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1.
MAbs ; 14(1): 2057832, 2022.
Article in English | MEDLINE | ID: covidwho-1774257

ABSTRACT

Anti-SARS-CoV-2 monoclonal antibodies and vaccines have shown improvement in lowering viral burden and hospitalization. However, emerging SARS-CoV-2 variants contain neutralizing antibody-escape mutations. Therefore, several reports have suggested the administration of recombinant angiotensin-converting enzyme 2 (rACE2) as a soluble receptor trap to block SARS-CoV-2 infection and limit viral escape potential. Several strategies have been implemented to enhance the efficacy of rACE2 as a therapeutic agent. Fc fusions have been used to improve pharmacokinetics and boost the affinity and avidity of ACE2 decoys for the virus spike protein. Furthermore, the intrinsic catalytic activity of ACE2 can be eliminated by introducing point mutations on the catalytic site of ACE2 to obtain an exclusive antiviral activity. This review summarizes different evolution platforms that have been used to enhance ACE2-Fc (i.e., immunoadhesins) as potential therapeutics for the current pandemic or future outbreaks of SARS-associated betacoronaviruses.


Subject(s)
COVID-19 , SARS-CoV-2 , Angiotensin-Converting Enzyme 2/genetics , COVID-19/drug therapy , Humans , Protein Binding , Receptors, Fc/metabolism , Spike Glycoprotein, Coronavirus/genetics
2.
PLoS One ; 16(12): e0261656, 2021.
Article in English | MEDLINE | ID: covidwho-1623659

ABSTRACT

SARS-CoV-2 infection elicits a robust B cell response, resulting in the generation of long-lived plasma cells and memory B cells. Here, we aimed to determine the effect of COVID-19 severity on the memory B cell response and characterize changes in the memory B cell compartment between recovery and five months post-symptom onset. Using high-parameter spectral flow cytometry, we analyzed the phenotype of memory B cells with reactivity against the SARS-CoV-2 spike protein or the spike receptor binding domain (RBD) in recovered individuals who had been hospitalized with non-severe (n = 8) or severe (n = 5) COVID-19. One month after symptom onset, a substantial proportion of spike-specific IgG+ B cells showed an activated phenotype. In individuals who experienced non-severe disease, spike-specific IgG+ B cells showed increased expression of markers associated with durable B cell memory, including T-bet and FcRL5, as compared to individuals who experienced severe disease. While the frequency of T-bet+ spike-specific IgG+ B cells differed between the two groups, these cells predominantly showed an activated switched memory B cell phenotype in both groups. Five months post-symptom onset, the majority of spike-specific memory B cells had a resting phenotype and the percentage of spike-specific T-bet+ IgG+ memory B cells decreased to baseline levels. Collectively, our results highlight subtle differences in the B cells response after non-severe and severe COVID-19 and suggest that the memory B cell response elicited during non-severe COVID-19 may be of higher quality than the response after severe disease.


Subject(s)
COVID-19/immunology , Receptors, Fc/metabolism , T-Box Domain Proteins/metabolism , Adult , Aged , Antibodies, Viral/blood , B-Lymphocytes/metabolism , Biomarkers/analysis , COVID-19/metabolism , Female , Flow Cytometry/methods , Hospitalization/trends , Humans , Immunoglobulin G/blood , Immunologic Memory , Male , /metabolism , Middle Aged , Receptors, Fc/blood , Receptors, Fc/genetics , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Severity of Illness Index , Spike Glycoprotein, Coronavirus/immunology , T-Box Domain Proteins/blood
3.
Immunity ; 55(2): 355-365.e4, 2022 02 08.
Article in English | MEDLINE | ID: covidwho-1611777

