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1.
Nat Rev Immunol ; 20(7): 442-447, 2020 07.
Article in English | MEDLINE | ID: covidwho-1830064

ABSTRACT

A male bias in mortality has emerged in the COVID-19 pandemic, which is consistent with the pathogenesis of other viral infections. Biological sex differences may manifest themselves in susceptibility to infection, early pathogenesis, innate viral control, adaptive immune responses or the balance of inflammation and tissue repair in the resolution of infection. We discuss available sex-disaggregated epidemiological data from the COVID-19 pandemic, introduce sex-differential features of immunity and highlight potential sex differences underlying COVID-19 severity. We propose that sex differences in immunopathogenesis will inform mechanisms of COVID-19, identify points for therapeutic intervention and improve vaccine design and increase vaccine efficacy.


Subject(s)
Coronavirus Infections/epidemiology , Pneumonia, Viral/epidemiology , Adaptive Immunity , Age Factors , Betacoronavirus/physiology , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Coronavirus Infections/physiopathology , Female , Humans , Interferons/immunology , Male , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Pneumonia, Viral/physiopathology , SARS-CoV-2 , Severity of Illness Index , Sex Factors , Sociological Factors
3.
Nat Commun ; 13(1): 1018, 2022 02 23.
Article in English | MEDLINE | ID: covidwho-1702467

ABSTRACT

The antiviral immune response to SARS-CoV-2 infection can limit viral spread and prevent development of pneumonic COVID-19. However, the protective immunological response associated with successful viral containment in the upper airways remains unclear. Here, we combine a multi-omics approach with longitudinal sampling to reveal temporally resolved protective immune signatures in non-pneumonic and ambulatory SARS-CoV-2 infected patients and associate specific immune trajectories with upper airway viral containment. We see a distinct systemic rather than local immune state associated with viral containment, characterized by interferon stimulated gene (ISG) upregulation across circulating immune cell subsets in non-pneumonic SARS-CoV2 infection. We report reduced cytotoxic potential of Natural Killer (NK) and T cells, and an immune-modulatory monocyte phenotype associated with protective immunity in COVID-19. Together, we show protective immune trajectories in SARS-CoV2 infection, which have important implications for patient prognosis and the development of immunomodulatory therapies.


Subject(s)
COVID-19/immunology , Adult , Aged , Aged, 80 and over , Ambulatory Care , Cytokines/blood , Female , Gene Expression Regulation , Gene Regulatory Networks , Humans , Interferons/immunology , Killer Cells, Natural/immunology , Longitudinal Studies , Male , Middle Aged , Monocytes/immunology , Nasopharynx/immunology , Nasopharynx/virology , SARS-CoV-2/physiology , T-Lymphocytes/immunology
4.
J Microbiol ; 60(3): 290-299, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1670004

ABSTRACT

With global expansion of the COVID-19 pandemic and the emergence of new variants, extensive efforts have been made to develop highly effective antiviral drugs and vaccines against SARS-CoV-2. The interactions of coronaviruses with host antiviral interferon pathways ultimately determine successful viral replication and SARS-CoV-2-induced pathogenesis. Innate immune receptors play an essential role in host defense against SARS-CoV-2 via the induction of IFN production and signaling. Here, we summarize the recent advances in innate immune sensing mechanisms of SARS-CoV-2 and various strategies by which SARS-CoV-2 antagonizes antiviral innate immune signaling pathways, with a particular focus on mechanisms utilized by multiple SARS-CoV-2 proteins to evade interferon induction and signaling in host cell. Understanding the underlying immune evasion mechanisms of SARS-CoV-2 is essential for the improvement of vaccines and therapeutic strategies.


Subject(s)
COVID-19 , Immune Evasion , Interferons/immunology , /immunology , COVID-19/immunology , COVID-19/virology , Humans , Immunity, Innate , Pandemics , SARS-CoV-2
5.
Front Immunol ; 12: 816745, 2021.
Article in English | MEDLINE | ID: covidwho-1662588

ABSTRACT

COVID-19 patients show heterogeneous and dynamic immune features which determine the clinical outcome. Here, we built a single-cell RNA sequencing (scRNA-seq) dataset for dissecting these complicated immune responses through a longitudinal survey of COVID-19 patients with various categories of outcomes. The data reveals a highly fluctuating peripheral immune landscape in severe COVID-19, whereas the one in asymptomatic/mild COVID-19 is relatively steady. Then, the perturbed immune landscape in peripheral blood returned to normal state in those recovered from severe COVID-19. Importantly, the imbalance of the excessively strong innate immune response and delayed adaptive immunity in the early stage of viral infection accelerates the progression of the disease, indicated by a transient strong IFN response and weak T/B-cell specific response. The proportion of abnormal monocytes appeared early and rose further throughout the severe disease. Our data indicate that a dynamic immune landscape is associated with the progression and recovery of severe COVID-19, and have provided multiple immune biomarkers for early warning of severe COVID-19.


