known to interact with viruses. In contrast, rapidly evolving viral-binding human proteins form few interactions with other cellular proteins and display high tissue specificity, and their interfaces have few inter-residue contacts. Our results distinguish between conserved and rapidly evolving host-virus interfaces and show how various factors limit host capacity to evolve, allowing for efficient viral subversion of host machineries.


Subject(s)
Proteins , Viruses , Amino Acid Motifs , Humans , Proteins/metabolism , Viruses/metabolism
9.
Cell Rep ; 40(11): 111359, 2022 09 13.
Article in English | MEDLINE | ID: covidwho-2003920

ABSTRACT

Despite being more transmissible, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant only causes milder diseases in laboratory animals, often accompanied by a lower viral load compared with previous variants of concern. In this study, we report the structural basis for a robust interaction between the receptor-binding domain of the Omicron spike protein and mouse ACE2. We show that pseudovirus bearing the Omicron spike protein efficiently utilizes mouse ACE2 for entry. By comparing viral load and disease severity among laboratory mice infected by a natural Omicron variant or recombinant ancestral viruses bearing either the entire Omicron spike or only the N501Y/Q493R mutations in its spike, we find that mutations outside the spike protein in the Omicron variant may be responsible for the observed lower viral load. Together, our results imply that a post-entry block to the Omicron variant exists in laboratory mice.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Animals , Mice , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization
10.
Cell Rep ; 40(9): 111299, 2022 08 30.
Article in English | MEDLINE | ID: covidwho-1982704

ABSTRACT

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019 has led to the development of a large number of vaccines, several of which are now approved for use in humans. Understanding vaccine-elicited antibody responses against emerging SARS-CoV-2 variants of concern (VOCs) in real time is key to inform public health policies. Serum neutralizing antibody titers are the current best correlate of protection from SARS-CoV-2 challenge in non-human primates and a key metric to understand immune evasion of VOCs. We report that vaccinated BALB/c mice do not recapitulate faithfully the breadth and potency of neutralizing antibody responses elicited by various vaccine platforms against VOCs, compared with non-human primates or humans, suggesting caution should be exercised when interpreting data obtained with this animal model.


Subject(s)
COVID-19 , Viral Vaccines , Animals , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , Humans , Mice , Mice, Inbred BALB C , Primates , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
11.
Cell Rep ; 40(8): 111276, 2022 08 23.
Article in English | MEDLINE | ID: covidwho-1982702

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike is the target for neutralizing antibodies elicited following both infection and vaccination. While extensive research has shown that the receptor binding domain (RBD) and, to a lesser extent, the N-terminal domain (NTD) are the predominant targets for neutralizing antibodies, identification of neutralizing epitopes beyond these regions is important for informing vaccine development and understanding antibody-mediated immune escape. Here, we identify a class of broadly neutralizing antibodies that bind an epitope on the spike subdomain 1 (SD1) and that have arisen from infection or vaccination. Using cryo-electron microscopy (cryo-EM) and hydrogen-deuterium exchange coupled to mass spectrometry (HDX-MS), we show that SD1-specific antibody P008_60 binds an epitope that is not accessible within the canonical prefusion states of the SARS-CoV-2 spike, suggesting a transient conformation of the viral glycoprotein that is vulnerable to neutralization.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Neutralizing , Antibodies, Viral , Cryoelectron Microscopy , Epitopes , Humans , Neutralization Tests , Spike Glycoprotein, Coronavirus , Syndactyly , Vaccination
12.
Cell Rep ; 40(7): 111220, 2022 08 16.
Article in English | MEDLINE | ID: covidwho-1966425

