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1.
Nat Commun ; 12(1): 1717, 2021 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-33741967

RESUMO

Myeloid-derived suppressor cells (MDSC) are pathologically activated neutrophils and monocytes with potent immune suppressive activity. These cells play an important role in accelerating tumor progression and undermining the efficacy of anti-cancer therapies. The natural mechanisms limiting MDSC activity are not well understood. Here, we present evidence that type I interferons (IFN1) receptor signaling serves as a universal mechanism that restricts acquisition of suppressive activity by these cells. Downregulation of the IFNAR1 chain of this receptor is found in MDSC from cancer patients and mouse tumor models. The decrease in IFNAR1 depends on the activation of the p38 protein kinase and is required for activation of the immune suppressive phenotype. Whereas deletion of IFNAR1 is not sufficient to convert neutrophils and monocytes to MDSC, genetic stabilization of IFNAR1 in tumor bearing mice undermines suppressive activity of MDSC and has potent antitumor effect. Stabilizing IFNAR1 using inhibitor of p38 combined with the interferon induction therapy elicits a robust anti-tumor effect. Thus, negative regulatory mechanisms of MDSC function can be exploited therapeutically.


Assuntos
Interferon Tipo I/metabolismo , Células Supressoras Mieloides/imunologia , Neoplasias/metabolismo , Receptor de Interferon alfa e beta/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antineoplásicos/farmacologia , Medula Óssea , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Monócitos/imunologia , Neutrófilos/imunologia , Receptor de Interferon alfa e beta/genética , Proteínas Quinases p38 Ativadas por Mitógeno/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
2.
Adv Exp Med Biol ; 1285: 1-15, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33770399

RESUMO

The pregnancy recognition signal from the conceptus (embryo/fetus and associated membranes) to the mother is interferon tau (IFNT) in ruminants and estradiol, possibly in concert with interferons gamma and delta in pigs. Those pregnancy recognition signals silence expression of interferon stimulated genes (ISG) in uterine luminal (LE) and superficial glandular (sGE) epithelia while inducing expression of genes for transport of nutrients, including glucose and amino acids, into the uterine lumen to support growth and development of the conceptus. In sheep and pigs, glucose not utilized immediately by the conceptus is converted to fructose. Glucose, fructose, serine and glycine in uterine histotroph can contribute to one carbon (1C) metabolism that provides one-carbon groups for the synthesis of purines and thymidylate, as well as S-adenosylmethionine for epigenetic methylation reactions. Serine and glycine are transported into the mitochondria of cells and metabolized to formate that is transported into the cytoplasm for the synthesis of purines, thymidine and S-adenosylmethionine. The unique aspects of one-carbon metabolism are discussed in the context of the hypoxic uterine environment, aerobic glycolysis, and similarities in metabolism between cancer cells and cells of the rapidly developing fetal-placental tissues during pregnancy. Further, the evolution of anatomical and functional aspects of the placentae of sheep and pigs versus primates is discussed in the context of mechanisms to efficiently obtain, store and utilize nutrients required for rapid fetal growth in the last one-half of gestation.


Assuntos
Embrião de Mamíferos , Interferon Tipo I , Animais , Carbono , Endométrio , Feminino , Desenvolvimento Fetal , Placenta , Gravidez , Ovinos , Suínos , Útero
4.
Cell Rep ; 34(13): 108916, 2021 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-33765414

RESUMO

The presence of an ORF6 gene distinguishes sarbecoviruses such as severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 from other betacoronaviruses. Here we show that ORF6 inhibits induction of innate immune signaling, including upregulation of type I interferon (IFN) upon viral infection as well as type I and III IFN signaling. Intriguingly, ORF6 proteins from SARS-CoV-2 lineages are more efficient antagonists of innate immunity than their orthologs from SARS-CoV lineages. Mutational analyses identified residues E46 and Q56 as important determinants of the antagonistic activity of SARS-CoV-2 ORF6. Moreover, we show that the anti-innate immune activity of ORF6 depends on its C-terminal region and that ORF6 inhibits nuclear translocation of IRF3. Finally, we identify naturally occurring frameshift/nonsense mutations that result in an inactivating truncation of ORF6 in approximately 0.2% of SARS-CoV-2 isolates. Our findings suggest that ORF6 contributes to the poor IFN activation observed in individuals with coronavirus disease 2019 (COVID-19).


