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1.
Nutrients ; 13(7)2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34371920

RESUMO

Nutraceuticals, including vitamin D, vitamin A, zinc, lactoferrin, polyphenols coenzyme Q, magnesium, and selenium, are implicated in the modulation of the complex molecular pathways involved in the immune response against viral pathogens. A common element of the activity of nutraceuticals is their ability to enhance the innate immune response against pathogens by acting on the major cellular subsets and inducing the release of pro-inflammatory cytokines and antimicrobial peptides. In some cases, this action is accompanied by a direct antimicrobial effect, as evidenced in the specific case of lactoferrin. Furthermore, nutraceuticals act through complex molecular mechanisms to minimize the damage caused by the activation of the immune system against pathogens, reducing the oxidative damage, influencing the antigen presentation, enhancing the differentiation and proliferation of regulatory T cells, driving the differentiation of lymphocyte subsets, and modulating the production of pro-inflammatory cytokines. In this paper, we review the main molecular mechanisms responsible for the immunomodulatory function of nutraceuticals, focusing on the most relevant aspects for the prevention and treatment of viral infections.


Assuntos
Antivirais/uso terapêutico , Suplementos Nutricionais , Sistema Imunitário/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Viroses/tratamento farmacológico , Vírus/efeitos dos fármacos , Animais , Antivirais/efeitos adversos , Suplementos Nutricionais/efeitos adversos , Interações Hospedeiro-Patógeno , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Sistema Imunitário/virologia , Fatores Imunológicos/efeitos adversos , Resultado do Tratamento , Viroses/imunologia , Viroses/metabolismo , Viroses/virologia , Vírus/imunologia , Vírus/patogenicidade
2.
Cells ; 10(7)2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34360004

RESUMO

Microglia are the resident immune cells of the central nervous system contributing substantially to health and disease. There is increasing evidence that inflammatory microglia may induce or accelerate brain aging, by interfering with physiological repair and remodeling processes. Many viral infections affect the brain and interfere with microglia functions, including human immune deficiency virus, flaviviruses, SARS-CoV-2, influenza, and human herpes viruses. Especially chronic viral infections causing low-grade neuroinflammation may contribute to brain aging. This review elucidates the potential role of various neurotropic viruses in microglia-driven neurocognitive deficiencies and possibly accelerated brain aging.


Assuntos
Envelhecimento , Encéfalo/fisiopatologia , Inflamação/fisiopatologia , Microglia/virologia , Viroses/fisiopatologia , Animais , Encéfalo/imunologia , Encéfalo/virologia , COVID-19/imunologia , COVID-19/fisiopatologia , COVID-19/virologia , Humanos , Inflamação/imunologia , Inflamação/virologia , Microglia/imunologia , Microglia/patologia , SARS-CoV-2/fisiologia , Viroses/imunologia , Viroses/virologia
3.
Microbiol Spectr ; 9(1): e0053621, 2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34378965

RESUMO

Transmission of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in millions of deaths and declining economies around the world. K18-hACE2 mice develop disease resembling severe SARS-CoV-2 infection in a virus dose-dependent manner. The relationship between SARS-CoV-2 and the intestinal or respiratory microbiome is not fully understood. In this context, we characterized the cecal and lung microbiomes of SARS-CoV-2-challenged K18-hACE2 transgenic mice in the presence or absence of treatment with the Mpro inhibitor GC-376. Cecum microbiome showed decreased Shannon and inverse (Inv) Simpson diversity indexes correlating with SARS-CoV-2 infection dosage and a difference of Bray-Curtis dissimilarity distances among control and infected mice. Bacterial phyla such as Firmicutes, particularly, Lachnospiraceae and Oscillospiraceae, were significantly less abundant, while Verrucomicrobia, particularly, the family Akkermansiaceae, were increasingly more prevalent during peak infection in mice challenged with a high virus dose. In contrast to the cecal microbiome, the lung microbiome showed similar microbial diversity among the control, low-, and high-dose challenge virus groups, independent of antiviral treatment. Bacterial phyla in the lungs such as Bacteroidetes decreased, while Firmicutes and Proteobacteria were significantly enriched in mice challenged with a high dose of SARS-CoV-2. In summary, we identified changes in the cecal and lung microbiomes of K18-hACE2 mice with severe clinical signs of SARS-CoV-2 infection. IMPORTANCE The COVID-19 pandemic has resulted in millions of deaths. The host's respiratory and intestinal microbiome can affect directly or indirectly the immune system during viral infections. We characterized the cecal and lung microbiomes in a relevant mouse model challenged with a low or high dose of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the presence or absence of an antiviral Mpro inhibitor, GC-376. Decreased microbial diversity and taxonomic abundances of the phyla Firmicutes, particularly, Lachnospiraceae, correlating with infection dosage were observed in the cecum. In addition, microbes within the family Akkermansiaceae were increasingly more prevalent during peak infection, which is observed in other viral infections. The lung microbiome showed similar microbial diversity to that of the control, independent of antiviral treatment. Decreased Bacteroidetes and increased Firmicutes and Proteobacteria were observed in the lungs in a virus dose-dependent manner. These studies add to a better understanding of the complexities associated with the intestinal microbiome during respiratory infections.


