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1.
Future Med Chem ; 13(6): 587-592, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33467912

RESUMO

Understanding the potential association between the poly (ADP-ribose) polymerase member 14 (PARP14) and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may aid in understanding the host immunopathological response to the virus. PARP14 has an emerging role in viral infections, and this article considers its potential mechanisms for action in either a pro- or anti-viral manner. It is evident that more experimental work is required; however, PARP14 appears vital in controlling the interferon response to the SARS-CoV-2 infection and has potential roles in balancing the proinflammatory cytokines of the cytokine storm. Furthermore, the SARS-CoV-2 macrodomain can prevent the PARP14-mediated antiviral response, suggesting a more complex relationship between PARP14 activity and SARS-CoV-2 infections.


Assuntos
/imunologia , Poli(ADP-Ribose) Polimerases/imunologia , /imunologia , /complicações , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/patologia , Humanos , Imunidade , Inflamação/complicações , Inflamação/imunologia , Inflamação/patologia , Interferons/imunologia
2.
Nature ; 590(7847): 635-641, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33429418

RESUMO

Some patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop severe pneumonia and acute respiratory distress syndrome1 (ARDS). Distinct clinical features in these patients have led to speculation that the immune response to virus in the SARS-CoV-2-infected alveolus differs from that in other types of pneumonia2. Here we investigate SARS-CoV-2 pathobiology by characterizing the immune response in the alveoli of patients infected with the virus. We collected bronchoalveolar lavage fluid samples from 88 patients with SARS-CoV-2-induced respiratory failure and 211 patients with known or suspected pneumonia from other pathogens, and analysed them using flow cytometry and bulk transcriptomic profiling. We performed single-cell RNA sequencing on 10 bronchoalveolar lavage fluid samples collected from patients with severe coronavirus disease 2019 (COVID-19) within 48 h of intubation. In the majority of patients with SARS-CoV-2 infection, the alveolar space was persistently enriched in T cells and monocytes. Bulk and single-cell transcriptomic profiling suggested that SARS-CoV-2 infects alveolar macrophages, which in turn respond by producing T cell chemoattractants. These T cells produce interferon-γ to induce inflammatory cytokine release from alveolar macrophages and further promote T cell activation. Collectively, our results suggest that SARS-CoV-2 causes a slowly unfolding, spatially limited alveolitis in which alveolar macrophages containing SARS-CoV-2 and T cells form a positive feedback loop that drives persistent alveolar inflammation.


Assuntos
/imunologia , Macrófagos Alveolares/imunologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Linfócitos T/imunologia , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/imunologia , Estudos de Coortes , Humanos , Interferon gama/imunologia , Interferons/imunologia , Interferons/metabolismo , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/virologia , Pneumonia Viral/genética , RNA-Seq , Transdução de Sinais/imunologia , Análise de Célula Única , Linfócitos T/metabolismo , Fatores de Tempo
3.
Proc Natl Acad Sci U S A ; 118(6)2021 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-33479167

RESUMO

Dendritic cells (DCs) and monocytes are crucial mediators of innate and adaptive immune responses during viral infection, but misdirected responses by these cells may contribute to immunopathology. Here, we performed high-dimensional flow cytometry-analysis focusing on mononuclear phagocyte (MNP) lineages in SARS-CoV-2-infected patients with moderate and severe COVID-19. We provide a deep and comprehensive map of the MNP landscape in COVID-19. A redistribution of monocyte subsets toward intermediate monocytes and a general decrease in circulating DCs was observed in response to infection. Severe disease coincided with the appearance of monocytic myeloid-derived suppressor cell-like cells and a higher frequency of pre-DC2. Furthermore, phenotypic alterations in MNPs, and their late precursors, were cell-lineage-specific and associated either with the general response against SARS-CoV-2 or COVID-19 severity. This included an interferon-imprint in DC1s observed in all patients and a decreased expression of the coinhibitory molecule CD200R in pre-DCs, DC2s, and DC3 subsets of severely sick patients. Finally, unsupervised analysis revealed that the MNP profile, alone, pointed to a cluster of COVID-19 nonsurvivors. This study provides a reference for the MNP response to SARS-CoV-2 infection and unravels mononuclear phagocyte dysregulations associated with severe COVID-19.