ABSTRACT

SARS-CoV-2 mRNA vaccines confer robust protection against COVID-19, but the emergence of variants has generated concerns regarding the protective efficacy of the currently approved vaccines, which lose neutralizing potency against some variants. Emerging data suggest that antibody functions beyond neutralization may contribute to protection from the disease, but little is known about SARS-CoV-2 antibody effector functions. Here, we profiled the binding and functional capacity of convalescent antibodies and Moderna mRNA-1273 COVID-19 vaccine-induced antibodies across SARS-CoV-2 variants of concern (VOCs). Although the neutralizing responses to VOCs decreased in both groups, the Fc-mediated responses were distinct. In convalescent individuals, although antibodies exhibited robust binding to VOCs, they showed compromised interactions with Fc-receptors. Conversely, vaccine-induced antibodies also bound robustly to VOCs but continued to interact with Fc-receptors and mediate antibody effector functions. These data point to a resilience in the mRNA-vaccine-induced humoral immune response that may continue to offer protection from SARS-CoV-2 VOCs independent of neutralization.


Subject(s)
/immunology , Antibodies, Viral/immunology , COVID-19/metabolism , COVID-19/prevention & control , Receptors, Fc/metabolism , SARS-CoV-2/immunology , /administration & dosage , Adult , Antibodies, Neutralizing/immunology , Cross Reactions/immunology , Female , Host-Pathogen Interactions , Humans , Male , Middle Aged , Neutralization Tests , Protein Binding , Spike Glycoprotein, Coronavirus/immunology , Vaccination , Young Adult
4.
mBio ; 12(5): e0239521, 2021 10 26.
Article in English | MEDLINE | ID: covidwho-1406605

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein is the main target for neutralizing antibodies. These antibodies can be elicited through immunization or passively transferred as therapeutics in the form of convalescent-phase sera or monoclonal antibodies (MAbs). Potently neutralizing antibodies are expected to confer protection; however, it is unclear whether weakly neutralizing antibodies contribute to protection. Also, their mechanism of action in vivo is incompletely understood. Here, we demonstrate that 2B04, an antibody with an ultrapotent neutralizing activity (50% inhibitory concentration [IC50] of 0.04 µg/ml), protects hamsters against SARS-CoV-2 in a prophylactic and therapeutic infection model. Protection is associated with reduced weight loss and viral loads in nasal turbinates and lungs after challenge. MAb 2B04 also blocked aerosol transmission of the virus to naive contacts. We next examined three additional MAbs (2C02, 2C03, and 2E06), recognizing distinct epitopes within the receptor binding domain of spike protein that possess either minimal (2C02 and 2E06, IC50 > 20 µg/ml) or weak (2C03, IC50 of 5 µg/ml) virus neutralization capacity in vitro. Only 2C03 protected Syrian hamsters from weight loss and reduced lung viral load after SARS-CoV-2 infection. Finally, we demonstrated that Fc-Fc receptor interactions were not required for protection when 2B04 and 2C03 were administered prophylactically. These findings inform the mechanism of protection and support the rational development of antibody-mediated protection against SARS-CoV-2 infections. IMPORTANCE The ongoing coronavirus disease 2019 (COVID-19) pandemic, caused by SARS-CoV-2, has resulted in the loss of millions of lives. Safe and effective vaccines are considered the ultimate remedy for the global social and economic disruption caused by the pandemic. However, a thorough understanding of the immune correlates of protection against this virus is lacking. Here, we characterized four different monoclonal antibodies and evaluated their ability to prevent or treat SARS-CoV-2 infection in Syrian hamsters. These antibodies varied in their ability to neutralize the virus in vitro. Prophylactic administration of potent and weakly neutralizing antibodies protected against SARS-CoV-2 infection, and this effect was Fc receptor independent. The potent neutralizing antibody also had therapeutic efficacy and eliminated onward aerosol transmission. In contrast, minimally neutralizing antibodies provided no protection against infection with SARS-CoV-2 in Syrian hamsters. Combined, these studies highlight the significance of weakly neutralizing antibodies in the protection against SARS-CoV-2 infection and associated disease.