Subject(s)
Adaptive Immunity/immunology , COVID-19/immunology , Interferons/immunology , B-Lymphocytes/immunology , Humans , Immunity, Innate/immunology , SARS-CoV-2/immunology , T-Lymphocytes/immunology
6.
J Microbiol ; 60(3): 300-307, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1653793

ABSTRACT

Type I and III interferons (IFNs) and the nucleotide-binding domain (NBD) leucine-rich repeat (LRR)-containing receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome play pivotal roles in the pathogenesis of SARS-CoV-2. While optimal IFN and inflammasome responses are essential for limiting SARS-CoV-2 infection, aberrant activation of these innate immune responses is associated with COVID-19 pathogenesis. In this review, we focus our discussion on recent findings on SARS-CoV-2-induced type I and III IFNs and NLRP3 inflammasome responses and the viral proteins regulating these mechanisms.


Subject(s)
COVID-19 , Inflammasomes , Interferons/immunology , NLR Family, Pyrin Domain-Containing 3 Protein , COVID-19/immunology , Humans , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , SARS-CoV-2 , Signal Transduction
7.
PLoS Biol ; 19(12): e3001065, 2021 12.
Article in English | MEDLINE | ID: covidwho-1594053

ABSTRACT

The pandemic spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent of Coronavirus Disease 2019 (COVID-19), represents an ongoing international health crisis. A key symptom of SARS-CoV-2 infection is the onset of fever, with a hyperthermic temperature range of 38 to 41°C. Fever is an evolutionarily conserved host response to microbial infection that can influence the outcome of viral pathogenicity and regulation of host innate and adaptive immune responses. However, it remains to be determined what effect elevated temperature has on SARS-CoV-2 replication. Utilizing a three-dimensional (3D) air-liquid interface (ALI) model that closely mimics the natural tissue physiology of SARS-CoV-2 infection in the respiratory airway, we identify tissue temperature to play an important role in the regulation of SARS-CoV-2 infection. Respiratory tissue incubated at 40°C remained permissive to SARS-CoV-2 entry but refractory to viral transcription, leading to significantly reduced levels of viral RNA replication and apical shedding of infectious virus. We identify tissue temperature to play an important role in the differential regulation of epithelial host responses to SARS-CoV-2 infection that impact upon multiple pathways, including intracellular immune regulation, without disruption to general transcription or epithelium integrity. We present the first evidence that febrile temperatures associated with COVID-19 inhibit SARS-CoV-2 replication in respiratory epithelia. Our data identify an important role for tissue temperature in the epithelial restriction of SARS-CoV-2 independently of canonical interferon (IFN)-mediated antiviral immune defenses.


Subject(s)
Epithelial Cells/immunology , Hot Temperature , Immunity, Innate/immunology , Interferons/immunology , Respiratory Mucosa/immunology , SARS-CoV-2/immunology , Virus Replication/immunology , Adolescent , Animals , COVID-19/genetics , COVID-19/immunology , COVID-19/virology , Chlorocebus aethiops , Epithelial Cells/metabolism , Epithelial Cells/virology , Female , Gene Expression Profiling/methods , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Immunity, Innate/genetics , Interferons/genetics , Interferons/metabolism , Male , Middle Aged , Models, Biological , RNA-Seq/methods , Respiratory Mucosa/metabolism , Respiratory Mucosa/virology , SARS-CoV-2/genetics , SARS-CoV-2/physiology , Tissue Culture Techniques , Vero Cells , Virus Replication/genetics , Virus Replication/physiology
8.
Viruses ; 13(12)2021 12 10.
Article in English | MEDLINE | ID: covidwho-1591709

ABSTRACT

RSV is a leading cause of respiratory tract disease in infants and the elderly. RSV has limited therapeutic interventions and no FDA-approved vaccine. Gaps in our understanding of virus-host interactions and immunity contribute to the lack of biological countermeasures. This review updates the current understanding of RSV immunity and immunopathology with a focus on interferon responses, animal modeling, and correlates of protection.


