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1.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360873

RESUMO

Staphylococcus aureus is a commensal bacterium that causes severe infections in soft tissue and the bloodstream. During infection, S. aureus manipulates host cell response to facilitate its own replication and dissemination. Here, we show that S. aureus significantly decreases the level of SUMOylation, an essential post-translational modification, in infected macrophages 24 h post-phagocytosis. The reduced level of SUMOylation correlates with a decrease in the SUMO-conjugating enzyme Ubc9. The over-expression of SUMO proteins in macrophages impaired bacterial intracellular proliferation and the inhibition of SUMOylation with ML-792 increased it. Together, these findings demonstrated for the first time the role of host SUMOylation response toward S. aureus infection.


Assuntos
Interações entre Hospedeiro e Microrganismos/imunologia , Macrófagos/imunologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/imunologia , Animais , Macrófagos/citologia , Camundongos , Células RAW 264.7 , Sumoilação , Enzimas de Conjugação de Ubiquitina/imunologia
2.
Front Immunol ; 12: 700184, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34408749

RESUMO

Coronavirus disease 2019 (COVID-19), which has high incidence rates with rapid rate of transmission, is a pandemic that spread across the world, resulting in more than 3,000,000 deaths globally. Currently, several drugs have been used for the clinical treatment of COVID-19, such as antivirals (radecivir, baritinib), monoclonal antibodies (tocilizumab), and glucocorticoids (dexamethasone). Accumulating evidence indicates that long noncoding RNAs (lncRNAs) are essential regulators of virus infections and antiviral immune responses including biological processes that are involved in the regulation of COVID-19 and subsequent disease states. Upon viral infections, cellular lncRNAs directly regulate viral genes and influence viral replication and pathology through virus-mediated changes in the host transcriptome. Additionally, several host lncRNAs could help the occurrence of viral immune escape by inhibiting type I interferons (IFN-1), while others could up-regulate IFN-1 production to play an antiviral role. Consequently, understanding the expression and function of lncRNAs during severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection will provide insights into the development of lncRNA-based methods. In this review, we summarized the current findings of lncRNAs in the regulation of the strong inflammatory response, immune dysfunction and thrombosis induced by SARS-CoV-2 infection, discussed the underlying mechanisms, and highlighted the therapeutic challenges of COVID-19 treatment and its future research directions.


Assuntos
COVID-19/imunologia , Interações entre Hospedeiro e Microrganismos/genética , Imunidade Inata/genética , RNA Longo não Codificante/metabolismo , Trombose/imunologia , Antivirais/farmacologia , Antivirais/uso terapêutico , Biomarcadores/análise , COVID-19/complicações , COVID-19/tratamento farmacológico , COVID-19/genética , Teste para COVID-19/métodos , Citocinas/genética , Citocinas/metabolismo , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Regulação Viral da Expressão Gênica/imunologia , Interações entre Hospedeiro e Microrganismos/efeitos dos fármacos , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Evasão da Resposta Imune/genética , Pandemias/prevenção & controle , RNA Longo não Codificante/análise , RNA Longo não Codificante/antagonistas & inibidores , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/genética , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Trombose/genética , Trombose/virologia , Replicação Viral/efeitos dos fármacos , Replicação Viral/genética , Replicação Viral/imunologia
3.
Hist Philos Life Sci ; 43(3): 99, 2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34370107