Assuntos
COVID-19/imunologia , COVID-19/microbiologia , Microbioma Gastrointestinal/fisiologia , SARS-CoV-2 , Enzima de Conversão de Angiotensina 2 , Animais , Antivirais , Biodiversidade , Modelos Animais de Doenças , Feminino , Pulmão/imunologia , Melfalan , Camundongos , Camundongos Transgênicos , Viroses/imunologia , gama-Globulinas
4.
Viruses ; 13(8)2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34452484

RESUMO

Given the impact of pandemics due to viruses of bat origin, there is increasing interest in comparative investigation into the differences between bat and human immune responses. The practice of comparative biology can be enhanced by computational methods used for dynamic knowledge representation to visualize and interrogate the putative differences between the two systems. We present an agent based model that encompasses and bridges differences between bat and human responses to viral infection: the comparative biology immune agent based model, or CBIABM. The CBIABM examines differences in innate immune mechanisms between bats and humans, specifically regarding inflammasome activity and type 1 interferon dynamics, in terms of tolerance to viral infection. Simulation experiments with the CBIABM demonstrate the efficacy of bat-related features in conferring viral tolerance and also suggest a crucial role for endothelial inflammasome activity as a mechanism for bat systemic viral tolerance and affecting the severity of disease in human viral infections. We hope that this initial study will inspire additional comparative modeling projects to link, compare, and contrast immunological functions shared across different species, and in so doing, provide insight and aid in preparation for future viral pandemics of zoonotic origin.


Assuntos
Quirópteros/imunologia , Imunidade Inata , Viroses/imunologia , Viroses/veterinária , Animais , Quirópteros/virologia , Simulação por Computador , Endotélio/fisiologia , Humanos , Inflamassomos/imunologia , Inflamassomos/metabolismo , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Índice de Gravidade de Doença , Estresse Fisiológico , Zoonoses Virais , Viroses/virologia , Fenômenos Fisiológicos Virais , Eliminação de Partículas Virais
5.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360810

RESUMO

Dendritic cells (DCs) are cells derived from the hematopoietic stem cells (HSCs) of the bone marrow and form a widely distributed cellular system throughout the body. They are the most efficient, potent, and professional antigen-presenting cells (APCs) of the immune system, inducing and dispersing a primary immune response by the activation of naïve T-cells, and playing an important role in the induction and maintenance of immune tolerance under homeostatic conditions. Thus, this review has elucidated the general aspects of DCs as well as the current dynamic perspectives and distribution of DCs in humans and in various species of animals that includes mouse, rat, birds, dog, cat, horse, cattle, sheep, pig, and non-human primates. Besides the role that DCs play in immune response, they also play a pathogenic role in many diseases, thus becoming a target in disease prevention and treatment. In addition, its roles in clinical immunology have also been addressed, which include its involvement in transplantation, autoimmune disease, viral infections, cancer, and as a vaccine target. Therefore, based on the current knowledge and understanding of the important roles they play, DCs can be used in the future as a powerful tool for manipulating the immune system.