Assuntos
/metabolismo , Interferon Tipo I/metabolismo , Proteínas Virais/metabolismo , Animais , Chlorocebus aethiops , Células HEK293 , Humanos , Imunidade Inata/imunologia , Transdução de Sinais/imunologia , Células Vero , Proteínas Virais/genética
5.
Nat Commun ; 12(1): 1858, 2021 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-33767151

RESUMO

Activating intra-tumor innate immunity might enhance tumor immune surveillance. Virotherapy is proposed to achieve tumor cell killing, while indirectly activating innate immunity. Here, we report that recombinant poliovirus therapy primarily mediates antitumor immunotherapy via direct infection of non-malignant tumor microenvironment (TME) cells, independent of malignant cell lysis. Relative to other innate immune agonists, virotherapy provokes selective, TBK1-IRF3 driven innate inflammation that is associated with sustained type-I/III interferon (IFN) release. Despite priming equivalent antitumor T cell quantities, MDA5-orchestrated TBK1-IRF3 signaling, but not NFκB-polarized TLR activation, culminates in polyfunctional and Th1-differentiated antitumor T cell phenotypes. Recombinant type-I IFN increases tumor-localized T cell function, but does not mediate durable antitumor immunotherapy without concomitant pattern recognition receptor (PRR) signaling. Thus, virus-induced MDA5-TBK1-IRF3 signaling in the TME provides PRR-contextualized IFN responses that elicit functional antitumor T cell immunity. TBK1-IRF3 innate signal transduction stimulates eventual function and differentiation of tumor-infiltrating T cells.


Assuntos
Neoplasias da Mama/terapia , Fator Regulador 3 de Interferon/imunologia , Melanoma/terapia , Terapia Viral Oncolítica , Proteínas Serina-Treonina Quinases/imunologia , Microambiente Tumoral/imunologia , Animais , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Humanos , Imunidade Inata/imunologia , Interferon Tipo I/imunologia , Helicase IFIH1 Induzida por Interferon/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Melanoma/imunologia , Melanoma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/metabolismo , Transdução de Sinais/imunologia , Células Th1/imunologia
6.
Science ; 371(6534): 1154-1159, 2021 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-33707263

RESUMO

Alterations of the mycobiota composition associated with Crohn's disease (CD) are challenging to link to defining elements of pathophysiology, such as poor injury repair. Using culture-dependent and -independent methods, we discovered that Debaryomyces hansenii preferentially localized to and was abundant within incompletely healed intestinal wounds of mice and inflamed mucosal tissues of CD human subjects. D. hansenii cultures from injured mice and inflamed CD tissues impaired colonic healing when introduced into injured conventionally raised or gnotobiotic mice. We reisolated D. hansenii from injured areas of these mice, fulfilling Koch's postulates. Mechanistically, D. hansenii impaired mucosal healing through the myeloid cell-specific type 1 interferon-CCL5 axis. Taken together, we have identified a fungus that inhabits inflamed CD tissue and can lead to dysregulated mucosal healing.


Assuntos
Doença de Crohn/microbiologia , Doença de Crohn/patologia , /fisiologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Anfotericina B/farmacologia , Animais , Antibacterianos/farmacologia , Antifúngicos/farmacologia , Quimiocina CCL5/metabolismo , Colo/microbiologia , Colo/patologia , Doença de Crohn/imunologia , Feminino , Microbioma Gastrointestinal , Vida Livre de Germes , Humanos , Íleo/microbiologia , Íleo/patologia , Inflamação , Interferon Tipo I/metabolismo , Mucosa Intestinal/imunologia , Macrófagos/imunologia , Macrófagos/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
7.
Nat Commun ; 12(1): 1582, 2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33707441

