RESUMO
The COVID-19 pandemic was caused by the recently emerged ß-coronavirus SARS-CoV-2. SARS-CoV-2 has had a catastrophic impact, resulting in nearly 7 million fatalities worldwide to date. The innate immune system is the first line of defense against infections, including the detection and response to SARS-CoV-2. Here, we discuss the innate immune mechanisms that sense coronaviruses, with a focus on SARS-CoV-2 infection and how these protective responses can become detrimental in severe cases of COVID-19, contributing to cytokine storm, inflammation, long-COVID, and other complications. We also highlight the complex cross talk among cytokines and the cellular components of the innate immune system, which can aid in viral clearance but also contribute to inflammatory cell death, cytokine storm, and organ damage in severe COVID-19 pathogenesis. Furthermore, we discuss how SARS-CoV-2 evades key protective innate immune mechanisms to enhance its virulence and pathogenicity, as well as how innate immunity can be therapeutically targeted as part of the vaccination and treatment strategy. Overall, we highlight how a comprehensive understanding of innate immune mechanisms has been crucial in the fight against SARS-CoV-2 infections and the development of novel host-directed immunotherapeutic strategies for various diseases.
Assuntos
COVID-19 , Imunidade Inata , SARS-CoV-2 , Humanos , COVID-19/imunologia , SARS-CoV-2/imunologia , SARS-CoV-2/fisiologia , Síndrome da Liberação de Citocina/imunologia , Citocinas/metabolismo , Animais , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Infecções por Coronavirus/prevenção & controle , Evasão da Resposta ImuneRESUMO
SARS-CoV-2 and other sarbecoviruses continue to threaten humanity, highlighting the need to characterize common mechanisms of viral immune evasion for pandemic preparedness. Cytotoxic lymphocytes are vital for antiviral immunity and express NKG2D, an activating receptor conserved among mammals that recognizes infection-induced stress ligands (e.g., MIC-A/B). We found that SARS-CoV-2 evades NKG2D recognition by surface downregulation of MIC-A/B via shedding, observed in human lung tissue and COVID-19 patient serum. Systematic testing of SARS-CoV-2 proteins revealed that ORF6, an accessory protein uniquely conserved among sarbecoviruses, was responsible for MIC-A/B downregulation via shedding. Further investigation demonstrated that natural killer (NK) cells efficiently killed SARS-CoV-2-infected cells and limited viral spread. However, inhibition of MIC-A/B shedding with a monoclonal antibody, 7C6, further enhanced NK-cell activity toward SARS-CoV-2-infected cells. Our findings unveil a strategy employed by SARS-CoV-2 to evade cytotoxic immunity, identify the culprit immunevasin shared among sarbecoviruses, and suggest a potential novel antiviral immunotherapy.
Assuntos
COVID-19 , Evasão da Resposta Imune , Células Matadoras Naturais , Subfamília K de Receptores Semelhantes a Lectina de Células NK , SARS-CoV-2 , Humanos , SARS-CoV-2/imunologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , COVID-19/imunologia , COVID-19/virologia , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Animais , Citotoxicidade Imunológica , Regulação para Baixo , Pulmão/imunologia , Pulmão/virologia , Pulmão/patologiaRESUMO
BA.2.86, a recently identified descendant of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.2 sublineage, contains â¼35 mutations in the spike (S) protein and spreads in multiple countries. Here, we investigated whether the virus exhibits altered biological traits, focusing on S protein-driven viral entry. Employing pseudotyped particles, we show that BA.2.86, unlike other Omicron sublineages, enters Calu-3 lung cells with high efficiency and in a serine- but not cysteine-protease-dependent manner. Robust lung cell infection was confirmed with authentic BA.2.86, but the virus exhibited low specific infectivity. Further, BA.2.86 was highly resistant against all therapeutic antibodies tested, efficiently evading neutralization by antibodies induced by non-adapted vaccines. In contrast, BA.2.86 and the currently circulating EG.5.1 sublineage were appreciably neutralized by antibodies induced by the XBB.1.5-adapted vaccine. Collectively, BA.2.86 has regained a trait characteristic of early SARS-CoV-2 lineages, robust lung cell entry, and evades neutralizing antibodies. However, BA.2.86 exhibits low specific infectivity, which might limit transmissibility.
Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , COVID-19 , SARS-CoV-2 , Humanos , Anticorpos Neutralizantes/metabolismo , Anticorpos Antivirais/metabolismo , Caspases/metabolismo , COVID-19/imunologia , COVID-19/virologia , Pulmão/virologia , SARS-CoV-2/classificação , SARS-CoV-2/genética , SARS-CoV-2/patogenicidade , SARS-CoV-2/fisiologia , Internalização do Vírus , Glicoproteína da Espícula de Coronavírus/genéticaRESUMO
Respiratory infections cause significant morbidity and mortality, yet it is unclear why some individuals succumb to severe disease. In patients hospitalized with avian A(H7N9) influenza, we investigated early drivers underpinning fatal disease. Transcriptomics strongly linked oleoyl-acyl-carrier-protein (ACP) hydrolase (OLAH), an enzyme mediating fatty acid production, with fatal A(H7N9) early after hospital admission, persisting until death. Recovered patients had low OLAH expression throughout hospitalization. High OLAH levels were also detected in patients hospitalized with life-threatening seasonal influenza, COVID-19, respiratory syncytial virus (RSV), and multisystem inflammatory syndrome in children (MIS-C) but not during mild disease. In olah-/- mice, lethal influenza infection led to survival and mild disease as well as reduced lung viral loads, tissue damage, infection-driven pulmonary cell infiltration, and inflammation. This was underpinned by differential lipid droplet dynamics as well as reduced viral replication and virus-induced inflammation in macrophages. Supplementation of oleic acid, the main product of OLAH, increased influenza replication in macrophages and their inflammatory potential. Our findings define how the expression of OLAH drives life-threatening viral disease.
RESUMO
The maturation of genomic surveillance in the past decade has enabled tracking of the emergence and spread of epidemics at an unprecedented level. During the COVID-19 pandemic, for example, genomic data revealed that local epidemics varied considerably in the frequency of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineage importation and persistence, likely due to a combination of COVID-19 restrictions and changing connectivity. Here, we show that local COVID-19 epidemics are driven by regional transmission, including across international boundaries, but can become increasingly connected to distant locations following the relaxation of public health interventions. By integrating genomic, mobility, and epidemiological data, we find abundant transmission occurring between both adjacent and distant locations, supported by dynamic mobility patterns. We find that changing connectivity significantly influences local COVID-19 incidence. Our findings demonstrate a complex meaning of "local" when investigating connected epidemics and emphasize the importance of collaborative interventions for pandemic prevention and mitigation.
Assuntos
COVID-19 , Humanos , COVID-19/epidemiologia , COVID-19/transmissão , COVID-19/virologia , Genômica , Pandemias/prevenção & controle , Saúde Pública , SARS-CoV-2/genética , Controle de Infecções , GeografiaRESUMO
Immune imprinting describes how the first exposure to a virus shapes immunological outcomes of subsequent exposures to antigenically related strains. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) Omicron breakthrough infections and bivalent COVID-19 vaccination primarily recall cross-reactive memory B cells induced by prior Wuhan-Hu-1 spike mRNA vaccination rather than priming Omicron-specific naive B cells. These findings indicate that immune imprinting occurs after repeated Wuhan-Hu-1 spike exposures, but whether it can be overcome remains unclear. To understand the persistence of immune imprinting, we investigated memory and plasma antibody responses after administration of the updated XBB.1.5 COVID-19 mRNA vaccine booster. We showed that the XBB.1.5 booster elicited neutralizing antibody responses against current variants that were dominated by recall of pre-existing memory B cells previously induced by the Wuhan-Hu-1 spike. Therefore, immune imprinting persists after multiple exposures to Omicron spikes through vaccination and infection, including post XBB.1.5 booster vaccination, which will need to be considered to guide future vaccination.