Assuntos
/imunologia , Sistema Fagocitário Mononuclear/imunologia , /imunologia , Adulto , /metabolismo , Citocinas/imunologia , Células Dendríticas/imunologia , Feminino , Humanos , Interferons/imunologia , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Sistema Fagocitário Mononuclear/metabolismo , Índice de Gravidade de Doença , Suécia
4.
Nat Genet ; 53(2): 205-214, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33432184

RESUMO

Angiotensin-converting enzyme 2 (ACE2) is the main entry point in airway epithelial cells for SARS-CoV-2. ACE2 binding to the SARS-CoV-2 protein spike triggers viral fusion with the cell plasma membrane, resulting in viral RNA genome delivery into the host. Despite ACE2's critical role in SARS-CoV-2 infection, full understanding of ACE2 expression, including in response to viral infection, remains unclear. ACE2 was thought to encode five transcripts and one protein of 805 amino acids. In the present study, we identify a novel short isoform of ACE2 expressed in the airway epithelium, the main site of SARS-CoV-2 infection. Short ACE2 is substantially upregulated in response to interferon stimulation and rhinovirus infection, but not SARS-CoV-2 infection. This short isoform lacks SARS-CoV-2 spike high-affinity binding sites and, altogether, our data are consistent with a model where short ACE2 is unlikely to directly contribute to host susceptibility to SARS-CoV-2 infection.


Assuntos
/genética , Células Epiteliais/metabolismo , Animais , Sítios de Ligação , Células Cultivadas , Chlorocebus aethiops , Éxons , Células HEK293 , Humanos , Interferons/imunologia , Ligação Proteica , Isoformas de Proteínas/genética , Sítios de Splice de RNA , RNA-Seq , Sistema Respiratório/citologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Transcriptoma , Regulação para Cima , Células Vero
5.
Nature ; 591(7848): 124-130, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33494096

RESUMO

Although infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has pleiotropic and systemic effects in some individuals1-3, many others experience milder symptoms. Here, to gain a more comprehensive understanding of the distinction between severe and mild phenotypes in the pathology of coronavirus disease 2019 (COVID-19) and its origins, we performed a whole-blood-preserving single-cell analysis protocol to integrate contributions from all major immune cell types of the blood-including neutrophils, monocytes, platelets, lymphocytes and the contents of the serum. Patients with mild COVID-19 exhibit a coordinated pattern of expression of interferon-stimulated genes (ISGs)3 across every cell population, whereas these ISG-expressing cells are systemically absent in patients with severe disease. Paradoxically, individuals with severe COVID-19 produce very high titres of anti-SARS-CoV-2 antibodies and have a lower viral load compared to individuals with mild disease. Examination of the serum from patients with severe COVID-19 shows that these patients uniquely produce antibodies that functionally block the production of the ISG-expressing cells associated with mild disease, by activating conserved signalling circuits that dampen cellular responses to interferons. Overzealous antibody responses pit the immune system against itself in many patients with COVID-19, and perhaps also in individuals with other viral infections. Our findings reveal potential targets for immunotherapies in patients with severe COVID-19 to re-engage viral defence.


Assuntos
Anticorpos Antivirais/imunologia , /fisiopatologia , Interferons/antagonistas & inibidores , Interferons/imunologia , /patogenicidade , Anticorpos Antivirais/sangue , Formação de Anticorpos , Sequência de Bases , /virologia , Feminino , Humanos , Imunoglobulina G/imunologia , Interferons/metabolismo , Masculino , Neutrófilos/imunologia , Neutrófilos/patologia , Domínios Proteicos , Receptor de Interferon alfa e beta/antagonistas & inibidores , Receptor de Interferon alfa e beta/imunologia , Receptor de Interferon alfa e beta/metabolismo , Receptores de IgG/imunologia , Análise de Célula Única , Carga Viral/imunologia
6.
PLoS Pathog ; 17(1): e1009292, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33507952