Subject(s)
Respiratory Syncytial Virus Infections/immunology , Respiratory Syncytial Virus Infections/virology , Respiratory Syncytial Virus, Human/immunology , Adaptive Immunity , Animals , Disease Models, Animal , Humans , Immunity, Innate , Interferons/immunology , Interferons/metabolism , Respiratory Syncytial Virus Infections/epidemiology , Respiratory Syncytial Virus Infections/prevention & control , Respiratory Syncytial Virus Vaccines/immunology , Respiratory Syncytial Virus, Human/physiology
9.
Nature ; 602(7896): 321-327, 2022 02.
Article in English | MEDLINE | ID: covidwho-1585831

ABSTRACT

It is not fully understood why COVID-19 is typically milder in children1-3. Here, to examine the differences between children and adults in their response to SARS-CoV-2 infection, we analysed paediatric and adult patients with COVID-19 as well as healthy control individuals (total n = 93) using single-cell multi-omic profiling of matched nasal, tracheal, bronchial and blood samples. In the airways of healthy paediatric individuals, we observed cells that were already in an interferon-activated state, which after SARS-CoV-2 infection was further induced especially in airway immune cells. We postulate that higher paediatric innate interferon responses restrict viral replication and disease progression. The systemic response in children was characterized by increases in naive lymphocytes and a depletion of natural killer cells, whereas, in adults, cytotoxic T cells and interferon-stimulated subpopulations were significantly increased. We provide evidence that dendritic cells initiate interferon signalling in early infection, and identify epithelial cell states associated with COVID-19 and age. Our matching nasal and blood data show a strong interferon response in the airways with the induction of systemic interferon-stimulated populations, which were substantially reduced in paediatric patients. Together, we provide several mechanisms that explain the milder clinical syndrome observed in children.


Subject(s)
COVID-19/blood , COVID-19/immunology , Dendritic Cells/immunology , Interferons/immunology , Killer Cells, Natural/immunology , SARS-CoV-2/immunology , T-Lymphocytes, Cytotoxic/immunology , Adult , Bronchi/immunology , Bronchi/virology , COVID-19/pathology , Chicago , Cohort Studies , Disease Progression , Epithelial Cells/cytology , Epithelial Cells/immunology , Epithelial Cells/virology , Female , Humans , Immunity, Innate , London , Male , Nasal Mucosa/immunology , Nasal Mucosa/virology , SARS-CoV-2/growth & development , Single-Cell Analysis , Trachea/virology , Young Adult
10.
Nature ; 602(7897): 487-495, 2022 02.
Article in English | MEDLINE | ID: covidwho-1585830

ABSTRACT

The emergence of SARS-CoV-2 variants of concern suggests viral adaptation to enhance human-to-human transmission1,2. Although much effort has focused on the characterization of changes in the spike protein in variants of concern, mutations outside of spike are likely to contribute to adaptation. Here, using unbiased abundance proteomics, phosphoproteomics, RNA sequencing and viral replication assays, we show that isolates of the Alpha (B.1.1.7) variant3 suppress innate immune responses in airway epithelial cells more effectively than first-wave isolates. We found that the Alpha variant has markedly increased subgenomic RNA and protein levels of the nucleocapsid protein (N), Orf9b and Orf6-all known innate immune antagonists. Expression of Orf9b alone suppressed the innate immune response through interaction with TOM70, a mitochondrial protein that is required for activation of the RNA-sensing adaptor MAVS. Moreover, the activity of Orf9b and its association with TOM70 was regulated by phosphorylation. We propose that more effective innate immune suppression, through enhanced expression of specific viral antagonist proteins, increases the likelihood of successful transmission of the Alpha variant, and may increase in vivo replication and duration of infection4. The importance of mutations outside the spike coding region in the adaptation of SARS-CoV-2 to humans is underscored by the observation that similar mutations exist in the N and Orf9b regulatory regions of the Delta and Omicron variants.