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike N-terminal domain (NTD) remains poorly characterized despite enrichment of mutations in this region across variants of concern (VOCs). Here, we examine the contribution of the NTD to infection and cell-cell fusion by constructing chimeric spikes bearing B.1.617 lineage (Delta and Kappa variants) NTDs and generating spike pseudotyped lentivirus. We find that the Delta NTD on a Kappa or wild-type (WT) background increases S1/S2 cleavage efficiency and virus entry, specifically in lung cells and airway organoids, through use of TMPRSS2. Delta exhibits increased cell-cell fusogenicity that could be conferred to WT and Kappa spikes by Delta NTD transfer. However, chimeras of Omicron BA.1 and BA.2 spikes with a Delta NTD do not show more efficient TMPRSS2 use or fusogenicity. We conclude that the NTD allosterically modulates S1/S2 cleavage and spike-mediated functions in a spike context-dependent manner, and allosteric interactions may be lost when combining regions from more distantly related VOCs.


Subject(s)
COVID-19 , Virus Internalization , Humans , SARS-CoV-2 , Serine Endopeptidases/genetics , Spike Glycoprotein, Coronavirus/genetics
13.
Cell Rep ; 40(7): 111214, 2022 08 16.
Article in English | MEDLINE | ID: covidwho-1966424

ABSTRACT

Vaccine-associated enhanced respiratory disease (VAERD) is a severe complication for some respiratory infections. To investigate the potential for VAERD induction in coronavirus disease 2019 (COVID-19), we evaluate two vaccine leads utilizing a severe hamster infection model: a T helper type 1 (TH1)-biased measles vaccine-derived candidate and a TH2-biased alum-adjuvanted, non-stabilized spike protein. The measles virus (MeV)-derived vaccine protects the animals, but the protein lead induces VAERD, which can be alleviated by dexamethasone treatment. Bulk transcriptomic analysis reveals that our protein vaccine prepares enhanced host gene dysregulation in the lung, exclusively up-regulating mRNAs encoding the eosinophil attractant CCL-11, TH2-driving interleukin (IL)-19, or TH2 cytokines IL-4, IL-5, and IL-13. Single-cell RNA sequencing (scRNA-seq) identifies lung macrophages or lymphoid cells as sources, respectively. Our findings imply that VAERD is caused by the concerted action of hyperstimulated macrophages and TH2 cytokine-secreting lymphoid cells and potentially links VAERD to antibody-dependent enhancement (ADE). In summary, we identify the cytokine drivers and cellular contributors that mediate VAERD after TH2-biased vaccination.


Subject(s)
COVID-19 , Vaccines , Animals , Antibodies, Viral , Cricetinae , Cytokines/metabolism , Immunization , Lung/pathology , Mice , Mice, Inbred BALB C , Th1 Cells , Th2 Cells , Vaccination
14.
Cell Rep ; 39(13): 111009, 2022 06 28.
Article in English | MEDLINE | ID: covidwho-1944463

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.2 sub-lineage has gained in proportion relative to BA.1. Because spike (S) protein variations may underlie differences in their pathobiology, here we determine cryoelectron microscopy (cryo-EM) structures of the BA.2 S ectodomain and compare these with previously determined BA.1 S structures. BA.2 receptor-binding domain (RBD) mutations induce remodeling of the RBD structure, resulting in tighter packing and improved thermostability. Interprotomer RBD interactions are enhanced in the closed (or 3-RBD-down) BA.2 S, while the fusion peptide is less accessible to antibodies than in BA.1. Binding and pseudovirus neutralization assays reveal extensive immune evasion while defining epitopes of two outer RBD face-binding antibodies, DH1044 and DH1193, that neutralize both BA.1 and BA.2. Taken together, our results indicate that stabilization of the closed state through interprotomer RBD-RBD packing is a hallmark of the Omicron variant and show differences in key functional regions in the BA.1 and BA.2 S proteins.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Viral , Cryoelectron Microscopy , Humans , Receptors, Virus/metabolism , Spike Glycoprotein, Coronavirus
15.
Cell Rep ; 40(4): 111148, 2022 07 26.
Article in English | MEDLINE | ID: covidwho-1926273