Assuntos
Vacinas contra COVID-19 , COVID-19 , Humanos , COVID-19/prevenção & controle , SARS-CoV-2 , Anticorpos Neutralizantes , RNA Mensageiro/genética , Vacinação , Anticorpos AntiviraisRESUMO
It is thought that mRNA-based vaccine-induced immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) wanes quickly, based mostly on short-term studies. Here, we analyzed the kinetics and durability of the humoral responses to SARS-CoV-2 infection and vaccination using >8,000 longitudinal samples collected over a 3-year period in New York City. Upon primary immunization, participants with pre-existing immunity mounted higher antibody responses faster and achieved higher steady-state antibody titers than naive individuals. Antibody kinetics were characterized by two phases: an initial rapid decay, followed by a stabilization phase with very slow decay. Booster vaccination equalized the differences in antibody concentration between participants with and without hybrid immunity, but the peak antibody titers decreased with each successive antigen exposure. Breakthrough infections increased antibodies to similar titers as an additional vaccine dose in naive individuals. Our study provides strong evidence that SARS-CoV-2 antibody responses are long lasting, with initial waning followed by stabilization.
Assuntos
COVID-19 , Vacinas , Humanos , SARS-CoV-2 , Formação de Anticorpos , Vacinação , Imunização Secundária , Vacinas de mRNA , Anticorpos AntiviraisRESUMO
Long COVID (LC) is a condition in which patients do not fully recover from the initial SARS-CoV-2 infection but rather have persistent or new symptoms for months to years following the infection. Ongoing research efforts are investigating the pathophysiologic mechanisms of LC and exploring preventative and therapeutic treatment approaches for patients. As a burgeoning area of investigation, LC research can be structured to be more inclusive, innovative, and effective. In this perspective, we highlight opportunities for patient engagement and diverse research expertise, as well as the challenges of developing definitions and reproducible studies. Our intention is to provide a foundation for collaboration and progress in understanding the biomarkers and mechanisms driving LC.
Assuntos
COVID-19 , Síndrome de COVID-19 Pós-Aguda , SARS-CoV-2 , Humanos , Biomarcadores , Pesquisa Biomédica , COVID-19/imunologia , COVID-19/virologia , SARS-CoV-2/fisiologia , SARS-CoV-2/imunologiaRESUMO
In response to viral infection, how cells balance translational shutdown to limit viral replication and the induction of antiviral components like interferons (IFNs) is not well understood. Moreover, how distinct isoforms of IFN-induced oligoadenylate synthetase 1 (OAS1) contribute to this antiviral response also requires further elucidation. Here, we show that human, but not mouse, OAS1 inhibits SARS-CoV-2 replication through its canonical enzyme activity via RNase L. In contrast, both mouse and human OAS1 protect against West Nile virus infection by a mechanism distinct from canonical RNase L activation. OAS1 binds AU-rich elements (AREs) of specific mRNAs, including IFNß. This binding leads to the sequestration of IFNß mRNA to the endomembrane regions, resulting in prolonged half-life and continued translation. Thus, OAS1 is an ARE-binding protein with two mechanisms of antiviral activity: driving inhibition of translation but also a broader, non-canonical function of protecting IFN expression from translational shutdown.
Assuntos
2',5'-Oligoadenilato Sintetase , Interferons , Oligorribonucleotídeos , Viroses , Febre do Nilo Ocidental , Animais , Humanos , Camundongos , 2',5'-Oligoadenilato Sintetase/genética , 2',5'-Oligoadenilato Sintetase/metabolismo , Nucleotídeos de Adenina , Antivirais/farmacologia , Febre do Nilo Ocidental/genética , Febre do Nilo Ocidental/metabolismo , Vírus do Nilo Ocidental/metabolismo , Vírus do Nilo Ocidental/patogenicidadeRESUMO
The spike glycoprotein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continues to accumulate substitutions, leading to breakthrough infections of vaccinated individuals. It remains unclear if exposures to antigenically distant SARS-CoV-2 variants can overcome memory B cell biases established by initial SARS-CoV-2 encounters. We determined the specificity and functionality of antibody and B cell responses following exposure to BA.5 and XBB variants in individuals who received ancestral SARS-CoV-2 mRNA vaccines. BA.5 exposures elicited antibody responses that targeted epitopes conserved between the BA.5 and ancestral spike. XBB exposures also elicited antibody responses that primarily targeted epitopes conserved between the XBB.1.5 and ancestral spike. However, unlike BA.5, a single XBB exposure elicited low frequencies of XBB.1.5-specific antibodies and B cells in some individuals. Pre-existing cross-reactive B cells and antibodies were correlated with stronger overall responses to XBB but weaker XBB-specific responses, suggesting that baseline immunity influences the activation of variant-specific SARS-CoV-2 responses.