RESUMO

The human airway epithelium is the initial site of SARS-CoV-2 infection. We used flow cytometry and single cell RNA-sequencing to understand how the heterogeneity of this diverse cell population contributes to elements of viral tropism and pathogenesis, antiviral immunity, and treatment response to remdesivir. We found that, while a variety of epithelial cell types are susceptible to infection, ciliated cells are the predominant cell target of SARS-CoV-2. The host protease TMPRSS2 was required for infection of these cells. Importantly, remdesivir treatment effectively inhibited viral replication across cell types, and blunted hyperinflammatory responses. Induction of interferon responses within infected cells was rare and there was significant heterogeneity in the antiviral gene signatures, varying with the burden of infection in each cell. We also found that heavily infected secretory cells expressed abundant IL-6, a potential mediator of COVID-19 pathogenesis.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/farmacologia , /virologia , Tropismo Viral , Monofosfato de Adenosina/farmacologia , Alanina/farmacologia , /genética , Epitélio/imunologia , Epitélio/virologia , Humanos , Interferons/genética , Interferons/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Pulmão/imunologia , Pulmão/virologia , Tropismo Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
7.
Cell Mol Immunol ; 18(3): 539-555, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33462384

RESUMO

Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are RNA sensor molecules that play essential roles in innate antiviral immunity. Among the three RLRs encoded by the human genome, RIG-I and melanoma differentiation-associated gene 5, which contain N-terminal caspase recruitment domains, are activated upon the detection of viral RNAs in the cytoplasm of virus-infected cells. Activated RLRs induce downstream signaling via their interactions with mitochondrial antiviral signaling proteins and activate the production of type I and III interferons and inflammatory cytokines. Recent studies have shown that RLR-mediated signaling is regulated by interactions with endogenous RNAs and host proteins, such as those involved in stress responses and posttranslational modifications. Since RLR-mediated cytokine production is also involved in the regulation of acquired immunity, the deregulation of RLR-mediated signaling is associated with autoimmune and autoinflammatory disorders. Moreover, RLR-mediated signaling might be involved in the aberrant cytokine production observed in coronavirus disease 2019. Since the discovery of RLRs in 2004, significant progress has been made in understanding the mechanisms underlying the activation and regulation of RLR-mediated signaling pathways. Here, we review the recent advances in the understanding of regulated RNA recognition and signal activation by RLRs, focusing on the interactions between various host and viral factors.


Assuntos
Proteína DEAD-box 58/imunologia , Mitocôndrias/imunologia , Receptores Imunológicos/imunologia , Transdução de Sinais , Viroses/imunologia , Vírus/imunologia , Animais , Humanos , Fatores Imunológicos , Interferon Tipo I/imunologia , Interferons/imunologia
8.
Viruses ; 13(2)2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33498196

RESUMO

The nuclear factor κB (NF-κB) family are the master transcription factors that control cell proliferation, apoptosis, the expression of interferons and proinflammatory factors, and viral infection. During viral infection, host innate immune system senses viral products, such as viral nucleic acids, to activate innate defense pathways, including the NF-κB signaling axis, thereby inhibiting viral infection. In these NF-κB signaling pathways, diverse types of ubiquitination have been shown to participate in different steps of the signal cascades. Recent advances find that viruses also modulate the ubiquitination in NF-κB signaling pathways to activate viral gene expression or inhibit host NF-κB activation and inflammation, thereby facilitating viral infection. Understanding the role of ubiquitination in NF-κB signaling during viral infection will advance our knowledge of regulatory mechanisms of NF-κB signaling and pave the avenue for potential antiviral therapeutics. Thus, here we systematically review the ubiquitination in NF-κB signaling, delineate how viruses modulate the NF-κB signaling via ubiquitination and discuss the potential future directions.