RESUMO

Both concepts of the holobiont and the immune system are at the heart of an ongoing scientific and philosophical examination concerning questions of the organism's individuality and identity as well as the relations between organisms and their environment. Examining the holobiont, the question of boundaries and individuality is challenging because it is both an assemblage of organisms with physiological cohesive aspects. I discuss the concept of immunity and the immune system function from the holobiont perspective. Because of the host-microbial close relations of codependence and interdependence, the holobiont is more often than not confused with the host, as the host is the domain in which this entity exists. I discuss the holobiont unique ecological characteristics of microbial assemblages connected to a host in a network of interactions in which the host is one of the organisms in the community but also its landscape. Therefore, I suggest viewing the holobiont as a host-ecosystem and discuss the implication of such a view on the concept of immunity and the meaning of protection. Furthermore, I show that viewing the holobiont as a host ecosystem opens the possibility of using the same ecological definition of boundaries and immunity dealing with an ecological system. Thus, the holobiont's boundaries and immunity are defined by the persistence of its complex system of interactions integrating existing and new interactions. This way of thinking presents a notion of immunity that materializes as the result of the complex interdependence relations between the different organisms composing the holobiont similar to that of an ecosystem. Taking this view further, I discuss the notion of immunogenicity that is ontologically heterogeneous with various causal explanations of the processes of tolerance and targeted immune response. Finally, I discuss the possible conceptualization of already existing and new biomedical practices.


Assuntos
Interações entre Hospedeiro e Microrganismos/fisiologia , Sistema Imunitário/fisiologia , Imunidade/fisiologia , Interações entre Hospedeiro e Microrganismos/imunologia
4.
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
5.
Int J Mol Sci ; 22(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34281276

RESUMO

Extracellular vesicles (EVs) are membranous, rounded vesicles released by prokaryotic and eukaryotic cells in their normal and pathophysiological states. These vesicles form a network of intercellular communication as they can transfer cell- and function-specific information (lipids, proteins and nucleic acids) to different cells and thus alter their function. Fungi are not an exception; they also release EVs to the extracellular space. The vesicles can also be retained in the periplasm as periplasmic vesicles (PVs) and the cell wall. Such fungal vesicles play various specific roles in the lives of these organisms. They are involved in creating wall architecture and maintaining its integrity, supporting cell isolation and defence against the environment. In the case of pathogenic strains, they might take part in the interactions with the host and affect the infection outcomes. The economic importance of fungi in manufacturing high-quality nutritional and pharmaceutical products and in remediation is considerable. The analysis of fungal EVs opens new horizons for diagnosing fungal infections and developing vaccines against mycoses and novel applications of nanotherapy and sensors in industrial processes.


Assuntos
Vesículas Extracelulares/fisiologia , Fungos/fisiologia , Transporte Biológico Ativo , Vesículas Extracelulares/genética , Vesículas Extracelulares/imunologia , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Fungos/genética , Fungos/patogenicidade , Genes Fúngicos , Interações entre Hospedeiro e Microrganismos/imunologia , Interações entre Hospedeiro e Microrganismos/fisiologia , Humanos , Modelos Biológicos , Micoses/diagnóstico , Micoses/microbiologia , RNA Fúngico/genética , RNA Fúngico/metabolismo
6.
Nat Commun ; 12(1): 4427, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285233

RESUMO

The membrane-associated RING-CH (MARCH) proteins are E3 ligases that regulate the stability of various cellular membrane proteins. MARCH8 has been reported to inhibit the infection of HIV-1 and a few other viruses, thus plays an important role in host antiviral defense. However, the antiviral spectrum and the underlying mechanisms of MARCH8 are incompletely defined. Here, we demonstrate that MARCH8 profoundly inhibits influenza A virus (IAV) replication both in vitro and in mice. Mechanistically, MARCH8 suppresses IAV release through redirecting viral M2 protein from the plasma membrane to lysosomes for degradation. Specifically, MARCH8 catalyzes the K63-linked polyubiquitination of M2 at lysine residue 78 (K78). A recombinant A/Puerto Rico/8/34 virus carrying the K78R M2 protein shows greater replication and more severe pathogenicity in cells and mice. More importantly, we found that the M2 protein of the H1N1 IAV has evolved to acquire non-lysine amino acids at positions 78/79 to resist MARCH8-mediated ubiquitination and degradation. Together, our data support the important role of MARCH8 in host anti-IAV intrinsic immune defense by targeting M2, and suggest the inhibitory pressure of MARCH8 on H1N1 IAV transmission in the human population.