Subject(s)
Antibodies, Monoclonal/metabolism , Antibodies, Neutralizing/metabolism , COVID-19/metabolism , Receptors, Fc/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Animals , COVID-19/prevention & control , Cricetinae , Male , Mesocricetus , Protein Binding
5.
Scand J Immunol ; 94(5): e13098, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1394026

ABSTRACT

Costimulatory and coinhibitory mechanisms appear to be involved throughout immune responses to control their specificity and level. Many mechanisms operate; therefore, various theoretical models should be considered complementary rather than competing. One such coinhibitory model, pictured in 1971, involves the crosslinking of antigen receptors with inhibitory Fc receptors by antigen/antibody complexes. This model was prompted by observations that the Fc portion of antibody was required for potent suppression of immune responses by antibody. The signal via the antigen receptor wakes up T or B cells, providing specificity, while costimulators and coinhibitors stimulate or inhibit these awoken cells. The recent observations that administration of monoclonal anti-SARS-CoV-2 spike antibodies in early COVID-19 patients inhibits the induction of clinically damaging autoimmune antibodies suggest they may provide negative Fc signals that are blocked in COVID-19 patients. Furthermore, the reduced ability of SARS-CoV-2 antigen to localize to germinal centres in COVID-19 patients also suggests a block in binding of the Fc of antibody bound to antigen on FcγRIIb of follicular dendritic cells. The distinction between self and foreign is made not only at the beginning of immune responses but also throughout, and involves multiple mechanisms and models. There are past beginnings (history of models) and current and future beginnings for solving serious clinical problems (such as COVID-19) and different types of models used for understanding the complexities of fundamental immunology.


Subject(s)
COVID-19/immunology , Models, Immunological , Receptors, Fc/metabolism , SARS-CoV-2/physiology , Animals , Antibodies, Viral/metabolism , Antigen-Antibody Complex/metabolism , Autoantibodies/metabolism , Humans
6.
Int J Mol Sci ; 22(6)2021 Mar 17.
Article in English | MEDLINE | ID: covidwho-1389395

ABSTRACT

As an essential modulator of IgG disposition, the neonatal Fc receptor (FcRn) governs the pharmacokinetics and functions many therapeutic modalities. In this review, we thoroughly reexamine the hitherto elucidated biological and thermodynamic properties of FcRn to provide context for our assessment of more recent advances, which covers antigen-binding fragment (Fab) determinants of FcRn affinity, transgenic preclinical models, and FcRn targeting as an immune-complex (IC)-clearing strategy. We further comment on therapeutic antibodies authorized for treating SARS-CoV-2 (bamlanivimab, casirivimab, and imdevimab) and evaluate their potential to saturate FcRn-mediated recycling. Finally, we discuss modeling and simulation studies that probe the quantitative relationship between in vivo IgG persistence and in vitro FcRn binding, emphasizing the importance of endosomal transit parameters.


Subject(s)
Histocompatibility Antigens Class I/chemistry , Histocompatibility Antigens Class I/metabolism , Receptors, Fc/chemistry , Receptors, Fc/metabolism , Animals , Antibodies, Monoclonal/metabolism , Antibodies, Monoclonal/pharmacokinetics , COVID-19/drug therapy , Histocompatibility Antigens Class I/immunology , Humans , Immunoglobulin G/immunology , Immunoglobulin G/metabolism , Receptors, Fc/immunology , Tissue Distribution/immunology
7.
Proc Natl Acad Sci U S A ; 118(27)2021 07 06.
Article in English | MEDLINE | ID: covidwho-1285962

ABSTRACT

IgA is the second most abundant antibody present in circulation and is enriched at mucosal surfaces. As such, IgA plays a key role in protection against a variety of mucosal pathogens including viruses. In addition to neutralizing viruses directly, IgA can also stimulate Fc-dependent effector functions via engagement of Fc alpha receptors (Fc-αRI) expressed on the surface of certain immune effector cells. Neutrophils are the most abundant leukocyte, express Fc-αRI, and are often the first to respond to sites of injury and infection. Here, we describe a function for IgA-virus immune complexes (ICs) during viral infections. We show that IgA-virus ICs potentiate NETosis-the programmed cell-death pathway through which neutrophils release neutrophil extracellular traps (NETs). Mechanistically, IgA-virus ICs potentiated a suicidal NETosis pathway via engagement of Fc-αRI on neutrophils through a toll-like receptor-independent, NADPH oxidase complex-dependent pathway. NETs also were capable of trapping and inactivating viruses, consistent with an antiviral function.