Assuntos
Interferons/imunologia , NF-kappa B/metabolismo , Ubiquitinação , Ubiquitinas/imunologia , Viroses/imunologia , Animais , Humanos , Ligação Proteica , Transdução de Sinais/imunologia , Relação Estrutura-Atividade , Ativação Transcricional/imunologia , Viroses/virologia
9.
Immunity ; 54(1): 164-175.e6, 2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33382973

RESUMO

Patients suffering from Coronavirus disease 2019 (COVID-19) can develop neurological sequelae, such as headache and neuroinflammatory or cerebrovascular disease. These conditions-termed here as Neuro-COVID-are more frequent in patients with severe COVID-19. To understand the etiology of these neurological sequelae, we utilized single-cell sequencing and examined the immune cell profiles from the cerebrospinal fluid (CSF) of Neuro-COVID patients compared with patients with non-inflammatory and autoimmune neurological diseases or with viral encephalitis. The CSF of Neuro-COVID patients exhibited an expansion of dedifferentiated monocytes and of exhausted CD4+ T cells. Neuro-COVID CSF leukocytes featured an enriched interferon signature; however, this was less pronounced than in viral encephalitis. Repertoire analysis revealed broad clonal T cell expansion and curtailed interferon response in severe compared with mild Neuro-COVID patients. Collectively, our findings document the CSF immune compartment in Neuro-COVID patients and suggest compromised antiviral responses in this setting.


Assuntos
/imunologia , Monócitos/imunologia , Doenças do Sistema Nervoso/imunologia , Linfócitos T/imunologia , /líquido cefalorraquidiano , /patologia , Diferenciação Celular , Líquido Cefalorraquidiano/imunologia , Encefalite Viral/líquido cefalorraquidiano , Encefalite Viral/imunologia , Perfilação da Expressão Gênica , Humanos , Interferons/genética , Interferons/imunologia , Leucócitos/imunologia , Ativação Linfocitária , Doenças do Sistema Nervoso/líquido cefalorraquidiano , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/patologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Análise de Célula Única
10.
Viruses ; 12(12)2020 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-33322160

RESUMO

Innate immune interferons (IFNs), including type I and III IFNs, constitute critical antiviral mechanisms. Recent studies reveal that IFN dysregulation is key to determine COVID-19 pathogenesis. Effective IFN stimulation or prophylactic administration of IFNs at the early stage prior to severe COVID-19 may elicit an autonomous antiviral state, restrict the virus infection, and prevent COVID-19 progression. Inborn genetic flaws and autoreactive antibodies that block IFN response have been significantly associated with about 14% of patients with life-threatening COVID-19 pneumonia. In most severe COVID-19 patients without genetic errors in IFN-relevant gene loci, IFN dysregulation is progressively worsened and associated with the situation of pro-inflammation and immunopathy, which is prone to autoimmunity. In addition, the high correlation of severe COVID-19 with seniority, males, and individuals with pre-existing comorbidities will be plausibly explained by the coincidence of IFN aberrance in these situations. Collectively, current studies call for a better understanding of the IFN response regarding the spatiotemporal determination and subtype-specificity against SARS-CoV-2 infections, which are warranted to devise IFN-related prophylactics and therapies.


Assuntos
Antivirais/imunologia , Interferons/imunologia , /patogenicidade , Antivirais/uso terapêutico , /patologia , Progressão da Doença , Humanos , Interferons/deficiência , Interferons/uso terapêutico , Cinética , Prognóstico , Transdução de Sinais , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Síndrome de Resposta Inflamatória Sistêmica/patologia
11.
Cell Rep ; 33(5): 108339, 2020 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-33147451

RESUMO

Here, we report our studies of immune-mediated regulation of Zika virus (ZIKV), herpes simplex virus 1 (HSV-1), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the human cornea. We find that ZIKV can be transmitted via corneal transplantation in mice. However, in human corneal explants, we report that ZIKV does not replicate efficiently and that SARS-CoV-2 does not replicate at all. Additionally, we demonstrate that type III interferon (IFN-λ) and its receptor (IFNλR1) are expressed in the corneal epithelium. Treatment of human corneal explants with IFN-λ, and treatment of mice with IFN-λ eye drops, upregulates antiviral interferon-stimulated genes. In human corneal explants, blockade of IFNλR1 enhances replication of ZIKV and HSV-1 but not SARS-CoV-2. In addition to an antiviral role for IFNλR1 in the cornea, our results suggest that the human cornea does not support SARS-CoV-2 infection despite expression of ACE2, a SARS-CoV-2 receptor, in the human corneal epithelium.