ABSTRACT

Plasmacytoid dendritic cells (pDCs) are specialized cells of the immune system that are thought to be the main cellular source of type I interferon alpha (IFNα) in response to viral infections. IFNs are powerful antivirals, whereas defects in their function or induction lead to impaired resistance to virus infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. IFN production needs to be controlled, because sustained IFN production can also have detrimental effects on disease outcome. As such, pDCs are likely important for acute antiviral protection against SARS-CoV-2 infection but could potentially also contribute to chronic IFN levels. Here, we provide a historical overview of pDC biology and summarize existing literature addressing their involvement and importance during viral infections of the airways. Furthermore, we outline recent reports focused on the potential role of pDCs during SARS-CoV-2 infection, as well as the potential for this cellular subset to impact COVID-19 disease outcome.


Subject(s)
COVID-19 , Interferon Type I , Antiviral Agents/pharmacology , Dendritic Cells , Humans , SARS-CoV-2
16.
Cell Rep ; 39(9): 110904, 2022 05 31.
Article in English | MEDLINE | ID: covidwho-1926270

ABSTRACT

Despite SARS-CoV-2 being a "novel" virus, early detection of anti-spike IgG in severe COVID-19 patients may be caused by the amplification of humoral memory responses against seasonal coronaviruses. Here, we examine this phenomenon by characterizing anti-spike IgG responses in non-hospitalized convalescent individuals across a spectrum of COVID-19 severity. We observe that disease severity positively correlates with anti-spike IgG levels, IgG cross-reactivity against other betacoronaviruses (ß-CoVs), and FcγR activation. Analysis of IgG targeting ß-CoV-conserved and non-conserved immunodominant epitopes within the SARS-CoV-2 spike protein revealed epitope-specific relationships: IgG targeting the conserved heptad repeat (HR) 2 region significantly correlates with milder disease, while targeting the conserved S2'FP region correlates with more severe disease. Furthermore, a lower HR2-to-S2'FP IgG-binding ratio correlates with greater disease severity, with ICU-hospitalized COVID-19 patients showing the lowest HR2/S2'FP ratios. These findings suggest that HR2/S2'FP IgG profiles may predict disease severity and offer insight into protective versus deleterious humoral recall responses.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Immunoglobulin G , Seasons , Spike Glycoprotein, Coronavirus
17.
Cell Rep ; 40(3): 111117, 2022 07 19.
Article in English | MEDLINE | ID: covidwho-1914214

ABSTRACT

As an enveloped virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) delivers its viral genome into host cells via fusion of the viral and cell membranes. Here, we show that ANO6/TMEM16F-mediated cell surface exposure of phosphatidylserine is critical for SARS-CoV-2 entry and that ANO6-selective inhibitors are effective against SARS-CoV-2 infections. Application of the SARS-CoV-2 Spike pseudotyped virus (SARS2-PsV) evokes a cytosolic Ca2+ elevation and ANO6-dependent phosphatidylserine externalization in ACE2/TMPRSS2-positive mammalian cells. A high-throughput screening of drug-like chemical libraries identifies three different structural classes of chemicals showing ANO6 inhibitory effects. Among them, A6-001 displays the highest potency and ANO6 selectivity and it inhibits the single-round infection of SARS2-PsV in ACE2/TMPRSS2-positive HEK 293T cells. More importantly, A6-001 strongly inhibits authentic SARS-CoV-2-induced phosphatidylserine scrambling and SARS-CoV-2 viral replications in Vero, Calu-3, and primarily cultured human nasal epithelial cells. These results provide mechanistic insights into the viral entry process and offer a potential target for pharmacological intervention to protect against coronavirus disease 2019 (COVID-19).