Subject(s)
Extracellular Traps/immunology , Immunoglobulin A/immunology , Neutrophils/immunology , Virus Diseases/immunology , Antigen-Antibody Complex/immunology , Antigens, CD/metabolism , Extracellular Traps/virology , Humans , Influenzavirus A/immunology , NADPH Oxidases/metabolism , Neutrophils/pathology , Neutrophils/virology , Receptors, Fc/metabolism , SARS-CoV-2/immunology , Signal Transduction , Virion
8.
Front Immunol ; 12: 700429, 2021.
Article in English | MEDLINE | ID: covidwho-1285298

ABSTRACT

The rapid spread of SARS-CoV-2 has induced a global pandemic. Severe forms of COVID-19 are characterized by dysregulated immune response and "cytokine storm". The role of IgG and IgM antibodies in COVID-19 pathology is reasonably well studied, whereas IgA is neglected. To improve clinical outcome of patients, immune modulatory drugs appear to be beneficial. Such drugs include intravenous immunoglobulin preparations, which were successfully tested in severe COVID-19 patients. Here we established a versatile in vitro model to study inflammatory as well as anti-inflammatory processes by therapeutic human immunoglobulins. We dissect the inflammatory activation on neutrophil-like HL60 cells, using an immune complex consisting of latex beads coated with spike protein of SARS-CoV-2 and opsonized with specific immunoglobulins from convalescent plasma. Our data clarifies the role of Fc-receptor-dependent phagocytosis via IgA-FcαRI and IgG-FcγR for COVID-19 disease followed by cytokine release. We show that COVID-19 associated inflammation could be reduced by addition of human immunoglobulin preparations (IVIG and trimodulin), while trimodulin elicits stronger immune modulation by more powerful ITAMi signaling. Besides IgG, the IgA component of trimodulin in particular, is of functional relevance for immune modulation in this assay setup, highlighting the need to study IgA mediated immune response.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Antigens, CD/metabolism , COVID-19/therapy , Cytokine Release Syndrome/therapy , Immunoglobulins, Intravenous/pharmacology , Neutrophils/immunology , Receptors, Fc/metabolism , Receptors, IgG/metabolism , SARS-CoV-2/physiology , Antibodies, Viral/metabolism , Antigen-Antibody Complex , Cell Line , Humans , Immunization, Passive , Immunomodulation , Phagocytosis , Signal Transduction , Spike Glycoprotein, Coronavirus/metabolism
9.
Cells ; 10(5)2021 05 12.
Article in English | MEDLINE | ID: covidwho-1234671

ABSTRACT

Macrophages play a key role in induction of inflammatory responses. These inflammatory responses are mostly considered to be instigated by activation of pattern recognition receptors (PRRs) or cytokine receptors. However, recently it has become clear that also antibodies and pentraxins, which can both activate Fc receptors (FcRs), induce very powerful inflammatory responses by macrophages that can even be an order of magnitude greater than PRRs. While the physiological function of this antibody-dependent inflammation (ADI) is to counteract infections, undesired activation or over-activation of this mechanism will lead to pathology, as observed in a variety of disorders, including viral infections such as COVID-19, chronic inflammatory disorders such as Crohn's disease, and autoimmune diseases such as rheumatoid arthritis. In this review we discuss how physiological ADI provides host defense by inducing pathogen-specific immunity, and how erroneous activation of this mechanism leads to pathology. Moreover, we will provide an overview of the currently known signaling and metabolic pathways that underlie ADI, and how these can be targeted to counteract pathological inflammation.