RESUMO

Double-stranded RNA (dsRNA) is a virus-encoded signature capable of triggering intracellular Rig-like receptors (RLR) to activate antiviral signaling, but whether intercellular dsRNA structural reshaping mediated by the N6-methyladenosine (m6A) modification modulates this process remains largely unknown. Here, we show that, in response to infection by the RNA virus Vesicular Stomatitis Virus (VSV), the m6A methyltransferase METTL3 translocates into the cytoplasm to increase m6A modification on virus-derived transcripts and decrease viral dsRNA formation, thereby reducing virus-sensing efficacy by RLRs such as RIG-I and MDA5 and dampening antiviral immune signaling. Meanwhile, the genetic ablation of METTL3 in monocyte or hepatocyte causes enhanced type I IFN expression and accelerates VSV clearance. Our findings thus implicate METTL3-mediated m6A RNA modification on viral RNAs as a negative regulator for innate sensing pathways of dsRNA, and also hint METTL3 as a potential therapeutic target for the modulation of anti-viral immunity.


Assuntos
Adenosina/análogos & derivados , Metiltransferases/metabolismo , RNA de Cadeia Dupla/genética , RNA Viral/genética , Vírus da Estomatite Vesicular Indiana/genética , Células A549 , Adenosina/genética , Animais , Linhagem Celular Tumoral , Chlorocebus aethiops , Células HEK293 , Células HeLa , Humanos , Imunidade Inata/imunologia , Interferon Tipo I/imunologia , Metiltransferases/genética , Camundongos , Células RAW 264.7 , Transdução de Sinais/imunologia , Células Vero
8.
Front Immunol ; 12: 631226, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33679778

RESUMO

Coronavirus disease-2019 (COVID-19) is a novel respiratory disease induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It remains poorly understood how the host immune system responds to the infection during disease progression. We applied microarray analysis of the whole genome transcriptome to peripheral blood mononuclear cells (PBMCs) taken from severe and mild COVID-19 patients as well as healthy controls. Functional enrichment analysis of genes associated with COVID-19 severity indicated that disease progression is featured by overactivation of myeloid cells and deficient T cell function. The upregulation of TLR6 and MMP9, which promote the neutrophils-mediated inflammatory response, and the downregulation of SKAP1 and LAG3, which regulate T cells function, were associated with disease severity. Importantly, the regulation of these four genes was absent in patients with influenza A (H1N1). And compared with stimulation with hemagglutinin (HA) of H1N1 virus, the regulation pattern of these genes was unique in PBMCs response to Spike protein of SARS-CoV-2 ex vivo. Our data also suggested that severe SARS-CoV-2 infection largely silenced the response of type I interferons (IFNs) and altered the proportion of immune cells, providing a potential mechanism for the hypercytokinemia. This study indicates that SARS-CoV-2 infection impairs inflammatory and immune signatures in patients, especially those at severe stage. The potential mechanisms underpinning severe COVID-19 progression include overactive myeloid cells, impaired function of T cells, and inadequate induction of type I IFNs signaling.


Assuntos
/imunologia , Leucócitos Mononucleares/imunologia , Transdução de Sinais/imunologia , Adolescente , Adulto , Idoso , Antígenos CD/imunologia , Feminino , Perfilação da Expressão Gênica , Humanos , Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana/imunologia , Interferon Tipo I/imunologia , Masculino , Metaloproteinase 9 da Matriz/imunologia , Pessoa de Meia-Idade , Fosfoproteínas/imunologia , Receptor 6 Toll-Like/imunologia
9.
J Exp Med ; 218(4)2021 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-33533916

RESUMO

Several studies have analyzed antiviral immune pathways in late-stage severe COVID-19. However, the initial steps of SARS-CoV-2 antiviral immunity are poorly understood. Here we have isolated primary SARS-CoV-2 viral strains and studied their interaction with human plasmacytoid predendritic cells (pDCs), a key player in antiviral immunity. We show that pDCs are not productively infected by SARS-CoV-2. However, they efficiently diversified into activated P1-, P2-, and P3-pDC effector subsets in response to viral stimulation. They expressed CD80, CD86, CCR7, and OX40 ligand at levels similar to influenza virus-induced activation. They rapidly produced high levels of interferon-α, interferon-λ1, IL-6, IP-10, and IL-8. All major aspects of SARS-CoV-2-induced pDC activation were inhibited by hydroxychloroquine. Mechanistically, SARS-CoV-2-induced pDC activation critically depended on IRAK4 and UNC93B1, as established using pDC from genetically deficient patients. Overall, our data indicate that human pDC are efficiently activated by SARS-CoV-2 particles and may thus contribute to type I IFN-dependent immunity against SARS-CoV-2 infection.