Assuntos
Células Dendríticas/imunologia , Animais , Doenças Autoimunes/imunologia , Células Dendríticas/citologia , Humanos , Neoplasias/imunologia , Viroses/imunologia
6.
Front Immunol ; 12: 690976, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335596

RESUMO

Different emerging viral infections may emerge in different regions of the world and pose a global pandemic threat with high fatality. Clarification of the immunopathogenesis of different emerging viral infections can provide a plan for the crisis management and prevention of emerging infections. This perspective article describes how an emerging viral infection evolves from microbial mutation, zoonotic and/or vector-borne transmission that progresses to a fatal infection due to overt viremia, tissue-specific cytotropic damage or/and immunopathology. We classified immunopathogenesis of common emerging viral infections into 4 categories: 1) deficient immunity with disseminated viremia (e.g., Ebola); 2) pneumocytotropism with/without later hyperinflammation (e.g., COVID-19); 3) augmented immunopathology (e.g., Hanta); and 4) antibody-dependent enhancement of infection with altered immunity (e.g., Dengue). A practical guide to early blocking of viral evasion, limiting viral load and identifying the fatal mechanism of an emerging viral infection is provided to prevent and reduce the transmission, and to do rapid diagnoses followed by the early treatment of virus neutralization for reduction of morbidity and mortality of an emerging viral infection such as COVID-19.


Assuntos
COVID-19/imunologia , Doenças Transmissíveis Emergentes/imunologia , Evasão da Resposta Imune/imunologia , SARS-CoV-2/fisiologia , Viroses/imunologia , Animais , Anticorpos Facilitadores , COVID-19/mortalidade , COVID-19/prevenção & controle , Humanos , Pandemias , Análise de Sobrevida , Viroses/mortalidade , Viroses/prevenção & controle
8.
Viruses ; 13(7)2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34372578

RESUMO

Viral infections cause a variety of acute and chronic human diseases, sometimes resulting in small local outbreaks, or in some cases spreading across the globe and leading to global pandemics. Understanding and exploiting virus-host interactions is instrumental for identifying host factors involved in viral replication, developing effective antiviral agents, and mitigating the severity of virus-borne infectious diseases. The diversity of CRISPR systems and CRISPR-based tools enables the specific modulation of innate immune responses and has contributed impressively to the fields of virology and immunology in a very short time. In this review, we describe the most recent advances in the use of CRISPR systems for basic and translational studies of virus-host interactions.


Assuntos
Antivirais/imunologia , Antivirais/farmacologia , Sistemas CRISPR-Cas , Viroses/imunologia , Animais , Exorribonucleases/metabolismo , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Evasão da Resposta Imune , Imunidade Inata , Interferons/genética , Interferons/imunologia , Edição de RNA , Transcriptoma , Viroses/virologia , Internalização do Vírus , Replicação Viral/efeitos dos fármacos
9.
Front Immunol ; 12: 621440, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248930

RESUMO

The risk of severe outcomes following respiratory tract infections is significantly increased in individuals over 60 years, especially in those with chronic medical conditions, i.e., hypertension, diabetes, cardiovascular disease, dementia, chronic respiratory disease, and cancer. Down Syndrome (DS), the most prevalent intellectual disability, is caused by trisomy-21 in ~1:750 live births worldwide. Over the past few decades, a substantial body of evidence has accumulated, pointing at the occurrence of alterations, impairments, and subsequently dysfunction of the various components of the immune system in individuals with DS. This associates with increased vulnerability to respiratory tract infections in this population, such as the influenza virus, respiratory syncytial virus, SARS-CoV-2 (COVID-19), and bacterial pneumonias. To emphasize this link, here we comprehensively review the immunobiology of DS and its contribution to higher susceptibility to severe illness and mortality from respiratory tract infections.


Assuntos
Síndrome de Down/imunologia , Sistema Imunitário/fisiologia , Orthomyxoviridae/fisiologia , Vírus Sinciciais Respiratórios/fisiologia , Infecções Respiratórias/imunologia , SARS-CoV-2/fisiologia , Viroses/imunologia , Adulto , Animais , COVID-19 , Síndrome de Down/genética , Síndrome de Down/mortalidade , Humanos , Pneumonia , Infecções Respiratórias/genética , Infecções Respiratórias/mortalidade , Risco , Viroses/genética , Viroses/mortalidade
10.
Int J Mol Sci ; 22(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203268