Subject(s)
COVID-19/immunology , COVID-19/virology , Evolution, Molecular , Immune Evasion , Immunity, Innate/immunology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , COVID-19/transmission , Coronavirus Nucleocapsid Proteins/chemistry , Coronavirus Nucleocapsid Proteins/metabolism , Humans , Immunity, Innate/genetics , Interferons/immunology , Phosphoproteins/chemistry , Phosphoproteins/metabolism , Phosphorylation , Proteomics , RNA, Viral/genetics , RNA-Seq , SARS-CoV-2/classification , SARS-CoV-2/growth & development
11.
Sci Rep ; 11(1): 23741, 2021 12 09.
Article in English | MEDLINE | ID: covidwho-1565734

ABSTRACT

The mechanisms explaining excess morbidity and mortality in respiratory infections among males are poorly understood. Innate immune responses are critical in protection against respiratory virus infections. We hypothesised that innate immune responses to respiratory viruses may be deficient in males. We stimulated peripheral blood mononuclear cells from 345 participants at age 16 years in a population-based birth cohort with three live respiratory viruses (rhinoviruses A16 and A1, and respiratory syncytial virus) and two viral mimics (R848 and CpG-A, to mimic responses to SARS-CoV-2) and investigated sex differences in interferon (IFN) responses. IFN-α responses to all viruses and stimuli were 1.34-2.06-fold lower in males than females (P = 0.018 - < 0.001). IFN-ß, IFN-γ and IFN-induced chemokines were also deficient in males across all stimuli/viruses. Healthcare records revealed 12.1% of males and 6.6% of females were hospitalized with respiratory infections in infancy (P = 0.017). In conclusion, impaired innate anti-viral immunity in males likely results in high male morbidity and mortality from respiratory virus infections.


Subject(s)
Imidazoles/immunology , Immunity, Innate , Oligodeoxyribonucleotides/immunology , Picornaviridae Infections/immunology , Respiratory Syncytial Virus Infections/immunology , Respiratory Syncytial Virus, Human/immunology , Rhinovirus/immunology , Adolescent , Cohort Studies , Female , Humans , Interferons/immunology , Interferons/metabolism , Leukocytes, Mononuclear/immunology , Male , Picornaviridae Infections/mortality , Picornaviridae Infections/virology , Respiratory Syncytial Virus Infections/mortality , Respiratory Syncytial Virus Infections/virology , Respiratory Tract Infections/immunology , Respiratory Tract Infections/mortality , Respiratory Tract Infections/virology , SARS-CoV-2 , Sex Factors
12.
Nat Commun ; 12(1): 7092, 2021 12 07.
Article in English | MEDLINE | ID: covidwho-1561304

ABSTRACT

The nasal epithelium is a plausible entry point for SARS-CoV-2, a site of pathogenesis and transmission, and may initiate the host response to SARS-CoV-2. Antiviral interferon (IFN) responses are critical to outcome of SARS-CoV-2. Yet little is known about the interaction between SARS-CoV-2 and innate immunity in this tissue. Here we apply single-cell RNA sequencing and proteomics to a primary cell model of human nasal epithelium differentiated at air-liquid interface. SARS-CoV-2 demonstrates widespread tropism for nasal epithelial cell types. The host response is dominated by type I and III IFNs and interferon-stimulated gene products. This response is notably delayed in onset relative to viral gene expression and compared to other respiratory viruses. Nevertheless, once established, the paracrine IFN response begins to impact on SARS-CoV-2 replication. When provided prior to infection, recombinant IFNß or IFNλ1 induces an efficient antiviral state that potently restricts SARS-CoV-2 viral replication, preserving epithelial barrier integrity. These data imply that the IFN-I/III response to SARS-CoV-2 initiates in the nasal airway and suggest nasal delivery of recombinant IFNs to be a potential chemoprophylactic strategy.


Subject(s)
Epithelial Cells/virology , Interferon Type I/immunology , Interferons/immunology , Nasal Mucosa/virology , SARS-CoV-2/physiology , Antiviral Agents/immunology , Antiviral Agents/pharmacology , COVID-19/immunology , COVID-19/virology , Cells, Cultured , Epithelial Cells/cytology , Epithelial Cells/immunology , Humans , Immunity, Innate , Kinetics , Nasal Mucosa/cytology , Nasal Mucosa/immunology , SARS-CoV-2/drug effects , Signal Transduction/drug effects , Viral Tropism , Virus Replication/drug effects
13.
Nature ; 602(7895): 148-155, 2022 02.
Article in English | MEDLINE | ID: covidwho-1556858