Subject(s)
COVID-19 , Angiotensin-Converting Enzyme 2 , Animals , Anoctamins , COVID-19/drug therapy , Humans , Mammals/metabolism , Phosphatidylserines , Phospholipid Transfer Proteins/metabolism , SARS-CoV-2 , Virus Internalization
18.
Cell Rep ; 40(3): 111088, 2022 07 19.
Article in English | MEDLINE | ID: covidwho-1906848

ABSTRACT

Inhibitors of bromodomain and extraterminal domain (BET) proteins are possible anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prophylactics as they downregulate angiotensin-converting enzyme 2 (ACE2). Here we show that BET proteins should not be inactivated therapeutically because they are critical antiviral factors at the post-entry level. Depletion of BRD3 or BRD4 in cells overexpressing ACE2 exacerbates SARS-CoV-2 infection; the same is observed when cells with endogenous ACE2 expression are treated with BET inhibitors during infection and not before. Viral replication and mortality are also enhanced in BET inhibitor-treated mice overexpressing ACE2. BET inactivation suppresses interferon production induced by SARS-CoV-2, a process phenocopied by the envelope (E) protein previously identified as a possible "histone mimetic." E protein, in an acetylated form, directly binds the second bromodomain of BRD4. Our data support a model where SARS-CoV-2 E protein evolved to antagonize interferon responses via BET protein inhibition; this neutralization should not be further enhanced with BET inhibitor treatment.


Subject(s)
COVID-19 , SARS-CoV-2 , Angiotensin-Converting Enzyme 2 , Animals , Antiviral Agents/pharmacology , Interferons , Mice , Nuclear Proteins , Transcription Factors , Viral Proteins
19.
Cell Rep ; 40(1): 111022, 2022 07 05.
Article in English | MEDLINE | ID: covidwho-1885676

ABSTRACT

The COVID-19 pandemic has triggered the first widespread vaccination campaign against a coronavirus. Many vaccinated subjects are previously naive to SARS-CoV-2; however, almost all have previously encountered other coronaviruses (CoVs), and the role of this immunity in shaping the vaccine response remains uncharacterized. Here, we use longitudinal samples and highly multiplexed serology to identify mRNA-1273 vaccine-induced antibody responses against a range of CoV Spike epitopes, in both phylogenetically conserved and non-conserved regions. Whereas reactivity to SARS-CoV-2 epitopes shows a delayed but progressive increase following vaccination, we observe distinct kinetics for the endemic CoV homologs at conserved sites in Spike S2: these become detectable sooner and decay at later time points. Using homolog-specific antibody depletion and alanine-substitution experiments, we show that these distinct trajectories reflect an evolving cross-reactive response that can distinguish rare, polymorphic residues within these epitopes. Our results reveal mechanisms for the formation of antibodies with broad reactivity against CoVs.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , 2019-nCoV Vaccine mRNA-1273 , Antibodies, Viral , Antibody Formation , COVID-19/prevention & control , COVID-19 Vaccines , Epitopes , Humans , Pandemics , SARS-CoV-2 , Vaccination
20.
Cell Rep ; 39(13): 111020, 2022 06 28.
Article in English | MEDLINE | ID: covidwho-1885675

ABSTRACT

While there have been extensive analyses characterizing cellular and humoral responses across the severity spectrum in COVID-19, outcome predictors within severe COVID-19 remain less comprehensively elucidated. Furthermore, properties of antibodies (Abs) directed against viral antigens beyond spike and their associations with disease outcomes remain poorly defined. We perform deep molecular profiling of Abs directed against a wide range of antigenic specificities in severe COVID-19 patients. The profiles included canonical (spike [S], receptor-binding domain [RBD], and nucleocapsid [N]) and non-canonical (orf3a, orf8, nsp3, nsp13, and membrane [M]) antigenic specificities. Notably, multivariate Ab profiles directed against canonical or non-canonical antigens are equally discriminative of survival in severe COVID-19. Intriguingly, pre-pandemic healthy controls have cross-reactive Abs directed against nsp13, a protein conserved across coronaviruses. Consistent with these findings, a model built on Ab profiles for endemic coronavirus antigens also predicts COVID-19 outcome. Our results suggest the importance of studying Abs targeting non-canonical severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and endemic coronavirus antigens in COVID-19.


Subject(s)
COVID-19 , Antibodies, Viral , Humans , Pandemics , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
SELECTION OF CITATIONS
SEARCH DETAIL