Assuntos
COVID-19 , SARS-CoV-2 , Humanos , Formação de Anticorpos , Anticorpos , Epitopos , Anticorpos Neutralizantes , Anticorpos AntiviraisRESUMO
SARS-CoV-2 RNA interacts with host factors to suppress interferon responses and simultaneously induces cytokine release to drive the development of severe coronavirus disease 2019 (COVID-19). However, how SARS-CoV-2 hijacks host RNAs to elicit such imbalanced immune responses remains elusive. Here, we analyzed SARS-CoV-2 RNA in situ structures and interactions in infected cells and patient lung samples using RIC-seq. We discovered that SARS-CoV-2 RNA forms 2,095 potential duplexes with the 3' UTRs of 205 host mRNAs to increase their stability by recruiting RNA-binding protein YBX3 in A549 cells. Disrupting the SARS-CoV-2-to-host RNA duplex or knocking down YBX3 decreased host mRNA stability and reduced viral replication. Among SARS-CoV-2-stabilized host targets, NFKBIZ was crucial for promoting cytokine production and reducing interferon responses, probably contributing to cytokine storm induction. Our study uncovers the crucial roles of RNA-RNA interactions in the immunopathogenesis of RNA viruses such as SARS-CoV-2 and provides valuable host targets for drug development.
Assuntos
COVID-19 , Humanos , COVID-19/genética , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , RNA Viral/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Interferons/genética , CitocinasRESUMO
Since SARS-CoV-2 Omicron variant emerged, it is constantly evolving into multiple sub-variants, including BF.7, BQ.1, BQ.1.1, XBB, XBB.1.5 and the recently emerged BA.2.86 and JN.1. Receptor binding and immune evasion are recognized as two major drivers for evolution of the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein. However, the underlying mechanism of interplay between two factors remains incompletely understood. Herein, we determined the structures of human ACE2 complexed with BF.7, BQ.1, BQ.1.1, XBB and XBB.1.5 RBDs. Based on the ACE2/RBD structures of these sub-variants and a comparison with the known complex structures, we found that R346T substitution in the RBD enhanced ACE2 binding upon an interaction with the residue R493, but not Q493, via a mechanism involving long-range conformation changes. Furthermore, we found that R493Q and F486V exert a balanced impact, through which immune evasion capability was somewhat compromised to achieve an optimal receptor binding. We propose a "two-steps-forward and one-step-backward" model to describe such a compromise between receptor binding affinity and immune evasion during RBD evolution of Omicron sub-variants.
Assuntos
COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , Enzima de Conversão de Angiotensina 2 , Glicoproteína da Espícula de Coronavírus/genética , AnticorposRESUMO
Coronaviruses are a group of related RNA viruses that cause respiratory diseases in humans and animals. Understanding the mechanisms of translation regulation during coronaviral infections is critical for developing antiviral therapies and preventing viral spread. Translation of the viral single-stranded RNA genome in the host cell cytoplasm is an essential step in the life cycle of coronaviruses, which affects the cellular mRNA translation landscape in many ways. Here we discuss various viral strategies of translation control, including how members of the Betacoronavirus genus shut down host cell translation and suppress host innate immune functions, as well as the role of the viral non-structural protein 1 (Nsp1) in the process. We also outline the fate of viral RNA, considering stress response mechanisms triggered in infected cells, and describe how unique viral RNA features contribute to programmed ribosomal -1 frameshifting, RNA editing, and translation shutdown evasion.