Assuntos
Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana/imunologia , Ubiquitina-Proteína Ligases/metabolismo , Proteínas da Matriz Viral/metabolismo , Células A549 , Sequência de Aminoácidos , Animais , Modelos Animais de Doenças , Cães , Técnicas de Silenciamento de Genes , Células HEK293 , Células HeLa , Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/metabolismo , Vírus da Influenza A Subtipo H1N1/patogenicidade , Influenza Humana/virologia , Lisina/genética , Lisina/metabolismo , Lisossomos/metabolismo , Lisossomos/virologia , Células Madin Darby de Rim Canino , Masculino , Camundongos , Ubiquitina-Proteína Ligases/genética , Ubiquitinação/genética , Ubiquitinação/imunologia , Proteínas da Matriz Viral/genética , Replicação Viral
7.
Cell Host Microbe ; 29(7): 1043-1047, 2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34265243

RESUMO

Severe COVID-19 arises from the convergence of inadequate pre-existing immunity and a host response that damages, rather than repairs, tissues. We outline clinical presentations of COVID-19 that are likely driven by dysregulated host immunity, discuss potential mechanisms underlying pathological responses, and highlight important areas for basic research on this topic.


Assuntos
COVID-19/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Inflamação/imunologia , COVID-19/patologia , Humanos , Imunidade , Hospedeiro Imunocomprometido , SARS-CoV-2/imunologia
8.
Front Immunol ; 12: 666991, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34276657

RESUMO

The HIV-1 viral inhibition assay (VIA) measures CD8 T cell-mediated inhibition of HIV replication in CD4 T cells and is increasingly used for clinical testing of HIV vaccines and immunotherapies. The VIA has multiple sources of variability arising from in vitro HIV infection and co-culture of two T cell populations. Here, we describe multiple modifications to a 7-day VIA protocol, the most impactful being the introduction of independent replicate cultures for both HIV infected-CD4 (HIV-CD4) and HIV-CD4:CD8 T cell cultures. Virus inhibition was quantified using a ratio of weighted averages of p24+ cells in replicate cultures and the corresponding 95% confidence interval. An Excel template is provided to facilitate calculations. Virus inhibition was higher in people living with HIV suppressed on antiretroviral therapy (n=14, mean: 40.0%, median: 43.8%, range: 8.2 to 73.3%; p < 0.0001, two-tailed, exact Mann-Whitney test) compared to HIV-seronegative donors (n = 21, mean: -13.7%, median: -14.4%, range: -49.9 to 20.9%) and was stable over time (n = 6, mean %COV 9.4%, range 0.9 to 17.3%). Cross-sectional data were used to define 8% inhibition as the threshold to confidently detect specific CD8 T cell activity and determine the minimum number of culture replicates and p24+ cells needed to have 90% statistical power to detect this threshold. Last, we note that, in HIV seronegative donors, the addition of CD8 T cells to HIV infected CD4 T cells consistently increased HIV replication, though the level of increase varied markedly between donors. This co-culture effect may contribute to the weak correlations observed between CD8 T cell VIA and other measures of HIV-specific CD8 T cell function.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Soropositividade para HIV/imunologia , HIV-1/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Replicação Viral/imunologia , Antivirais/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Estudos de Casos e Controles , Células Cultivadas , Técnicas de Cocultura , Estudos Transversais , Proteína do Núcleo p24 do HIV/imunologia , Soropositividade para HIV/sangue , Soropositividade para HIV/tratamento farmacológico , Soropositividade para HIV/virologia , Humanos , Resultado do Tratamento
9.
Front Immunol ; 12: 658519, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34276652