Assuntos
Betacoronavirus/fisiologia , Córnea/virologia , Infecções por Coronavirus/transmissão , Herpesvirus Humano 1/fisiologia , Interferons/imunologia , Pneumonia Viral/transmissão , Zika virus/fisiologia , Animais , Betacoronavirus/imunologia , Córnea/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Herpes Simples/imunologia , Herpes Simples/transmissão , Herpes Simples/virologia , Humanos , Camundongos , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Replicação Viral/fisiologia , Infecção por Zika virus/imunologia , Infecção por Zika virus/transmissão , Infecção por Zika virus/virologia
12.
Nat Protoc ; 15(11): 3678-3698, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33097923

RESUMO

This protocol assesses proinflammatory properties of nucleic acid nanoparticles (NANPs) using a validated preclinical model, peripheral blood mononuclear cells (PBMCs), that is highly predictive of cytokine responses. The experimental procedure details the preparation of pyrogen-free NANPs, isolation of PBMCs from freshly collected human blood, and analysis of characteristic biomarkers (type I and III interferons) produced by PBMCs transfected with NANPs. Although representative NANPs with high and low immunostimulatory potential are used as standards throughout the procedure, this protocol can be adapted to any NANPs or therapeutic nucleic acids, irrespective of whether they are carrier based or carrier free; additional cytokine biomarkers can also be included. We test several commercial platforms and controls broadly accessible to the research community to quantify all biomarkers in either single- or multiplex format. The continuous execution of this protocol takes <48 h; when immediate analysis is not feasible, single-use aliquots of the supernatants can be frozen and stored (-20 °C; 12 months).


Assuntos
Leucócitos Mononucleares/imunologia , Nanopartículas , Ácidos Nucleicos/imunologia , Linhagem Celular , Células Cultivadas , Humanos , Interferons/imunologia , Leucócitos Mononucleares/metabolismo , Modelos Moleculares , Nanopartículas/administração & dosagem , Ácidos Nucleicos/administração & dosagem , Ácidos Nucleicos/genética , Transfecção
13.
PLoS One ; 15(10): e0239804, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33031404

RESUMO

Mitochondrial OXPHOS generates most of the energy required for cellular function. OXPHOS biogenesis requires the coordinated expression of the nuclear and mitochondrial genomes. This represents a unique challenge that highlights the importance of nuclear-mitochondrial genetic communication to cellular function. Here we investigated the transcriptomic and functional consequences of nuclear-mitochondrial genetic divergence in vitro and in vivo. We utilized xenomitochondrial cybrid cell lines containing nuclear DNA from the common laboratory mouse Mus musculus domesticus and mitochondrial DNA (mtDNA) from Mus musculus domesticus, or exogenous mtDNA from progressively divergent mouse species Mus spretus, Mus terricolor, Mus caroli and Mus pahari. These cybrids model a wide range of nuclear-mitochondrial genetic divergence that cannot be achieved with other research models. Furthermore, we used a xenomitochondrial mouse model generated in our laboratory that harbors wild-type, C57BL/6J Mus musculus domesticus nuclear DNA and homoplasmic mtDNA from Mus terricolor. RNA sequencing analysis of xenomitochondrial cybrids revealed an activation of interferon signaling pathways even in the absence of OXPHOS dysfunction or immune challenge. In contrast, xenomitochondrial mice displayed lower baseline interferon gene expression and an impairment in the interferon-dependent innate immune response upon immune challenge with herpes simplex virus, which resulted in decreased viral control. Our work demonstrates that nuclear-mitochondrial genetic divergence caused by the introduction of exogenous mtDNA can modulate the interferon immune response both in vitro and in vivo, even when OXPHOS function is not compromised. This work may lead to future insights into the role of mitochondrial genetic variation and the immune function in humans, as patients affected by mitochondrial disease are known to be more susceptible to immune challenges.