Assuntos
Infecções por Coronavirus , Coronavirus , Animais , Humanos , Coronavirus/genética , Infecções por Coronavirus/genética , Betacoronavirus/fisiologia , Antivirais/farmacologia , RNA Viral/genéticaRESUMO
PARP-catalysed ADP-ribosylation (ADPr) is important in regulating various cellular pathways. Until recently, PARP-dependent mono-ADP-ribosylation has been poorly understood due to the lack of sensitive detection methods. Here, we utilised an improved antibody to detect mono-ADP-ribosylation. We visualised endogenous interferon (IFN)-induced ADP-ribosylation and show that PARP14 is a major enzyme responsible for this modification. Fittingly, this signalling is reversed by the macrodomain from SARS-CoV-2 (Mac1), providing a possible mechanism by which Mac1 counteracts the activity of antiviral PARPs. Our data also elucidate a major role of PARP9 and its binding partner, the E3 ubiquitin ligase DTX3L, in regulating PARP14 activity through protein-protein interactions and by the hydrolytic activity of PARP9 macrodomain 1. Finally, we also present the first visualisation of ADPr-dependent ubiquitylation in the IFN response. These approaches should further advance our understanding of IFN-induced ADPr and ubiquitin signalling processes and could shed light on how different pathogens avoid such defence pathways.
Assuntos
ADP-Ribosilação , Interferons , Poli(ADP-Ribose) Polimerases , Ubiquitina-Proteína Ligases , Humanos , Poli(ADP-Ribose) Polimerases/metabolismo , Poli(ADP-Ribose) Polimerases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Interferons/metabolismo , Ubiquitinação , Células HEK293 , SARS-CoV-2/metabolismo , Transdução de Sinais , COVID-19/virologia , COVID-19/metabolismo , Proteínas de NeoplasiasRESUMO
Dysregulated immune responses contribute to the excessive and uncontrolled inflammation observed in severe COVID-19. However, how immunity to SARS-CoV-2 is induced and regulated remains unclear. Here, we uncover the role of the complement system in the induction of innate and adaptive immunity to SARS-CoV-2. Complement rapidly opsonizes SARS-CoV-2 particles via the lectin pathway. Complement-opsonized SARS-CoV-2 efficiently induces type-I interferon and pro-inflammatory cytokine responses via activation of dendritic cells, which are inhibited by antibodies against the complement receptors (CR) 3 and 4. Serum from COVID-19 patients, or monoclonal antibodies against SARS-CoV-2, attenuate innate and adaptive immunity induced by complement-opsonized SARS-CoV-2. Blocking of CD32, the FcγRII antibody receptor of dendritic cells, restores complement-induced immunity. These results suggest that opsonization of SARS-CoV-2 by complement is involved in the induction of innate and adaptive immunity to SARS-CoV-2 in the acute phase of infection. Subsequent antibody responses limit inflammation and restore immune homeostasis. These findings suggest that dysregulation of the complement system and FcγRII signaling may contribute to severe COVID-19.
Assuntos
COVID-19 , Humanos , SARS-CoV-2 , Anticorpos Antivirais , Proteínas do Sistema Complemento , Inflamação , Imunidade InataRESUMO
Since the onset of the COVID-19 pandemic, significant progress has been made in developing effective preventive and therapeutic strategies against severe acute SARS-CoV-2 infection. However, the management of Long COVID (LC), an infection-associated chronic condition that has been estimated to affect 5-20% of individuals following SARS-CoV-2 infection, remains challenging due to our limited understanding of its mechanisms. Although LC is a heterogeneous disease that is likely to have several subtypes, immune system disturbances appear common across many cases. The extent to which these immune perturbations contribute to LC symptoms, however, is not entirely clear. Recent advancements in multi-omics technologies, capable of detailed, cell-level analysis, have provided valuable insights into the immune perturbations associated with LC. Although these studies are largely descriptive in nature, they are the crucial first step towards a deeper understanding of the condition and the immune system's role in its development, progression, and resolution. In this review, we summarize the current understanding of immune perturbations in LC, covering both innate and adaptive immune responses, and the cytokines and analytes involved. We explore whether these findings support or challenge the primary hypotheses about LC's underlying mechanisms. We also discuss the crosstalk between various immune system components and how it can be disrupted in LC. Finally, we emphasize the need for more tissue- and subtype-focused analyses of LC, and for enhanced collaborative efforts to analyze common specimens from large cohorts, including those undergoing therapeutic interventions. These collective efforts are vital to unravel the fundaments of this new disease, and could also shed light on the prevention and treatment of the larger family of chronic illnesses linked to other microbial infections.