RESUMO

Viral-associated respiratory infectious diseases are one of the most prominent subsets of respiratory failures, known as viral respiratory infections (VRI). VRIs are proceeded by an infection caused by viruses infecting the respiratory system. For the past 100 years, viral associated respiratory epidemics have been the most common cause of infectious disease worldwide. Due to several drawbacks of the current anti-viral treatments, such as drug resistance generation and non-targeting of viral proteins, the development of novel nanotherapeutic or nano-vaccine strategies can be considered essential. Due to their specific physical and biological properties, nanoparticles hold promising opportunities for both anti-viral treatments and vaccines against viral infections. Besides the specific physiological properties of the respiratory system, there is a significant demand for utilizing nano-designs in the production of vaccines or antiviral agents for airway-localized administration. SARS-CoV-2, as an immediate example of respiratory viruses, is an enveloped, positive-sense, single-stranded RNA virus belonging to the coronaviridae family. COVID-19 can lead to acute respiratory distress syndrome, similarly to other members of the coronaviridae. Hence, reviewing the current and past emerging nanotechnology-based medications on similar respiratory viral diseases can identify pathways towards generating novel SARS-CoV-2 nanotherapeutics and/or nano-vaccines.


Assuntos
Antivirais/química , Portadores de Fármacos/química , Nanomedicina , Infecções Respiratórias/patologia , Vacinas Virais/química , Viroses/patologia , Antivirais/uso terapêutico , COVID-19/imunologia , COVID-19/patologia , COVID-19/terapia , COVID-19/virologia , Humanos , Sistema Imunitário/metabolismo , Infecções Respiratórias/terapia , Infecções Respiratórias/virologia , SARS-CoV-2/isolamento & purificação , Vacinas Virais/administração & dosagem , Vacinas Virais/imunologia , Viroses/imunologia , Viroses/prevenção & controle , Viroses/terapia
11.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209586

RESUMO

Amyloid beta (Aß)-induced abnormal neuroinflammation is recognized as a major pathological feature of Alzheimer's disease (AD), which results in memory impairment. Research exploring low-grade systemic inflammation and its impact on the development and progression of neurodegenerative disease has increased. A particular research focus has been whether systemic inflammation arises only as a secondary effect of disease, or it is also a cause of pathology. The inflammasomes, and more specifically the NLRP3 inflammasome, are crucial components of the innate immune system and are usually activated in response to infection or tissue damage. Although inflammasome activation plays critical roles against various pathogens in host defense, overactivation of inflammasome contributes to the pathogenesis of inflammatory diseases, including acute central nervous system (CNS) injuries and chronic neurodegenerative diseases, such as AD. This review summarizes the current literature on the role of the NLRP3 inflammasome in the pathogenesis of AD, and its involvement in infections, particularly SARS-CoV-2. NLRP3 might represent the crossroad between the hypothesized neurodegeneration and the primary COVID-19 infection.


Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Doença de Alzheimer/metabolismo , Animais , Coronavirus/patogenicidade , Humanos , Imunidade Inata , Microglia/metabolismo , Viroses/imunologia , Viroses/patologia
12.
Viruses ; 13(6)2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207696

RESUMO

Mammalian cells have developed an elaborate network of immunoproteins that serve to identify and combat viral pathogens. Interferon-stimulated gene 15 (ISG15) is a 15.2 kDa tandem ubiquitin-like protein (UBL) that is used by specific E1-E2-E3 ubiquitin cascade enzymes to interfere with the activity of viral proteins. Recent biochemical studies have demonstrated how the E3 ligase HECT and RCC1-containing protein 5 (HERC5) regulates ISG15 signaling in response to hepatitis C (HCV), influenza-A (IAV), human immunodeficiency virus (HIV), SARS-CoV-2 and other viral infections. Taken together, the potent antiviral activity displayed by HERC5 and ISG15 make them promising drug targets for the development of novel antiviral therapeutics that can augment the host antiviral response. In this review, we examine the emerging role of ISG15 in antiviral immunity with a particular focus on how HERC5 orchestrates the specific and timely ISGylation of viral proteins in response to infection.