Subject(s)
Antibodies/metabolism , C-Reactive Protein/metabolism , Inflammation/immunology , Serum Amyloid P-Component/metabolism , Antibodies/immunology , C-Reactive Protein/immunology , Host-Pathogen Interactions/immunology , Humans , Immunity, Innate , Inflammation/metabolism , Inflammation/microbiology , Macrophages/immunology , Macrophages/metabolism , Metabolic Networks and Pathways/immunology , Receptors, Fc/metabolism , Serum Amyloid P-Component/immunology , Signal Transduction/immunology
10.
Front Immunol ; 12: 640093, 2021.
Article in English | MEDLINE | ID: covidwho-1133915

ABSTRACT

COVID-19 (SARS-CoV-2) disease severity and stages varies from asymptomatic, mild flu-like symptoms, moderate, severe, critical, and chronic disease. COVID-19 disease progression include lymphopenia, elevated proinflammatory cytokines and chemokines, accumulation of macrophages and neutrophils in lungs, immune dysregulation, cytokine storms, acute respiratory distress syndrome (ARDS), etc. Development of vaccines to severe acute respiratory syndrome (SARS), Middle East Respiratory Syndrome coronavirus (MERS-CoV), and other coronavirus has been difficult to create due to vaccine induced enhanced disease responses in animal models. Multiple betacoronaviruses including SARS-CoV-2 and SARS-CoV-1 expand cellular tropism by infecting some phagocytic cells (immature macrophages and dendritic cells) via antibody bound Fc receptor uptake of virus. Antibody-dependent enhancement (ADE) may be involved in the clinical observation of increased severity of symptoms associated with early high levels of SARS-CoV-2 antibodies in patients. Infants with multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 may also have ADE caused by maternally acquired SARS-CoV-2 antibodies bound to mast cells. ADE risks associated with SARS-CoV-2 has implications for COVID-19 and MIS-C treatments, B-cell vaccines, SARS-CoV-2 antibody therapy, and convalescent plasma therapy for patients. SARS-CoV-2 antibodies bound to mast cells may be involved in MIS-C and multisystem inflammatory syndrome in adults (MIS-A) following initial COVID-19 infection. SARS-CoV-2 antibodies bound to Fc receptors on macrophages and mast cells may represent two different mechanisms for ADE in patients. These two different ADE risks have possible implications for SARS-CoV-2 B-cell vaccines for subsets of populations based on age, cross-reactive antibodies, variabilities in antibody levels over time, and pregnancy. These models place increased emphasis on the importance of developing safe SARS-CoV-2 T cell vaccines that are not dependent upon antibodies.


Subject(s)
Antibody-Dependent Enhancement , COVID-19/immunology , Mast Cells/immunology , Middle East Respiratory Syndrome Coronavirus/physiology , Phagocytes/immunology , SARS-CoV-2/physiology , Systemic Inflammatory Response Syndrome/immunology , Animals , Antibodies, Viral/metabolism , COVID-19/transmission , Child , Cross Reactions , Female , Humans , Infant, Newborn , Infectious Disease Transmission, Vertical , Models, Immunological , Pregnancy , Receptors, Fc/metabolism , Risk , T-Lymphocytes/immunology
11.
Immunity ; 52(6): 1039-1056.e9, 2020 06 16.
Article in English | MEDLINE | ID: covidwho-209829

ABSTRACT

The phenotypic and functional dichotomy between IRF8+ type 1 and IRF4+ type 2 conventional dendritic cells (cDC1s and cDC2s, respectively) is well accepted; it is unknown how robust this dichotomy is under inflammatory conditions, when additionally monocyte-derived cells (MCs) become competent antigen-presenting cells (APCs). Using single-cell technologies in models of respiratory viral infection, we found that lung cDC2s acquired expression of the Fc receptor CD64 shared with MCs and of IRF8 shared with cDC1s. These inflammatory cDC2s (inf-cDC2s) were superior in inducing CD4+ T helper (Th) cell polarization while simultaneously presenting antigen to CD8+ T cells. When carefully separated from inf-cDC2s, MCs lacked APC function. Inf-cDC2s matured in response to cell-intrinsic Toll-like receptor and type 1 interferon receptor signaling, upregulated an IRF8-dependent maturation module, and acquired antigens via convalescent serum and Fc receptors. Because hybrid inf-cDC2s are easily confused with monocyte-derived cells, their existence could explain why APC functions have been attributed to MCs.