ABSTRACT

Immunological memory is a hallmark of adaptive immunity and facilitates an accelerated and enhanced immune response upon re-infection with the same pathogen1,2. Since the outbreak of the ongoing COVID-19 pandemic, a key question has focused on which SARS-CoV-2-specific T cells stimulated during acute infection give rise to long-lived memory T cells3. Here, using spectral flow cytometry combined with cellular indexing of transcriptomes and T cell receptor sequencing, we longitudinally characterized individual SARS-CoV-2-specific CD8+ T cells of patients with COVID-19 from acute infection to 1 year into recovery and found a distinct signature identifying long-lived memory CD8+ T cells. SARS-CoV-2-specific memory CD8+ T cells persisting 1 year after acute infection express CD45RA, IL-7 receptor-α and T cell factor 1, but they maintain low expression of CCR7, thus resembling CD45RA+ effector memory T cells. Tracking individual clones of SARS-CoV-2-specific CD8+ T cells, we reveal that an interferon signature marks clones that give rise to long-lived cells, whereas prolonged proliferation and mechanistic target of rapamycin signalling are associated with clonal disappearance from the blood. Collectively, we describe a transcriptional signature that marks long-lived, circulating human memory CD8+ T cells following an acute viral infection.


Subject(s)
Antigens, Viral/immunology , Biomarkers/metabolism , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , COVID-19/immunology , /metabolism , SARS-CoV-2/immunology , Acute Disease , COVID-19/virology , Cell Proliferation , Clone Cells/cytology , Clone Cells/immunology , Humans , Interferons/immunology , Interleukin-7 Receptor alpha Subunit/metabolism , Leukocyte Common Antigens/metabolism , Longitudinal Studies , Mechanistic Target of Rapamycin Complex 1/metabolism , Receptors, Antigen, T-Cell/metabolism , Receptors, CCR7/metabolism , T Cell Transcription Factor 1/metabolism , Time Factors , Transcriptome
14.
Front Immunol ; 12: 750279, 2021.
Article in English | MEDLINE | ID: covidwho-1551505

ABSTRACT

SARS-CoV-2 coronavirus infection induces heterogeneous symptoms, ranging from asymptomatic to lethal forms. Severe forms usually occur in the elderly and/or individuals with comorbidities. Children generally remain asymptomatic to primary infection, suggesting that they may have an effective local innate immune response. IFN-I and -III have non-redundant protective roles against SARS-CoV-2, although sometimes damaging the host. The expression and role of anti-viral peptides during SARS-CoV-2 infection have thus far been little studied. We aimed to identify the innate immune molecules present at the SARS-CoV-2 entry point. We analyzed the mRNA levels of type I (IFN-α and -ß) and type III (IFN-λ1-3) interferons and selected antiviral peptides (i.e., ß-defensins 1-3, α-defensins [HNP1-3, HD5] pentraxin-3, surfactant protein D, the cathelicidin LL-37 and interleukin-26) in nasopharyngeal swabs from 226 individuals of various ages, either infected with SARS-CoV-2 (symptomatic or asymptomatic) or negative for the virus. We observed that infection induced selective upregulation of IFN-λ1 expression in pediatric subjects (≤15 years), whereas IFN-α, IFN-ß, IFN-λ2/λ3, and ß-defensin 1-3 expression was unaffected. Conversely, infection triggered upregulation of IFN-α, IFN-ß, IFN-λ2/λ3, and ß-defensin 1-3 mRNA expression in adults (15-65 years) and the elderly (≥ 65 years), but without modulation of IFN-λ1. The expression of these innate molecules was not associated with gender or symptoms. Expression of the interferon-stimulated genes IFITM1 and IFITM3 was upregulated in SARS-CoV-2-positive subjects and reached similar levels in the three age groups. Finally, age-related differences in nasopharyngeal innate immunity were also observed in SARS-CoV-2-negative subjects. This study shows that the expression patterns of IFN-I/-III and certain anti-viral molecules in the nasopharyngeal mucosa of SARS-CoV-2-infected subjects differ with age and suggests that susceptibility to SARS-CoV-2 may be related to intrinsic differences in the nature of mucosal anti-viral innate immunity.