Assuntos
/imunologia , Plasticidade Celular/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , /imunologia , Biomarcadores , /virologia , Citocinas/metabolismo , Células Dendríticas/virologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Hidroxicloroquina/farmacologia , Hidroxicloroquina/uso terapêutico , Imunomodulação , Imunofenotipagem , Mediadores da Inflamação/metabolismo , Interferon Tipo I/metabolismo , Interferons/metabolismo
10.
Trends Immunol ; 42(4): 312-322, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33622601

RESUMO

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The ability of our cells to secrete type I interferons (IFN-Is) is essential for the control of virus replication and for effective antiviral immune responses; for this reason, viruses have evolved the means to antagonize IFN-I. Inhibition of IFN-I production is pronounced in SARS-CoV-2 infection, which can impair the adaptive immune response and exacerbate inflammatory disease at late stages of infection. However, therapeutic boosting of IFN-I offers a narrow time window for efficacy and safety. Here, we discuss how limits placed on IFN-I by SARS-CoV-2 shape the immune response and whether this might be countered with therapeutic approaches and vaccine design.


Assuntos
/imunologia , Inflamação/imunologia , Interferon Tipo I/imunologia , /complicações , Humanos , Inflamação/virologia , Replicação Viral
11.
Nature ; 591(7850): 451-457, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33561864

RESUMO

All coronaviruses known to have recently emerged as human pathogens probably originated in bats1. Here we use a single experimental platform based on immunodeficient mice implanted with human lung tissue (hereafter, human lung-only mice (LoM)) to demonstrate the efficient in vivo replication of severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as well as two endogenous SARS-like bat coronaviruses that show potential for emergence as human pathogens. Virus replication in this model occurs in bona fide human lung tissue and does not require any type of adaptation of the virus or the host. Our results indicate that bats contain endogenous coronaviruses that are capable of direct transmission to humans. Our detailed analysis of in vivo infection with SARS-CoV-2 in human lung tissue from LoM showed a predominant infection of human lung epithelial cells, including type-2 pneumocytes that are present in alveoli and ciliated airway cells. Acute infection with SARS-CoV-2 was highly cytopathic and induced a robust and sustained type-I interferon and inflammatory cytokine and chemokine response. Finally, we evaluated a therapeutic and pre-exposure prophylaxis strategy for SARS-CoV-2 infection. Our results show that therapeutic and prophylactic administration of EIDD-2801-an oral broad-spectrum antiviral agent that is currently in phase II/III clinical trials-markedly inhibited SARS-CoV-2 replication in vivo, and thus has considerable potential for the prevention and treatment of COVID-19.


Assuntos
/tratamento farmacológico , Citidina/análogos & derivados , Hidroxilaminas/administração & dosagem , Hidroxilaminas/uso terapêutico , Administração Oral , Células Epiteliais Alveolares/imunologia , Células Epiteliais Alveolares/patologia , Células Epiteliais Alveolares/virologia , Animais , Quimioprevenção , Quirópteros/virologia , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Citidina/administração & dosagem , Citidina/uso terapêutico , Citocinas/imunologia , Células Epiteliais/virologia , Feminino , Xenoenxertos , Humanos , Imunidade Inata , Interferon Tipo I/imunologia , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Transplante de Pulmão , Masculino , Camundongos , Profilaxia Pós-Exposição , Profilaxia Pré-Exposição , /patogenicidade , Replicação Viral
12.
Immunity ; 54(3): 557-570.e5, 2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33577760