Assuntos
Citocinas/genética , Interferons/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Ubiquitinas/genética , Viroses/imunologia , Animais , COVID-19/imunologia , Citocinas/imunologia , Células HeLa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Camundongos , SARS-CoV-2/imunologia , Ubiquitinas/imunologia , Proteínas Virais/genética , Proteínas Virais/metabolismo
13.
Nat Commun ; 12(1): 4303, 2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34262037

RESUMO

Lipid droplets (LDs) are increasingly recognized as critical organelles in signalling events, transient protein sequestration and inter-organelle interactions. However, the role LDs play in antiviral innate immune pathways remains unknown. Here we demonstrate that induction of LDs occurs as early as 2 h post-viral infection, is transient and returns to basal levels by 72 h. This phenomenon occurs following viral infections, both in vitro and in vivo. Virally driven in vitro LD induction is type-I interferon (IFN) independent, and dependent on Epidermal Growth Factor Receptor (EGFR) engagement, offering an alternate mechanism of LD induction in comparison to our traditional understanding of their biogenesis. Additionally, LD induction corresponds with enhanced cellular type-I and -III IFN production in infected cells, with enhanced LD accumulation decreasing viral replication of both Herpes Simplex virus 1 (HSV-1) and Zika virus (ZIKV). Here, we demonstrate, that LDs play vital roles in facilitating the magnitude of the early antiviral immune response specifically through the enhanced modulation of IFN following viral infection, and control of viral replication. By identifying LDs as a critical signalling organelle, this data represents a paradigm shift in our understanding of the molecular mechanisms which coordinate an effective antiviral response.


Assuntos
Interferons/imunologia , Gotículas Lipídicas/imunologia , Viroses/imunologia , Animais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Herpesvirus Humano 1/fisiologia , Humanos , Imunidade Inata , Interferons/genética , Interferons/metabolismo , Gotículas Lipídicas/metabolismo , Camundongos , Ácidos Nucleicos/metabolismo , Replicação Viral/efeitos dos fármacos , Zika virus/fisiologia
14.
Proc Natl Acad Sci U S A ; 118(27)2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34183391

RESUMO

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


Assuntos
Armadilhas Extracelulares/imunologia , Imunoglobulina A/imunologia , Neutrófilos/imunologia , Viroses/imunologia , Complexo Antígeno-Anticorpo/imunologia , Antígenos CD/metabolismo , Armadilhas Extracelulares/virologia , Humanos , Influenzavirus A/imunologia , NADPH Oxidases/metabolismo , Neutrófilos/patologia , Neutrófilos/virologia , Receptores Fc/metabolismo , SARS-CoV-2/imunologia , Transdução de Sinais , Vírion
15.
Genes Immun ; 22(3): 141-160, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34140652

RESUMO

When surveying the current literature on COVID-19, the "cytokine storm" is considered to be pathogenetically involved in its severe outcomes such as acute respiratory distress syndrome, systemic inflammatory response syndrome, and eventually multiple organ failure. In this review, the similar role of DAMPs is addressed, that is, of those molecules, which operate upstream of the inflammatory pathway by activating those cells, which ultimately release the cytokines. Given the still limited reports on their role in COVID-19, the emerging topic is extended to respiratory viral infections with focus on influenza. At first, a brief introduction is given on the function of various classes of activating DAMPs and counterbalancing suppressing DAMPs (SAMPs) in initiating controlled inflammation-promoting and inflammation-resolving defense responses upon infectious and sterile insults. It is stressed that the excessive emission of DAMPs upon severe injury uncovers their fateful property in triggering dysregulated life-threatening hyperinflammatory responses. Such a scenario may happen when the viral load is too high, for example, in the respiratory tract, "forcing" many virus-infected host cells to decide to commit "suicidal" regulated cell death (e.g., necroptosis, pyroptosis) associated with release of large amounts of DAMPs: an important topic of this review. Ironically, although the aim of this "suicidal" cell death is to save and restore organismal homeostasis, the intrinsic release of excessive amounts of DAMPs leads to those dysregulated hyperinflammatory responses-as typically involved in the pathogenesis of acute respiratory distress syndrome and systemic inflammatory response syndrome in respiratory viral infections. Consequently, as briefly outlined in this review, these molecules can be considered valuable diagnostic and prognostic biomarkers to monitor and evaluate the course of the viral disorder, in particular, to grasp the eventual transition precociously from a controlled defense response as observed in mild/moderate cases to a dysregulated life-threatening hyperinflammatory response as seen, for example, in severe/fatal COVID-19. Moreover, the pathogenetic involvement of these molecules qualifies them as relevant future therapeutic targets to prevent severe/ fatal outcomes. Finally, a theory is presented proposing that the superimposition of coronavirus-induced DAMPs with non-virus-induced DAMPs from other origins such as air pollution or high age may contribute to severe and fatal courses of coronavirus pneumonia.