Subject(s)
/analysis , Interferon Type I/biosynthesis , Interferon-gamma/biosynthesis , Nasal Mucosa/immunology , SARS-CoV-2/immunology , beta-Defensins/biosynthesis , Adolescent , Adult , Age Factors , Aged , COVID-19/immunology , Cells, Cultured , Female , Humans , Immunity, Innate/immunology , Interferon Type I/immunology , Interferon-gamma/immunology , Interferons/biosynthesis , Interferons/immunology , Interleukins/biosynthesis , Interleukins/immunology , Male , Middle Aged , Nasopharynx/immunology , Young Adult , beta-Defensins/immunology
15.
Nat Med ; 28(1): 201-211, 2022 01.
Article in English | MEDLINE | ID: covidwho-1517637

ABSTRACT

Although critical for host defense, innate immune cells are also pathologic drivers of acute respiratory distress syndrome (ARDS). Innate immune dynamics during Coronavirus Disease 2019 (COVID-19) ARDS, compared to ARDS from other respiratory pathogens, is unclear. Moreover, mechanisms underlying the beneficial effects of dexamethasone during severe COVID-19 remain elusive. Using single-cell RNA sequencing and plasma proteomics, we discovered that, compared to bacterial ARDS, COVID-19 was associated with expansion of distinct neutrophil states characterized by interferon (IFN) and prostaglandin signaling. Dexamethasone during severe COVID-19 affected circulating neutrophils, altered IFNactive neutrophils, downregulated interferon-stimulated genes and activated IL-1R2+ neutrophils. Dexamethasone also expanded immunosuppressive immature neutrophils and remodeled cellular interactions by changing neutrophils from information receivers into information providers. Male patients had higher proportions of IFNactive neutrophils and preferential steroid-induced immature neutrophil expansion, potentially affecting outcomes. Our single-cell atlas (see 'Data availability' section) defines COVID-19-enriched neutrophil states and molecular mechanisms of dexamethasone action to develop targeted immunotherapies for severe COVID-19.


Subject(s)
COVID-19/immunology , Cytokines/immunology , Dexamethasone/therapeutic use , Glucocorticoids/therapeutic use , Neutrophils/immunology , Pneumonia, Bacterial/immunology , Respiratory Distress Syndrome/immunology , Adult , Aged , COVID-19/complications , COVID-19/drug therapy , COVID-19/genetics , Cell Communication , Chromatography, Liquid , Down-Regulation , Female , Gene Regulatory Networks , Humans , Immunity, Innate/immunology , Interferons/immunology , Male , Middle Aged , Neutrophils/metabolism , Pneumonia, Bacterial/complications , Pneumonia, Bacterial/drug therapy , Pneumonia, Bacterial/genetics , Prostaglandins/immunology , Proteomics , RNA-Seq , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/genetics , SARS-CoV-2 , Severity of Illness Index , Sex Factors , Single-Cell Analysis , Tandem Mass Spectrometry
16.
mBio ; 12(6): e0275621, 2021 12 21.
Article in English | MEDLINE | ID: covidwho-1494976

ABSTRACT

Outbreaks of emerging viral pathogens like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are a major medical challenge. There is a pressing need for antivirals that can be rapidly deployed to curb infection and dissemination. We determined the efficacy of interferon lambda-1 (IFN-λ) as a broad-spectrum antiviral agent to inhibit SARS-CoV-2 infection and reduce pathology in a mouse model of disease. IFN-λ significantly limited SARS-CoV-2 production in primary human bronchial epithelial cells in culture. Pretreatment of human lung cells with IFN-λ completely blocked infectious virus production, and treatment with IFN-λ at the time of infection inhibited virus production more than 10-fold. To interrogate the protective effects of IFN-λ in response to SARS-CoV-2 infection, transgenic mice expressing the human angiotensin-converting enzyme 2 (ACE-2) were tested. One dose of IFN-λ administered intranasally was found to reduce animal morbidity and mortality. Our study with SARS-CoV-2 also revealed a sex differential in disease outcome. Male mice had higher mortality, reflecting the more severe symptoms and mortality found in male patients infected with SARS-CoV-2. The results indicate that IFN-λ potentially can treat early stages of SARS-CoV-2 infection and decrease pathology, and this murine model can be used to investigate the sex differential documented in COVID-19. IMPORTANCE The COVID-19 pandemic has claimed millions of lives worldwide. In this report, we used a preclinical mouse model to investigate the prophylactic and therapeutic value of intranasal IFN-λ for this acute respiratory disease. Specific vaccines have been responsible for curbing the transmission of SARS-CoV-2 in developed nations. However, vaccines require time to generate and keep pace with antigenic variants. There is a need for broad-spectrum prophylactic and therapeutic agents to combat new emerging viral pathogens. Our mouse model suggests IFN-λ has clinical utility, and it reflects the well-documented finding that male COVID-19 patients manifest more severe symptoms and mortality. Understanding this sex bias is critical for considering therapeutic approaches to COVID-19.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/immunology , COVID-19/therapy , Epithelial Cells/drug effects , Interferons/immunology , Interferons/pharmacology , SARS-CoV-2/immunology , Administration, Intranasal , Angiotensin-Converting Enzyme 2/genetics , Animals , Antiviral Agents/pharmacology , Bronchi/cytology , Disease Models, Animal , Epithelial Cells/immunology , Epithelial Cells/virology , Female , HEK293 Cells , Humans , Interferons/classification , Lung/drug effects , Lung/pathology , Lung/virology , Male , Mice , Mice, Transgenic , Risk Factors , SARS-CoV-2/drug effects , Sex Factors
17.
PLoS Comput Biol ; 17(10): e1008874, 2021 10.
Article in English | MEDLINE | ID: covidwho-1484838