RESUMO

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a highly pathogenic novel virus that has caused a massive pandemic called coronavirus disease 2019 (COVID-19) worldwide. Wuhan, a city in China became the epicenter of the outbreak of COVID-19 in December 2019. The disease was declared a pandemic globally by the World Health Organization (WHO) on 11 March 2020. SARS-CoV-2 is a beta CoV of the Coronaviridae family which usually causes respiratory symptoms that resemble common cold. Multiple countries have experienced multiple waves of the disease and scientific experts are consistently working to find answers to several unresolved questions, with the aim to find the most suitable ways to contain the virus. Furthermore, potential therapeutic strategies and vaccine development for COVID-19 management are also considered. Currently, substantial efforts have been made to develop successful and safe treatments and SARS-CoV-2 vaccines. Some vaccines, such as inactivated vaccines, nucleic acid-based, and vector-based vaccines, have entered phase 3 clinical trials. Additionally, diverse small molecule drugs, peptides and antibodies are being developed to treat COVID-19. We present here an overview of the virus interaction with the host and environment and anti-CoV therapeutic strategies; including vaccines and other methodologies, designed for prophylaxis and treatment of SARS-CoV-2 infection with the hope that this integrative analysis could help develop novel therapeutic approaches against COVID-19.


Assuntos
Vacinas contra COVID-19/uso terapêutico , COVID-19/epidemiologia , COVID-19/prevenção & controle , Pandemias/prevenção & controle , SARS-CoV-2/imunologia , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/uso terapêutico , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/imunologia , Vacinas contra COVID-19/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Imunidade , Taxa de Mutação , SARS-CoV-2/genética , Bibliotecas de Moléculas Pequenas/uso terapêutico , Vacinas de DNA/imunologia , Vacinas de DNA/uso terapêutico , Vacinas de Produtos Inativados/imunologia , Vacinas de Produtos Inativados/uso terapêutico
10.
Front Immunol ; 12: 690416, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34276680

RESUMO

The AID (activation-induced cytidine deaminase)/APOBEC (apolipoprotein B mRNA editing enzyme catalytic subunit) family with its multifaceted mode of action emerges as potent intrinsic host antiviral system that acts against a variety of DNA and RNA viruses including coronaviruses. All family members are cytosine-to-uracil deaminases that either have a profound role in driving a strong and specific humoral immune response (AID) or restricting the virus itself by a plethora of mechanisms (APOBECs). In this article, we highlight some of the key aspects apparently linking the AID/APOBECs and SARS-CoV-2. Among those is our discovery that APOBEC4 shows high expression in cell types and anatomical parts targeted by SARS-CoV-2. Additional focus is given by us to the lymphoid structures and AID as the master regulator of germinal center reactions, which result in antibody production by plasma and memory B cells. We propose the dissection of the AID/APOBECs gene signature towards decisive determinants of the patient-specific and/or the patient group-specific antiviral response. Finally, the patient-specific mapping of the AID/APOBEC polymorphisms should be considered in the light of COVID-19.


Assuntos
Desaminase APOBEC-1/genética , COVID-19/enzimologia , COVID-19/imunologia , Citidina Desaminase/genética , SARS-CoV-2/genética , Transcriptoma , Anticorpos Antivirais/imunologia , Linfócitos B/imunologia , COVID-19/virologia , Centro Germinativo/imunologia , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Imunidade Humoral/genética , Plasmócitos/imunologia , Polimorfismo Genético , Edição de RNA/genética , RNA Viral/genética
11.
Viruses ; 13(6)2021 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-34198852