RESUMO

The emergence and spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in significant global morbidity, mortality, and societal disruption. A better understanding of virus-host interactions may potentiate therapeutic insights toward limiting this infection. Here we investigated the dynamics of the systemic response to SARS-CoV-2 in hamsters by histological analysis and transcriptional profiling. Infection resulted in consistently high levels of virus in the upper and lower respiratory tracts and sporadic occurrence in other distal tissues. A longitudinal cohort revealed a wave of inflammation, including a type I interferon (IFN-I) response, that was evident in all tissues regardless of viral presence but was insufficient to prevent disease progression. Bolstering the antiviral response with intranasal administration of recombinant IFN-I reduced viral disease, prevented transmission, and lowered inflammation in vivo. This study defines the systemic host response to SARS-CoV-2 infection and supports use of intranasal IFN-I as an effective means of early treatment.


Assuntos
/metabolismo , Interações Hospedeiro-Patógeno , Interferon Tipo I/metabolismo , /fisiologia , Animais , Biópsia , /imunologia , Cricetinae , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata , Interferon Tipo I/genética , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Especificidade de Órgãos/imunologia , Virulência , Replicação Viral/imunologia
13.
Cell Host Microbe ; 29(3): 489-502.e8, 2021 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-33548198

RESUMO

The SARS-CoV-2 virus, the causative agent of COVID-19, is undergoing constant mutation. Here, we utilized an integrative approach combining epidemiology, virus genome sequencing, clinical phenotyping, and experimental validation to locate mutations of clinical importance. We identified 35 recurrent variants, some of which are associated with clinical phenotypes related to severity. One variant, containing a deletion in the Nsp1-coding region (Δ500-532), was found in more than 20% of our sequenced samples and associates with higher RT-PCR cycle thresholds and lower serum IFN-ß levels of infected patients. Deletion variants in this locus were found in 37 countries worldwide, and viruses isolated from clinical samples or engineered by reverse genetics with related deletions in Nsp1 also induce lower IFN-ß responses in infected Calu-3 cells. Taken together, our virologic surveillance characterizes recurrent genetic diversity and identified mutations in Nsp1 of biological and clinical importance, which collectively may aid molecular diagnostics and drug design.


Assuntos
/imunologia , Interferon Tipo I/imunologia , /imunologia , Proteínas não Estruturais Virais/genética , Células A549 , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Sequência de Bases , Linhagem Celular , Criança , Pré-Escolar , Chlorocebus aethiops , Feminino , Deleção de Genes , Genômica , Células HEK293 , Humanos , Lactente , Interferon Tipo I/sangue , Interferon beta/sangue , Interferon beta/metabolismo , Masculino , Pessoa de Meia-Idade , Epidemiologia Molecular , Genética Reversa , Células Vero , Proteínas não Estruturais Virais/imunologia , Adulto Jovem
14.
Cell Rep ; 34(7): 108761, 2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33567255

RESUMO

Coronavirus disease 2019 (COVID-19) is a current global health threat caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Emerging evidence indicates that SARS-CoV-2 elicits a dysregulated immune response and a delayed interferon (IFN) expression in patients, which contribute largely to the viral pathogenesis and development of COVID-19. However, underlying mechanisms remain to be elucidated. Here, we report the activation and repression of the innate immune response by SARS-CoV-2. We show that SARS-CoV-2 RNA activates the RIG-I-MAVS-dependent IFN signaling pathway. We further uncover that ORF9b immediately accumulates and antagonizes the antiviral type I IFN response during SARS-CoV-2 infection on primary human pulmonary alveolar epithelial cells. ORF9b targets the nuclear factor κB (NF-κB) essential modulator NEMO and interrupts its K63-linked polyubiquitination upon viral stimulation, thereby inhibiting the canonical IκB kinase alpha (IKKα)/ß/γ-NF-κB signaling and subsequent IFN production. Our findings thus unveil the innate immunosuppression by ORF9b and provide insights into the host-virus interplay during the early stage of SARS-CoV-2 infection.