Assuntos
Alarminas/imunologia , COVID-19/imunologia , Síndrome da Liberação de Citocina/imunologia , Síndrome do Desconforto Respiratório/imunologia , SARS-CoV-2/imunologia , Viroses/imunologia , Alarminas/metabolismo , COVID-19/metabolismo , COVID-19/virologia , Síndrome da Liberação de Citocina/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Modelos Imunológicos , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/metabolismo , SARS-CoV-2/fisiologia , Viroses/complicações , Viroses/metabolismo
16.
Commun Biol ; 4(1): 820, 2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34188173

RESUMO

Host lipid metabolism and viral responses are intimately connected. However, the process by which the acquired immune systems adapts lipid metabolism to meet demands, and whether or not the metabolic rewiring confers a selective advantage to host immunity, remains unclear. Here we show that viral infection attenuates the expression of genes related to lipid metabolism in murine CD4+ T cells, which in turn increases the expression of antiviral genes. Inhibition of the fatty acid synthesis pathway substantially increases the basal expression of antiviral genes via the spontaneous production of type I interferon (IFN). Using a combination of CRISPR/Cas9-mediated genome editing technology and a global lipidomics analysis, we found that the decrease in monounsaturated fatty acid caused by genetic deletion of Scd2 in mice was crucial for the induction of an antiviral response through activation of the cGAS-STING pathway. These findings demonstrate the important relationship between fatty acid biosynthesis and type I IFN responses that enhances the antiviral response.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Ácidos Graxos Monoinsaturados/metabolismo , Interferon Tipo I/farmacologia , Proteínas de Membrana/fisiologia , Nucleotidiltransferases/fisiologia , Estearoil-CoA Dessaturase/fisiologia , Viroses/imunologia , Animais , Interações Hospedeiro-Patógeno , Metabolismo dos Lipídeos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Transdução de Sinais , Viroses/metabolismo
18.
Viruses ; 13(6)2021 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072720

RESUMO

Identification of therapeutics against emerging and re-emerging viruses remains a continued priority that is only reinforced by the recent SARS-CoV-2 pandemic. Advances in monoclonal antibody (mAb) isolation, characterization, and production make it a viable option for rapid treatment development. While mAbs are traditionally screened and selected based on potency of neutralization in vitro, it is clear that additional factors contribute to the in vivo efficacy of a mAb beyond viral neutralization. These factors include interactions with Fc receptors (FcRs) and complement that can enhance neutralization, clearance of infected cells, opsonization of virions, and modulation of the innate and adaptive immune response. In this review, we discuss recent studies, primarily using mouse models, that identified a role for Fc-FcγR interactions for optimal antibody-based protection against emerging and re-emerging virus infections.


Assuntos
Doenças Transmissíveis Emergentes/imunologia , Fragmentos Fc das Imunoglobulinas/imunologia , Receptores de IgG/imunologia , Viroses/imunologia , Vírus/imunologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/uso terapêutico , Citotoxicidade Celular Dependente de Anticorpos , Doenças Transmissíveis Emergentes/terapia , Doenças Transmissíveis Emergentes/virologia , Humanos , Imunização Passiva , Fagocitose , Viroses/terapia , Viroses/virologia , Vírus/classificação
19.
J Biol Chem ; 297(1): 100856, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34097873