Assuntos
Núcleo Celular/genética , DNA Mitocondrial , Interferons/imunologia , Mitocôndrias/genética , Animais , Linhagem Celular , Feminino , Genótipo , Imunidade Inata , Masculino , Camundongos/classificação , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fosforilação Oxidativa
14.
Vet Microbiol ; 250: 108853, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32992291

RESUMO

Coronaviruses (CoVs) is showing obvious interspecies transmission, such as the SARS-CoV, MERS-CoV and SARS-CoV-2. Here, the emerging porcine deltacoronavirus (PDCoV) strain, isolated from Shanghai, China, broadly infects porcine, human and chicken cells in vitro. Previously studies by our group and others have confirmed that PDCoV nucleocapsid (N) protein performs an important role in antagonizing retinoic acid-induced gene I-like receptor (RLR) activation. However, the mechanism of PDCoV N protein suppressing porcine type I IFN production remains unclear, especially the downstream of porcine RLR signaling pathway. In the present study, porcine IRF7 (poIRF7) was identified as the interaction protein of PDCoV N protein through LC-MS/MS. The poIRF7 (268-487aa) was the key region of binding PDCoV N protein. Although IRF7 is a conserved functional protein in species, the PDCoV N protein has been confirmed to interact with only poIRF7 and significantly decrease poIRF7-induced type I IFN production, but not human or chicken IRF7. Furthermore, PDCoV N protein can promote poIRF7 degradation via the ubiquitin-proteasome pathway, which directly increased the K6, K11, and K29-linked polyubiquitination of poIRF7. Lysine 359 of poIRF7 was a key site in PDCoV N protein inducing poIRF7 degradation. Taken together, our results reveal a novel mechanism that PDCoV N protein could species-specifically interact with poIRF7 and then promote its degradation to suppress porcine type I IFN production. The novel findings provide a new insight into PDCoV and other zoonotic coronavirus evading the innate immune response of different species.


Assuntos
Coronavirus/química , Fator Regulador 7 de Interferon/imunologia , Interferons/metabolismo , Proteínas do Nucleocapsídeo/imunologia , Animais , Western Blotting , Linhagem Celular , Galinhas , China , Cromatografia Líquida , Coronavirus/classificação , Técnica Indireta de Fluorescência para Anticorpo , Células HEK293 , Humanos , Imunoprecipitação , Interferons/imunologia , Células LLC-PK1 , Filogenia , Plasmídeos , Complexo de Endopeptidases do Proteassoma/metabolismo , Especificidade da Espécie , Suínos , Espectrometria de Massas em Tandem , Ubiquitina/metabolismo , Sequenciamento Completo do Genoma/veterinária
15.
Recenti Prog Med ; 111(9): 480-486, 2020 09.
Artigo em Italiano | MEDLINE | ID: mdl-32914775

RESUMO

At the end of March 2020, just over a month after the first ascertained case of CoViD-19 infection in Italy, the first reports of acute lesions of acro-ischemia appeared, especially in pre-adolescents and adolescents. These manifestations have been called in the course of these months in various ways, from "acro-ischemia acuta", "erythema pernio", "chilblains", up to characterize them more recently as "CoViD Toes". Clinical manifestations do not usually associate with other typical symptoms of Covid-19 and do not find a classical and defined serological antibody response (IgG and IgM). From a clinical point of view it is a localized and self-resolving problem of an interesting and relatively new pathogenetic model of disease in relation to a viral agent. Future studies must make us understand if there is in this specific condition a low viral load is not detectable by current methods and if this explains the inability to produce an adequate immune response for CoViD-19. It is important to determine whether the interferon immune response in some subjects can be the cause of both the low viremia and the endothelial damage so localized in the acral-site, as happens in other models of diseases (chilblain-lupus like). On the contrary, some authors believe that the acral lesions are attributable to chilblains caused by a series of favourable environmental conditions due to forced enclosure. We report the descriptive experience of 14 cases of acro-ischemia in children and adolescents observed in the territorial area of Ravenna and Rimini. The cases were subjected to the nasopharyngeal swab and to the search for antibodies with ELISA method for CoViD-19 both with negative results.