Assuntos
/genética , Quinase I-kappa B/metabolismo , /metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/virologia , /metabolismo , Células HEK293 , Humanos , Imunidade Inata/imunologia , Interferon Tipo I/metabolismo , Interferons/metabolismo , NF-kappa B/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Cultura Primária de Células , Receptores do Ácido Retinoico/metabolismo , /imunologia , Transdução de Sinais , Ubiquitinação
16.
Nat Commun ; 12(1): 1194, 2021 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-33608556

RESUMO

Ubiquitination is one of the most prevalent protein posttranslational modifications. Here, we show that E3 ligase Nedd4l positively regulates antiviral immunity by catalyzing K29-linked cysteine ubiquitination of TRAF3. Deficiency of Nedd4l significantly impairs type I interferon and proinflammatory cytokine production induced by virus infection both in vitro and in vivo. Nedd4l deficiency inhibits virus-induced ubiquitination of TRAF3, the binding between TRAF3 and TBK1, and subsequent phosphorylation of TBK1 and IRF3. Nedd4l directly interacts with TRAF3 and catalyzes K29-linked ubiquitination of Cys56 and Cys124, two cysteines that constitute zinc fingers, resulting in enhanced association between TRAF3 and E3 ligases, cIAP1/2 and HECTD3, and also increased K48/K63-linked ubiquitination of TRAF3. Mutation of Cys56 and Cys124 diminishes Nedd4l-catalyzed K29-linked ubiquitination, but enhances association between TRAF3 and the E3 ligases, supporting Nedd4l promotes type I interferon production in response to virus by catalyzing ubiquitination of the cysteines in TRAF3.


Assuntos
Antivirais/farmacologia , Imunidade Inata/efeitos dos fármacos , Ubiquitina-Proteína Ligases Nedd4/genética , Ubiquitina-Proteína Ligases Nedd4/metabolismo , Fator 3 Associado a Receptor de TNF/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação , Animais , Proteína 3 com Repetições IAP de Baculovírus/metabolismo , Catálise , Cisteína/metabolismo , Feminino , Células HEK293 , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Fator Regulador 3 de Interferon/metabolismo , Interferon Tipo I/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ubiquitina-Proteína Ligases Nedd4/deficiência , Processamento de Proteína Pós-Traducional , Proteínas Serina-Treonina Quinases , Fator 3 Associado a Receptor de TNF/genética , Ubiquitina-Proteína Ligases/genética
17.
J Clin Immunol ; 41(3): 536-544, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33616813

RESUMO

PURPOSE: To report four cases of life-threatening COVID-19 pneumonia in patients with high blood concentrations of neutralizing autoantibodies against type I interferons (IFNs), who were treated with plasma exchange (PE) as a rescue therapy. METHODS: Prospective case series, which included patients, diagnosed with RT-PCR-confirmed SARS-CoV-2 infection and positive autoantibodies against type I IFNs in two French intensive care units (ICUs) between October 8 and November 14, 2020. Six critically ill COVID-19 patients with no anti-IFN antibodies were used as controls. Anti-IFN autoantibodies and IFN concentrations, together with the levels of anti-SARS-CoV-2 antibodies, were measured sequentially in serum. Viral load was determined in the upper and lower respiratory tract. Patients were followed during hospital stay. RESULTS: Three men and one woman were included. Three of the patients had four PE sessions each, while another had three PE sessions. PE decreased the concentrations of autoantibodies against type I IFN in all four patients, whereas anti-SARS-CoV-2 antibody levels remained stable. Autoantibodies against type I IFN levels were high in tracheal aspirates of one patient and decreased after three PE sessions. By contrast, anti-IFN autoantibodies were not detected in tracheal aspirates from five control patients without detectable anti-IFN autoantibodies in serum. During PE, serum IFN-α levels slightly increased in three out of four patients, and upper respiratory tract viral load decreased in all patients. All patients were alive at day 28 of ICU admission. Two patients eventually died in the ICU, while the two survivors were discharged from the ICU at days 50 and 66. CONCLUSIONS: PE efficiently removes autoantibodies against type I IFNs, including those detected in tracheal aspirates, without affecting anti-SARS-CoV-2 antibody levels, in patients with life-threatening COVID-19 pneumonia. The clinical benefit of PE in patients with autoantibodies against type I IFNs should be tested in a larger study.