ABSTRACT

Respiratory viruses present major public health challenges, as evidenced by the 1918 Spanish Flu, the 1957 H2N2, 1968 H3N2, and 2009 H1N1 influenza pandemics, and the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Severe RNA virus respiratory infections often correlate with high viral load and excessive inflammation. Understanding the dynamics of the innate immune response and its manifestations at the cell and tissue levels is vital to understanding the mechanisms of immunopathology and to developing strain-independent treatments. Here, we present a novel spatialized multicellular computational model of RNA virus infection and the type-I interferon-mediated antiviral response that it induces within lung epithelial cells. The model is built using the CompuCell3D multicellular simulation environment and is parameterized using data from influenza virus-infected cell cultures. Consistent with experimental observations, it exhibits either linear radial growth of viral plaques or arrested plaque growth depending on the local concentration of type I interferons. The model suggests that modifying the activity of signaling molecules in the JAK/STAT pathway or altering the ratio of the diffusion lengths of interferon and virus in the cell culture could lead to plaque growth arrest. The dependence of plaque growth arrest on diffusion lengths highlights the importance of developing validated spatial models of cytokine signaling and the need for in vitro measurement of these diffusion coefficients. Sensitivity analyses under conditions leading to continuous or arrested plaque growth found that plaque growth is more sensitive to variations of most parameters and more likely to have identifiable model parameters when conditions lead to plaque arrest. This result suggests that cytokine assay measurements may be most informative under conditions leading to arrested plaque growth. The model is easy to extend to include SARS-CoV-2-specific mechanisms or to use as a component in models linking epithelial cell signaling to systemic immune models.


Subject(s)
Host-Pathogen Interactions/immunology , Interferons , RNA Virus Infections , RNA Viruses , Virus Replication , Cells, Cultured , Computational Biology , Epithelial Cells/immunology , Humans , Immunity, Innate/immunology , Interferons/immunology , Interferons/metabolism , Lung/cytology , Lung/immunology , Models, Biological , RNA Virus Infections/immunology , RNA Virus Infections/virology , RNA Viruses/immunology , RNA Viruses/physiology , Virus Replication/immunology , Virus Replication/physiology
18.
J Interferon Cytokine Res ; 41(10): 360-362, 2021 10.
Article in English | MEDLINE | ID: covidwho-1483361
19.
mBio ; 12(4): e0178121, 2021 08 31.
Article in English | MEDLINE | ID: covidwho-1349195