Subject(s)
Cell Plasticity/immunology , Dendritic Cells/immunology , Dendritic Cells/metabolism , Immunity , Macrophages/immunology , Macrophages/metabolism , Respirovirus Infections/etiology , Antigen Presentation , Biomarkers , Disease Susceptibility , Gene Expression Profiling , Gene Expression Regulation , Gene Regulatory Networks , Immunophenotyping , Interferon Type I/metabolism , Monocytes/immunology , Monocytes/metabolism , Organ Specificity/immunology , Receptors, Fc/metabolism , Respirovirus Infections/metabolism , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Transcription Factors , Virus Diseases/genetics , Virus Diseases/immunology , Virus Diseases/metabolism , Virus Diseases/virology
12.
J Virol ; 94(5)2020 02 14.
Article in English | MEDLINE | ID: covidwho-908

ABSTRACT

Antibody-dependent enhancement (ADE) of viral entry has been a major concern for epidemiology, vaccine development, and antibody-based drug therapy. However, the molecular mechanism behind ADE is still elusive. Coronavirus spike protein mediates viral entry into cells by first binding to a receptor on the host cell surface and then fusing viral and host membranes. In this study, we investigated how a neutralizing monoclonal antibody (MAb), which targets the receptor-binding domain (RBD) of Middle East respiratory syndrome (MERS) coronavirus spike, mediates viral entry using pseudovirus entry and biochemical assays. Our results showed that MAb binds to the virus surface spike, allowing it to undergo conformational changes and become prone to proteolytic activation. Meanwhile, MAb binds to cell surface IgG Fc receptor, guiding viral entry through canonical viral-receptor-dependent pathways. Our data suggest that the antibody/Fc-receptor complex functionally mimics viral receptor in mediating viral entry. Moreover, we characterized MAb dosages in viral-receptor-dependent, Fc-receptor-dependent, and both-receptors-dependent viral entry pathways, delineating guidelines on MAb usages in treating viral infections. Our study reveals a novel molecular mechanism for antibody-enhanced viral entry and can guide future vaccination and antiviral strategies.IMPORTANCE Antibody-dependent enhancement (ADE) of viral entry has been observed for many viruses. It was shown that antibodies target one serotype of viruses but only subneutralize another, leading to ADE of the latter viruses. Here we identify a novel mechanism for ADE: a neutralizing antibody binds to the surface spike protein of coronaviruses like a viral receptor, triggers a conformational change of the spike, and mediates viral entry into IgG Fc receptor-expressing cells through canonical viral-receptor-dependent pathways. We further evaluated how antibody dosages impacted viral entry into cells expressing viral receptor, Fc receptor, or both receptors. This study reveals complex roles of antibodies in viral entry and can guide future vaccine design and antibody-based drug therapy.


Subject(s)
Antibodies, Viral/immunology , Antibody-Dependent Enhancement , Middle East Respiratory Syndrome Coronavirus/immunology , Middle East Respiratory Syndrome Coronavirus/physiology , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/metabolism , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/metabolism , Antibodies, Viral/metabolism , Cell Line , Dipeptidyl Peptidase 4/metabolism , Humans , Immunoglobulin Fab Fragments/immunology , Immunoglobulin Fab Fragments/metabolism , Middle East Respiratory Syndrome Coronavirus/pathogenicity , Peptide Hydrolases/metabolism , Proprotein Convertases/antagonists & inhibitors , Proprotein Convertases/metabolism , Protein Conformation , Protein Domains , Protein Multimerization , Receptors, Fc/metabolism , Receptors, IgG/immunology , Receptors, IgG/metabolism , Receptors, Virus/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Trypsin/metabolism
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