Assuntos
Autoanticorpos/sangue , Interferon Tipo I/imunologia , Troca Plasmática , Adulto , Idoso , Autoanticorpos/isolamento & purificação , Feminino , Humanos , Masculino , Estudos Prospectivos
18.
BMC Infect Dis ; 21(1): 47, 2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33430799

RESUMO

BACKGROUND: The spread of a highly pathogenic, novel coronavirus (SARS-CoV-2) has emerged as a once-in-a-century pandemic, having already infected over 63 million people worldwide. Novel therapies are urgently needed. Janus kinase-inhibitors and Type I interferons have emerged as potential antiviral candidates for COVID-19 patients due to their proven efficacy against diseases with excessive cytokine release and their direct antiviral ability against viruses including coronaviruses, respectively. METHODS: A search of MEDLINE and MedRxiv was conducted by three investigators from inception until July 30th 2020 and included any study type that compared treatment outcomes of humans treated with Janus kinase-inhibitor or Type I interferon against controls. Inclusion necessitated data with clearly indicated risk estimates or those that permitted their back-calculation. Outcomes were synthesized using RevMan. RESULTS: Of 733 searched studies, we included four randomized and eleven non-randomized trials. Five of the studies were unpublished. Those who received Janus kinase-inhibitor had significantly reduced odds of mortality (OR, 0.12; 95% CI, 0.03-0.39, p< 0.001) and ICU admission (OR, 0.05; 95% CI, 0.01-0.26, p< 0.001), and had significantly increased odds of hospital discharge (OR, 22.76; 95% CI, 10.68-48.54, p< 0.00001) when compared to standard treatment group. Type I interferon recipients had significantly reduced odds of mortality (OR, 0.19; 95% CI, 0.04-0.85, p< 0.05), and increased odds of discharge bordering significance (OR, 1.89; 95% CI, 1.00-3.59, p=0.05). CONCLUSIONS: Janus kinase-inhibitor treatment is significantly associated with positive clinical outcomes in terms of mortality, ICU admission, and discharge. Type I interferon treatment is associated with positive clinical outcomes in regard to mortality and discharge. While these data show promise, additional well-conducted RCTs are needed to further elucidate the relationship between clinical outcomes and Janus kinase-inhibitors and Type I interferons in COVID-19 patients.


Assuntos
/tratamento farmacológico , Interferon Tipo I/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Humanos , Interferon Tipo I/imunologia , /patogenicidade , Resultado do Tratamento
19.
Viruses ; 13(2)2021 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-33498715

RESUMO

Viral infections remain a global public health concern and cause a severe societal and economic burden. At the organismal level, the innate immune system is essential for the detection of viruses and constitutes the first line of defense. Viral components are sensed by host pattern recognition receptors (PRRs). PRRs can be further classified based on their localization into Toll-like receptors (TLRs), C-type lectin receptors (CLR), retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), NOD-like receptors (NLRs) and cytosolic DNA sensors (CDS). TLR and RLR signaling results in production of type I interferons (IFNα and -ß) and pro-inflammatory cytokines in a cell-specific manner, whereas NLR signaling leads to the production of interleukin-1 family proteins. On the other hand, CLRs are capable of sensing glycans present in viral pathogens, which can induce phagocytic, endocytic, antimicrobial, and pro- inflammatory responses. Peripheral immune sensing of viruses and the ensuing cytokine response can significantly affect the central nervous system (CNS). But viruses can also directly enter the CNS via a multitude of routes, such as the nasal epithelium, along nerve fibers connecting to the periphery and as cargo of infiltrating infected cells passing through the blood brain barrier, triggering innate immune sensing and cytokine responses directly in the CNS. Here, we review mechanisms of viral immune sensing and currently recognized consequences for the CNS of innate immune responses to viruses.


Assuntos
Sistema Nervoso Central/imunologia , Sistema Nervoso Central/virologia , Citocinas/metabolismo , Imunidade Inata , Viroses/imunologia , Animais , Humanos , Inflamassomos , Interferon Tipo I/metabolismo , Lectinas Tipo C/metabolismo , Receptores de Reconhecimento de Padrão , Transdução de Sinais , Receptores Toll-Like/metabolismo
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