RESUMO

Epithelial characteristics underlying the differential susceptibility of chronic asthma to SARS-CoV-2 (COVID-19) and other viral infections are currently unclear. By revisiting transcriptomic data from patients with Th2 low versus Th2 high asthma, as well as mild, moderate, and severe asthmatics, we characterized the changes in expression of human coronavirus and influenza viral entry genes relative to sex, airway location, and disease endotype. We found sexual dimorphism in the expression of SARS-CoV-2-related genes ACE2, TMPRSS2, TMPRSS4, and SLC6A19. ACE2 receptor downregulation occurred specifically in females in Th2 high asthma, while proteases broadly assisting coronavirus and influenza viral entry, TMPRSS2, and TMPRSS4, were highly upregulated in both sexes. Overall, changes in SARS-CoV-2-related gene expression were specific to the Th2 high molecular endotype of asthma and different by asthma severity and airway location. The downregulation of ACE2 (COVID-19, SARS) and ANPEP (HCoV-229E) viral receptors wascorrelated with loss of club and ciliated cells in Th2 high asthma. Meanwhile, the increase in DPP4 (MERS-CoV), ST3GAL4, and ST6GAL1 (influenza) was associated with increased goblet and basal activated cells. Overall, this study elucidates sex, airway location, disease endotype, and changes in epithelial heterogeneity as potential factors underlying asthmatic susceptibility, or lack thereof, to SARS-CoV-2.


Assuntos
Asma/imunologia , COVID-19/imunologia , Infecções por Coronavirus/imunologia , Células Epiteliais/virologia , Expressão Gênica , Interações entre Hospedeiro e Microrganismos , Influenza Humana/imunologia , Índice de Gravidade de Doença , Asma/genética , Asma/virologia , COVID-19/genética , Coronavirus Humano 229E/genética , Coronavirus Humano 229E/imunologia , Infecções por Coronavirus/genética , Células Epiteliais/classificação , Feminino , Perfilação da Expressão Gênica , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Influenza Humana/genética , Masculino , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Orthomyxoviridae/genética , Orthomyxoviridae/imunologia , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Caracteres Sexuais
12.
PLoS Pathog ; 17(7): e1009753, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34260666

RESUMO

To understand the diversity of immune responses to SARS-CoV-2 and distinguish features that predispose individuals to severe COVID-19, we developed a mechanistic, within-host mathematical model and virtual patient cohort. Our results suggest that virtual patients with low production rates of infected cell derived IFN subsequently experienced highly inflammatory disease phenotypes, compared to those with early and robust IFN responses. In these in silico patients, the maximum concentration of IL-6 was also a major predictor of CD8+ T cell depletion. Our analyses predicted that individuals with severe COVID-19 also have accelerated monocyte-to-macrophage differentiation mediated by increased IL-6 and reduced type I IFN signalling. Together, these findings suggest biomarkers driving the development of severe COVID-19 and support early interventions aimed at reducing inflammation.


Assuntos
COVID-19/imunologia , Modelos Imunológicos , SARS-CoV-2 , Biomarcadores/metabolismo , Linfócitos T CD8-Positivos/imunologia , COVID-19/virologia , Estudos de Coortes , Biologia Computacional , Simulação por Computador , Suscetibilidade a Doenças/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Imunidade Inata , Imunossupressão , Interferons/metabolismo , Interleucina-6/metabolismo , Macrófagos/imunologia , Pandemias , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Interface Usuário-Computador
13.
PLoS Pathog ; 17(7): e1009761, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34270631

RESUMO

T-cell immunity is likely to play a role in protection against SARS-CoV-2 by helping generate neutralizing antibodies. We longitudinally studied CD4 T-cell responses to the M, N, and S structural proteins of SARS-CoV-2 in 26 convalescent individuals. Within the first two months following symptom onset, a majority of individuals (81%) mounted at least one CD4 T-cell response, and 48% of individuals mounted detectable SARS-CoV-2-specific circulating T follicular helper cells (cTfh, defined as CXCR5+PD1+ CD4 T cells). SARS-CoV-2-specific cTfh responses across all three protein specificities correlated with antibody neutralization with the strongest correlation observed for S protein-specific responses. When examined over time, cTfh responses, particularly to the M protein, increased in convalescence, and robust cTfh responses with magnitudes greater than 5% were detected at the second convalescent visit, a median of 38 days post-symptom onset. CD4 T-cell responses declined but persisted at low magnitudes three months and six months after symptom onset. These data deepen our understanding of antigen-specific cTfh responses in SARS-CoV-2 infection, suggesting that in addition to S protein, M and N protein-specific cTfh may also assist in the development of neutralizing antibodies and that cTfh response formation may be delayed in SARS-CoV-2 infection.