Assuntos
Infecções por Coronavirus/epidemiologia , Interferons/imunologia , Isquemia/epidemiologia , Estilo de Vida , Pneumonia Viral/epidemiologia , Adolescente , Pérnio/epidemiologia , Pérnio/etiologia , Pérnio/imunologia , Criança , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Feminino , Humanos , Isquemia/etiologia , Isquemia/imunologia , Itália/epidemiologia , Masculino , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Quarentena , Dedos do Pé
16.
Nat Rev Immunol ; 20(10): 585-586, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32788708
17.
Arch Virol ; 165(10): 2165-2176, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32740830

RESUMO

The PI3K/Akt signalling pathway is a crucial signalling cascade that regulates transcription, protein translation, cell growth, proliferation, cell survival, and metabolism. During viral infection, viruses exploit a variety of cellular pathways, including the well-known PI3K/Akt signalling pathway. Conversely, cells rely on this pathway to stimulate an antiviral response. The PI3K/Akt pathway is manipulated by a number of viruses, including DNA and RNA viruses and retroviruses. The aim of this review is to provide up-to-date information about the role of the PI3K-Akt pathway in infection with members of five different families of negative-sense ssRNA viruses. This pathway is hijacked for viral entry, regulation of endocytosis, suppression of premature apoptosis, viral protein expression, and replication. Although less common, the PI3K/Akt pathway can be downregulated as an immunomodulatory strategy or as a mechanism for inducing autophagy. Moreover, the cell activates this pathway as an antiviral strategy for interferon and cytokine production, among other strategies. Here, we present new data concerning the role of this pathway in infection with the paramyxovirus Newcastle disease virus (NDV). Our data seem to indicate that NDV uses the PI3K/Akt pathway to delay cell death and increase cell survival as a means of improving its replication. The interference of negative-sense ssRNA viruses with this essential pathway might have implications for the development of antiviral therapies.


Assuntos
Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Fosfatidilinositol 3-Quinase/genética , Proteínas Proto-Oncogênicas c-akt/genética , Infecções por Vírus de RNA/genética , Apoptose/genética , Autofagia/genética , Autofagia/imunologia , Citocinas/genética , Citocinas/imunologia , Endocitose/genética , Endocitose/imunologia , Filoviridae/genética , Filoviridae/metabolismo , Filoviridae/patogenicidade , Interações Hospedeiro-Patógeno/imunologia , Interferons/genética , Interferons/imunologia , Orthomyxoviridae/genética , Orthomyxoviridae/metabolismo , Orthomyxoviridae/patogenicidade , Paramyxoviridae/genética , Paramyxoviridae/metabolismo , Paramyxoviridae/patogenicidade , Fosfatidilinositol 3-Quinase/imunologia , Pneumovirinae/genética , Pneumovirinae/metabolismo , Pneumovirinae/patogenicidade , Biossíntese de Proteínas , Proteínas Proto-Oncogênicas c-akt/imunologia , Infecções por Vírus de RNA/imunologia , Infecções por Vírus de RNA/virologia , Rhabdoviridae/genética , Rhabdoviridae/metabolismo , Rhabdoviridae/patogenicidade , Transdução de Sinais , Proteínas Virais/genética , Proteínas Virais/imunologia , Internalização do Vírus , Replicação Viral
18.
Vet Microbiol ; 247: 108785, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32768229

RESUMO

Porcine deltacoronavirus (PDCoV) is a novel swine enteropathogenic coronavirus that causes watery diarrhea, vomiting and mortality in nursing piglets. Type III interferons (IFN-λs) are the major antiviral cytokines in intestinal epithelial cells, the target cells in vivo for PDCoV. In this study, we found that PDCoV infection remarkably inhibited Sendai virus-induced IFN-λ1 production by suppressing transcription factors IRF and NF-κB in IPI-2I cells, a line of porcine intestinal mucosal epithelial cells. We also confirmed that PDCoV infection impeded the activation of IFN-λ1 promoter stimulated by RIG-I, MDA5 and MAVS, but not by TBK1 and IRF1. Although the expression levels of IRF1 and MAVS were not changed, PDCoV infection resulted in reduction of the number of peroxisomes, the platform for MAVS to activate IRF1, and subsequent type III IFN production. Taken together, our study demonstrates that PDCoV suppresses type III IFN responses to circumvent the host's antiviral immunity.