Assuntos
COVID-19 , Síndrome de COVID-19 Pós-Aguda , Humanos , Pandemias , SARS-CoV-2 , Imunidade Adaptativa , Análise de Sistemas , Imunidade InataRESUMO
Infection with SARS-CoV-2 in humans has caused a pandemic of unprecedented dimensions. SARS-CoV-2 is primarily transmitted through respiratory droplets and targets ciliated epithelial cells in the nasal cavity, trachea, and lungs by utilizing the cellular receptor angiotensin-converting enzyme 2 (ACE2). The innate immune response, including type I and III interferons, inflammatory cytokines (IL-6, TNF-α, IL-1ß), innate immune cells (monocytes, DCs, neutrophils, natural killer cells), antibodies (IgG, sIgA, neutralizing antibodies), and adaptive immune cells (B cells, CD8+ and CD4+ T cells) play pivotal roles in mitigating COVID-19 disease. Broad and durable B-cell- and T-cell immunity elicited by infection and vaccination is essential for protection against severe disease, hospitalization and death. However, the emergence of SARS-CoV-2 variants that evade neutralizing antibodies continue to jeopardize vaccine efficacy. In this review, we highlight our understanding the infection- and vaccine-mediated humoral, B and T cell responses, the durability of the immune responses, and how variants continue to threaten the efficacy of SARS-CoV-2 vaccines.
RESUMO
The persistence or recurrence of symptoms after acute SARS-CoV-2 infection, termed 'long COVID', presents a formidable challenge to global healthcare systems. Recent research by Cervia-Hasler and colleagues delves into the intricate immunological landscape in patients with long COVID, demonstrating an interplay between complement and coagulation, driven by antiviral antibodies and tissue damage.
Assuntos
COVID-19 , Proteínas do Sistema Complemento , SARS-CoV-2 , Humanos , COVID-19/imunologia , SARS-CoV-2/imunologia , Proteínas do Sistema Complemento/imunologia , Proteínas do Sistema Complemento/metabolismo , Tromboinflamação/imunologia , Coagulação Sanguínea/imunologia , Síndrome de COVID-19 Pós-Aguda , Ativação do Complemento/imunologia , Anticorpos Antivirais/imunologiaRESUMO
The effect of COVID-19 on the high number of immunocompromised people living with HIV-1 (PLWH), particularly in Africa, remains a critical concern. Here, we identify key areas that still require further investigation, by examining COVID-19 vaccine effectiveness, and understanding antibody responses in SARS-CoV-2 infection and vaccination in comparison with people without HIV-1 (PWOH). We also assess the potential impact of pre-existing immunity against endemic human coronaviruses on SARS-CoV-2 responses in these individuals. Lastly, we discuss the consequences of persistent infection in PLWH (or other immunocompromised individuals), including prolonged shedding, increased viral diversity within the host, and the implications on SARS-CoV-2 evolution in Africa.
Assuntos
Anticorpos Antivirais , COVID-19 , Infecções por HIV , HIV-1 , Imunidade Humoral , SARS-CoV-2 , Humanos , COVID-19/imunologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , SARS-CoV-2/imunologia , HIV-1/imunologia , Anticorpos Antivirais/imunologia , Vacinas contra COVID-19/imunologia , Hospedeiro Imunocomprometido/imunologiaRESUMO
Recent studies show an important role for non-neutralizing anti-spike antibodies, including monoclonal antibodies (mAbs), in robustly protecting against SARS-CoV-2 infection. These mAbs use Fc-mediated functions such as complement activation, phagocytosis, and cellular cytotoxicity. There is an untapped potential for using non-neutralizing mAbs in durable antibody treatments; because of their available conserved epitopes, they may not be as sensitive to virus mutations as neutralizing mAbs. Here, we discuss evidence of non-neutralizing mAb-mediated protection against SARS-CoV-2 infection. We explore how non-neutralizing mAb Fc-mediated functions can be enhanced via novel antibody-engineering techniques. Important questions remain to be answered regarding the characteristics of protective non-neutralizing mAbs, including the models and assays used for study, the risks of ensuing detrimental inflammation, as well as the durability and mechanisms of protection.