Assuntos
Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , COVID-19/imunologia , COVID-19/virologia , SARS-CoV-2/imunologia , Células T Auxiliares Foliculares/imunologia , Células T Auxiliares Foliculares/virologia , Adulto , Idoso , Especificidade de Anticorpos , Estudos de Casos e Controles , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , Feminino , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Pandemias , Fosfoproteínas/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Fatores de Tempo , Proteínas da Matriz Viral/imunologia , Adulto Jovem
14.
Commun Biol ; 4(1): 663, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-34079066

RESUMO

The reciprocal interactions between pathogens and hosts are complicated and profound. A comprehensive understanding of these interactions is essential for developing effective therapies against infectious diseases. Interferon responses induced upon virus infection are critical for establishing host antiviral innate immunity. Here, we provide a molecular mechanism wherein isoform switching of the host IKKε gene, an interferon-associated molecule, leads to alterations in IFN production during EV71 infection. We found that IKKε isoform 2 (IKKε v2) is upregulated while IKKε v1 is downregulated in EV71 infection. IKKε v2 interacts with IRF7 and promotes IRF7 activation through phosphorylation and translocation of IRF7 in the presence of ubiquitin, by which the expression of IFNß and ISGs is elicited and virus propagation is attenuated. We also identified that IKKε v2 is activated via K63-linked ubiquitination. Our results suggest that host cells induce IKKε isoform switching and result in IFN production against EV71 infection. This finding highlights a gene regulatory mechanism in pathogen-host interactions and provides a potential strategy for establishing host first-line defense against pathogens.


Assuntos
Enterovirus Humano A/imunologia , Enterovirus Humano A/patogenicidade , Quinase I-kappa B/genética , Quinase I-kappa B/imunologia , Processamento Alternativo , Linhagem Celular , Genes de Troca , Células HEK293 , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Quinase I-kappa B/metabolismo , Imunidade Inata/genética , Fator Regulador 7 de Interferon/metabolismo , Interferon beta/biossíntese , Isoenzimas/genética , Isoenzimas/imunologia , Fosforilação , Ubiquitina/metabolismo
15.
Cells ; 10(6)2021 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-34070971

RESUMO

The recent SARS-CoV-2 pandemic has refocused attention to the betacoronaviruses, only eight years after the emergence of another zoonotic betacoronavirus, the Middle East respiratory syndrome coronavirus (MERS-CoV). While the wild source of SARS-CoV-2 may be disputed, for MERS-CoV, dromedaries are considered as source of zoonotic human infections. Testing 100 immune-response genes in 121 dromedaries from United Arab Emirates (UAE) for potential association with present MERS-CoV infection, we identified candidate genes with important functions in the adaptive, MHC-class I (HLA-A-24-like) and II (HLA-DPB1-like), and innate immune response (PTPN4, MAGOHB), and in cilia coating the respiratory tract (DNAH7). Some of these genes previously have been associated with viral replication in SARS-CoV-1/-2 in humans, others have an important role in the movement of bronchial cilia. These results suggest similar host genetic pathways associated with these betacoronaviruses, although further work is required to better understand the MERS-CoV disease dynamics in both dromedaries and humans.