ABSTRACT

The 2',5'-oligoadenylate (2-5A)-dependent endoribonuclease, RNase L, is a principal mediator of the interferon (IFN) antiviral response. Therefore, the regulation of cellular levels of 2-5A is a key point of control in antiviral innate immunity. Cellular 2-5A levels are determined by IFN-inducible 2',5'-oligoadenylate synthetases (OASs) and by enzymes that degrade 2-5A. Importantly, many coronaviruses (CoVs) and rotaviruses encode 2-5A-degrading enzymes, thereby antagonizing RNase L and its antiviral effects. A-kinase-anchoring protein 7 (AKAP7), a mammalian counterpart, could possibly limit tissue damage from excessive or prolonged RNase L activation during viral infections or from self-double-stranded RNAs that activate OAS. We show that these enzymes, members of the two-histidine phosphoesterase (2H-PE) superfamily, constitute a subfamily referred here as 2',5'-PEs. 2',5'-PEs from the mouse CoV mouse hepatitis virus (MHV) (NS2), Middle East respiratory syndrome coronavirus (MERS-CoV) (NS4b), group A rotavirus (VP3), and mouse (AKAP7) were investigated for their evolutionary relationships and activities. While there was no activity against 3',5'-oligoribonucleotides, they all cleaved 2',5'-oligoadenylates efficiently but with variable activity against other 2',5'-oligonucleotides. The 2',5'-PEs are shown to be metal ion-independent enzymes that cleave trimer 2-5A (2',5'-p3A3) producing mono- or diadenylates with 2',3'-cyclic phosphate termini. Our results suggest that the elimination of 2-5A might be the sole function of viral 2',5'-PEs, thereby promoting viral escape from innate immunity by preventing or limiting the activation of RNase L. IMPORTANCE Viruses often encode accessory proteins that antagonize the host antiviral immune response. Here, we probed the evolutionary relationships and biochemical activities of two-histidine phosphoesterases (2H-PEs) that allow some coronaviruses and rotaviruses to counteract antiviral innate immunity. In addition, we investigated the mammalian enzyme AKAP7, which has homology and shared activities with the viral enzymes and might reduce self-injury. These viral and host enzymes, which we refer to as 2',5'-PEs, specifically degrade 2',5'-oligoadenylate activators of the antiviral enzyme RNase L. We show that the host and viral enzymes are metal ion independent and exclusively cleave 2',5'- and not 3',5'-phosphodiester bonds, producing cleavage products with cyclic 2',3'-phosphate termini. Our study defines 2',5'-PEs as enzymes that share characteristic conserved features with the 2H-PE superfamily but have specific and distinct biochemical cleavage activities. These findings may eventually lead to pharmacological strategies for developing antiviral drugs against coronaviruses, rotaviruses, and other viruses.


Subject(s)
A Kinase Anchor Proteins/metabolism , Adenine Nucleotides/metabolism , Endoribonucleases/metabolism , Middle East Respiratory Syndrome Coronavirus/enzymology , Murine hepatitis virus/enzymology , Oligoribonucleotides/metabolism , Rotavirus/enzymology , Animals , Humans , Immunity, Innate/immunology , Interferons/immunology , Mice
20.
Science ; 374(6567): eabj3624, 2021 Oct 29.
Article in English | MEDLINE | ID: covidwho-1440797

ABSTRACT

Inherited genetic factors can influence the severity of COVID-19, but the molecular explanation underpinning a genetic association is often unclear. Intracellular antiviral defenses can inhibit the replication of viruses and reduce disease severity. To better understand the antiviral defenses relevant to COVID-19, we used interferon-stimulated gene (ISG) expression screening to reveal that 2'-5'-oligoadenylate synthetase 1 (OAS1), through ribonuclease L, potently inhibits severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We show that a common splice-acceptor single-nucleotide polymorphism (Rs10774671) governs whether patients express prenylated OAS1 isoforms that are membrane-associated and sense-specific regions of SARS-CoV-2 RNAs or if they only express cytosolic, nonprenylated OAS1 that does not efficiently detect SARS-CoV-2. In hospitalized patients, expression of prenylated OAS1 was associated with protection from severe COVID-19, suggesting that this antiviral defense is a major component of a protective antiviral response.


Subject(s)
2',5'-Oligoadenylate Synthetase/genetics , 2',5'-Oligoadenylate Synthetase/metabolism , COVID-19/genetics , COVID-19/physiopathology , RNA, Double-Stranded/metabolism , RNA, Viral/metabolism , SARS-CoV-2/physiology , 5' Untranslated Regions , A549 Cells , Animals , COVID-19/enzymology , COVID-19/immunology , Chiroptera/genetics , Chiroptera/virology , Coronaviridae/enzymology , Coronaviridae/genetics , Coronaviridae/physiology , Endoribonucleases/metabolism , Humans , Interferons/immunology , Isoenzymes/genetics , Isoenzymes/metabolism , Phosphoric Diester Hydrolases/genetics , Phosphoric Diester Hydrolases/metabolism , Polymorphism, Single Nucleotide , Protein Prenylation , RNA, Double-Stranded/chemistry , RNA, Double-Stranded/genetics , RNA, Viral/chemistry , RNA, Viral/genetics , Retroelements , SARS-CoV-2/genetics , Severity of Illness Index , Virus Replication
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