RESUMO

The nuclear pore complex is the sole gateway connecting the nucleoplasm and cytoplasm. In humans, the nuclear pore complex is one of the largest multiprotein assemblies in the cell, with a molecular mass of ∼110 MDa and consisting of 8 to 64 copies of about 34 different nuclear pore proteins, termed nucleoporins, for a total of 1000 subunits per pore. Trafficking events across the nuclear pore are mediated by nuclear transport receptors and are highly regulated. The nuclear pore complex is also used by several RNA viruses and almost all DNA viruses to access the host cell nucleoplasm for replication. Viruses hijack the nuclear pore complex, and nuclear transport receptors, to access the nucleoplasm where they replicate. In addition, the nuclear pore complex is used by the cell innate immune system, a network of signal transduction pathways that coordinates the first response to foreign invaders, including viruses and other pathogens. Several branches of this response depend on dynamic signaling events that involve the nuclear translocation of downstream signal transducers. Mounting evidence has shown that these signaling cascades, especially those steps that involve nucleocytoplasmic trafficking events, are targeted by viruses so that they can evade the innate immune system. This review summarizes how nuclear pore proteins and nuclear transport receptors contribute to the innate immune response and highlights how viruses manipulate this cellular machinery to favor infection. A comprehensive understanding of nuclear pore proteins in antiviral innate immunity will likely contribute to the development of new antiviral therapeutic strategies.


Assuntos
Imunidade Inata/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Poro Nuclear/genética , Viroses/genética , Transporte Ativo do Núcleo Celular/genética , Transporte Ativo do Núcleo Celular/imunologia , Vírus de DNA/genética , Vírus de DNA/patogenicidade , Humanos , Evasão da Resposta Imune/genética , Evasão da Resposta Imune/imunologia , NF-kappa B/genética , Poro Nuclear/imunologia , Complexo de Proteínas Formadoras de Poros Nucleares/imunologia , Vírus de RNA/genética , Vírus de RNA/patogenicidade , Proteínas não Estruturais Virais/genética , Viroses/imunologia , Viroses/virologia , Replicação Viral/genética , Replicação Viral/imunologia
20.
Fish Shellfish Immunol ; 116: 30-41, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34147615

RESUMO

Beclin-1, the ortholog of yeast autophagy-related gene 6 (Atg6), has a central role in autophagy, which has been linked to diverse biological processes including immunity, development, tumor suppression, and lifespan extension. However, understanding of function of fish Beclin-1 is limited now. In this study, the complete Beclin-1 cDNA of large yellow croaker Larimichthys crocea (LcBeclin-1) was cloned, whose open reading frame (ORF) is 1344 bp long and encodes a protein of 447 amino acids (aa). The deduced LcBeclin-1 possesses a typical Bcl-2 homology domain 3(BH3) and an APG6 domain that contains a central coiled-coil domain (CCD, residues 174 to 231) and a C-terminal evolutionarily conserved domain (ECD, residues 241 to 334). LcBeclin-1 shared a high amino acid identity of 81.66-98.66% with reported Beclin-1 molecules from other vertebrate species. LcBeclin-1 gene was constitutively expressed in all tissues tested, with the highest levels in heart. LcBeclin-1 transcripts were also detected in primary head kidney granulocytes (PKGs), primary head kidney macrophages (PKMs), primary head kidney leukocytes (PKLs), and large yellow croaker head kidney cell line (LYCK), and were significantly upregulated by poly (I:C) in PKMs and LYCK cells. Subcellular localization showed that LcBeclin-1 was evenly distributed in the cytoplasm and nucleus of LYCK cells. Overexpression of LcBeclin-1 significantly increased the replication of SVCV, as evidenced by increased severity of the cytopathic effects, enhanced viral titre, and upregulated transcriptional levels of viral genes. Further studies showed that LcBeclin-1 induced the occurrence of autophagy in LYCK cells. Additionally, LcBeclin-1 also decreased the expression levels of large yellow croaker interferons (IFNs; IFNc, IFNd, and IFNh), interferon regulatory factor 3 (IRF3) and IRF7, IFN-stimulated genes (ISGs; Mx, PKR, and Viperin) in LYCK cells. All these data suggest that LcBeclin-1 promoted the viral replication possibly by inducing autophagy or negatively modulating IFN response, which will help us to further understand the function of fish Beclin-1.


Assuntos
Proteína Beclina-1/genética , Proteína Beclina-1/imunologia , Doenças dos Peixes/imunologia , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Perciformes/genética , Perciformes/imunologia , Viroses/imunologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Rim Cefálico/citologia , Rim Cefálico/imunologia , Leucócitos/imunologia , Macrófagos/imunologia
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