Assuntos
Imunidade Adaptativa/genética , Camelus/virologia , Doenças Transmissíveis Emergentes/imunologia , Infecções por Coronavirus/imunologia , Imunidade Inata/genética , Zoonoses/imunologia , Animais , Anticorpos Antivirais , Brônquios/citologia , Brônquios/fisiologia , COVID-19/genética , COVID-19/imunologia , COVID-19/virologia , Camelus/genética , Camelus/imunologia , Cílios/fisiologia , Doenças Transmissíveis Emergentes/genética , Doenças Transmissíveis Emergentes/transmissão , Doenças Transmissíveis Emergentes/virologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Reservatórios de Doenças/virologia , Feminino , Predisposição Genética para Doença , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Masculino , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Coronavírus da Síndrome Respiratória do Oriente Médio/isolamento & purificação , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Mucosa Respiratória/citologia , Mucosa Respiratória/fisiologia , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Emirados Árabes Unidos , Replicação Viral/genética , Replicação Viral/imunologia , Zoonoses/genética , Zoonoses/transmissão , Zoonoses/virologia
16.
Cell Mol Life Sci ; 78(15): 5667-5679, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34152447

RESUMO

Gamma-aminobutyric acid (GABA) is best known as an essential neurotransmitter in the evolved central nervous system (CNS) of vertebrates. However, GABA antedates the development of the CNS as a bioactive molecule in metabolism and stress-coupled responses of prokaryotes, invertebrates and plants. Here, we focus on the emerging findings of GABA signaling in the mammalian immune system. Recent reports show that mononuclear phagocytes and lymphocytes, for instance dendritic cells, microglia, T cells and NK cells, express a GABAergic signaling machinery. Mounting evidence shows that GABA receptor signaling impacts central immune functions, such as cell migration, cytokine secretion, immune cell activation and cytotoxic responses. Furthermore, the GABAergic signaling machinery of leukocytes is implicated in responses to microbial infection and is co-opted by protozoan parasites for colonization of the host. Peripheral GABA signaling is also implicated in inflammatory conditions and diseases, such as type 1 diabetes, rheumatoid arthritis and cancer cell metastasis. Adding to its role in neurotransmission, growing evidence shows that the non-proteinogenic amino acid GABA acts as an intercellular signaling molecule in the immune system and, as an interspecies signaling molecule in host-microbe interactions. Altogether, the data raise the assumption of conserved GABA signaling in a broad range of mammalian cells and diversification of function in the immune system.


Assuntos
Sistema Imunitário/imunologia , Transdução de Sinais/imunologia , Ácido gama-Aminobutírico/imunologia , Animais , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Inflamação/imunologia , Transmissão Sináptica/imunologia
18.
Int J Mol Sci ; 22(9)2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33946994

RESUMO

The gastrointestinal lumen is a rich source of eukaryotic and prokaryotic viruses which, together with bacteria, fungi and other microorganisms comprise the gut microbiota. Pathogenic viruses inhabiting this niche have the potential to induce local as well as systemic complications; among them, the viral ability to disrupt the mucosal barrier is one mechanism associated with the promotion of diarrhea and tissue invasion. This review gathers recent evidence showing the contributing effects of diet, gut microbiota and the enteric nervous system to either support or impair the mucosal barrier in the context of viral attack.


Assuntos
Bacteriófagos/fisiologia , Dieta , Sistema Nervoso Entérico/fisiologia , Mucosa Gástrica/virologia , Microbioma Gastrointestinal , Interações entre Hospedeiro e Microrganismos/fisiologia , Mucosa Intestinal/virologia , Vírus , Defensinas/fisiologia , Digestão , Suscetibilidade a Doenças , Sistema Nervoso Entérico/virologia , Alimentos/virologia , Mucosa Gástrica/imunologia , Mucosa Gástrica/inervação , Mucosa Gástrica/metabolismo , Gastroenterite/virologia , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Mucosa Intestinal/imunologia , Mucosa Intestinal/inervação , Mucosa Intestinal/metabolismo , Desnutrição/virologia , Muco/metabolismo , Muco/virologia , Neurônios/virologia , Infecções Oportunistas/virologia , Vírus de Plantas , Viroses/microbiologia , Viroses/fisiopatologia
19.
Bull Math Biol ; 83(7): 79, 2021 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-34037874