Assuntos
Infecções por Coronavirus/veterinária , Células Epiteliais/imunologia , Células Epiteliais/virologia , Interações Hospedeiro-Patógeno/imunologia , Interferons/antagonistas & inibidores , Animais , Linhagem Celular , Coronavirus , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Fator Regulador 1 de Interferon/antagonistas & inibidores , Fator Regulador 1 de Interferon/imunologia , Interferons/imunologia , Intestinos/citologia , Intestinos/virologia , Rim/citologia , Rim/virologia , NF-kappa B/antagonistas & inibidores , NF-kappa B/imunologia , Vírus Sendai/imunologia , Transdução de Sinais/imunologia , Suínos/virologia , Doenças dos Suínos/imunologia , Doenças dos Suínos/virologia
19.
Clin Sci (Lond) ; 134(15): 1991-2017, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32749472

RESUMO

The major risk factors to fatal outcome in COVID-19 patients, i.e., elderliness and pre-existing metabolic and cardiovascular diseases (CVD), share in common the characteristic of being chronic degenerative diseases of inflammatory nature associated with defective heat shock response (HSR). The molecular components of the HSR, the principal metabolic pathway leading to the physiological resolution of inflammation, is an anti-inflammatory biochemical pathway that involves molecular chaperones of the heat shock protein (HSP) family during homeostasis-threatening stressful situations (e.g., thermal, oxidative and metabolic stresses). The entry of SARS coronaviruses in target cells, on the other hand, aggravates the already-jeopardized HSR of this specific group of patients. In addition, cellular counterattack against virus involves interferon (IFN)-mediated inflammatory responses. Therefore, individuals with impaired HSR cannot resolve virus-induced inflammatory burst physiologically, being susceptible to exacerbated forms of inflammation, which leads to a fatal "cytokine storm". Interestingly, some species of bats that are natural reservoirs of zoonotic viruses, including SARS-CoV-2, possess an IFN-based antiviral inflammatory response perpetually activated but do not show any sign of disease or cytokine storm. This is possible because bats present a constitutive HSR that is by far (hundreds of times) more intense and rapid than that of human, being associated with a high core temperature. Similarly in humans, fever is a physiological inducer of HSR while antipyretics, which block the initial phase of inflammation, impair the resolution phase of inflammation through the HSR. These findings offer a rationale for the reevaluation of patient care and fever reduction in SARS, including COVID-19.


Assuntos
Betacoronavirus/fisiologia , Quirópteros/imunologia , Infecções por Coronavirus/imunologia , Resposta ao Choque Térmico , Pneumonia Viral/imunologia , Animais , Betacoronavirus/genética , Quirópteros/virologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/genética , Infecções por Coronavirus/fisiopatologia , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/imunologia , Humanos , Interferons/imunologia , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/genética , Pneumonia Viral/fisiopatologia
20.
Mol Biol Rep ; 47(7): 5365-5376, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32601923

RESUMO

Emerging of the COVID-19 pandemic has raised interests in the field of biology and pathogenesis of coronaviruses; including interactions between host immune reactions specific, and viral factors. Deep knowledge about the interaction between coronaviruses and the host factors could be useful to provide a better support for the disease sufferers and be advantageous for managing and treatment of the lung infection caused by the virus. At this study, we reviewed the updated information on the pathogenesis of the COVID-19 and the immune responses toward it, with a special focus on structure, genetics, and viral accessory proteins, viral replication, viral receptors, the human immune reactions, cytopathic effects, and host-related factors.


Assuntos
Infecções por Coronavirus/etiologia , Infecções por Coronavirus/imunologia , Pneumonia Viral/etiologia , Pneumonia Viral/imunologia , Animais , Autoimunidade , Betacoronavirus/genética , Betacoronavirus/imunologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/virologia , Citocinas/imunologia , Humanos , Imunidade Inata , Interferons/imunologia , Pandemias , Pneumonia Viral/genética , Pneumonia Viral/virologia , Receptores Virais , Replicação Viral
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