RESUMO

The pandemic outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has quickly spread worldwide, creating a serious health crisis. The virus is primarily associated with flu-like symptoms but can also lead to severe pathologies and death. We here present an ordinary differential equation model of the intrahost immune response to SARS-CoV-2 infection, fitted to experimental data gleaned from rhesus macaques. The model is calibrated to data from a nonlethal infection, but the model can replicate behavior from various lethal scenarios as well. We evaluate the sensitivity of the model to biologically relevant parameters governing the strength and efficacy of the immune response. We also simulate the effect of both anti-inflammatory and antiviral drugs on the host immune response and demonstrate the ability of the model to lessen the severity of a formerly lethal infection with the addition of the appropriately calibrated drug. Our model emphasizes the importance of tight control of the innate immune response for host survival and viral clearance.


Assuntos
COVID-19/imunologia , Imunidade Inata , Macaca mulatta/imunologia , Modelos Imunológicos , SARS-CoV-2 , Imunidade Adaptativa , Envelhecimento/imunologia , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Antivirais/administração & dosagem , Antivirais/farmacologia , COVID-19/tratamento farmacológico , COVID-19/epidemiologia , Simulação por Computador , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Interações entre Hospedeiro e Microrganismos/efeitos dos fármacos , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Conceitos Matemáticos , Pandemias , Sistema Respiratório/imunologia , Sistema Respiratório/virologia , SARS-CoV-2/imunologia , Carga Viral/imunologia
20.
PLoS Pathog ; 17(4): e1009552, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33901257

RESUMO

Host genetic variation plays an important role in the structure and function of heritable microbial communities. Recent studies have shown that insects use immune mechanisms to regulate heritable symbionts. Here we test the hypothesis that variation in symbiont density among hosts is linked to intraspecific differences in the immune response to harboring symbionts. We show that pea aphids (Acyrthosiphon pisum) harboring the bacterial endosymbiont Regiella insecticola (but not all other species of symbionts) downregulate expression of key immune genes. We then functionally link immune expression with symbiont density using RNAi. The pea aphid species complex is comprised of multiple reproductively-isolated host plant-adapted populations. These 'biotypes' have distinct patterns of symbiont infections: for example, aphids from the Trifolium biotype are strongly associated with Regiella. Using RNAseq, we compare patterns of gene expression in response to Regiella in aphid genotypes from multiple biotypes, and we show that Trifolium aphids experience no downregulation of immune gene expression while hosting Regiella and harbor symbionts at lower densities. Using F1 hybrids between two biotypes, we find that symbiont density and immune gene expression are both intermediate in hybrids. We propose that in this system, Regiella symbionts are suppressing aphid immune mechanisms to increase their density, but that some hosts have adapted to prevent immune suppression in order to control symbiont numbers. This work therefore suggests that antagonistic coevolution can play a role in host-microbe interactions even when symbionts are transmitted vertically and provide a clear benefit to their hosts. The specific immune mechanisms that we find are downregulated in the presence of Regiella have been previously shown to combat pathogens in aphids, and thus this work also highlights the immune system's complex dual role in interacting with both beneficial and harmful microbes.


Assuntos
Afídeos/microbiologia , Carga Bacteriana/genética , Enterobacteriaceae/imunologia , Imunidade Inata/genética , Simbiose , Animais , Afídeos/classificação , Afídeos/genética , Afídeos/imunologia , Carga Bacteriana/fisiologia , Enterobacteriaceae/classificação , Enterobacteriaceae/citologia , Enterobacteriaceae/genética , Expressão Gênica , Regulação Bacteriana da Expressão Gênica , Genes de Insetos/genética , Variação Genética/fisiologia , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/imunologia , Especificidade da Espécie , Simbiose/genética , Simbiose/imunologia
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