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1.
Nat Commun ; 12(1): 5841, 2021 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-34615883

RESUMO

Phenotypic definition of helper ILC1 and NK cells is problematic due to overlapping markers. Recently we showed the identification of cytotoxic ILC3s characterized by expression of CD94. Here we analyse CD127+ ILCs and NK cells in intestinal lamina propria from healthy donors and Crohn's disease patients and identify two populations of CD127+CD94+ ILCs, designated population A and B, that can be distinguished on the expression of CD117, CD18 and cytotoxic molecules. Population B expresses granulysin, a cytotoxic molecule linked to bacterial lysis and/or chemotaxis of monocytes. Granulysin protein is secreted by population B cells upon stimulation with IL-15. Activation of population B in the presence of TGF-ß strongly reduces the expression of cytotoxic effector molecules of population B. Strikingly, samples from individuals that suffer from active Crohn's disease display enhanced frequencies of granulysin-expressing effector CD127+CD94+ ILCs in comparison to controls. Thus this study identifies group 1 ILC populations which accumulate in inflamed intestinal tissue of Crohn's disease patients and may play a role in the pathology of the disease.


Assuntos
Antígenos de Diferenciação de Linfócitos T/metabolismo , Doença de Crohn/imunologia , Doença de Crohn/metabolismo , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Linfócitos/metabolismo , Subfamília D de Receptores Semelhantes a Lectina de Células NK/metabolismo , Perforina/metabolismo , Antígenos de Diferenciação de Linfócitos T/genética , Células Cultivadas , Doença de Crohn/genética , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Imunidade Inata/genética , Imunidade Inata/fisiologia , Inflamação/imunologia , Inflamação/metabolismo , Linfócitos/imunologia , Perforina/genética , Reação em Cadeia da Polimerase em Tempo Real
3.
Nat Cell Biol ; 23(7): 718-732, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34239064

RESUMO

Patients with Coronavirus disease 2019 exhibit low expression of interferon-stimulated genes, contributing to a limited antiviral response. Uncovering the underlying mechanism of innate immune suppression and rescuing the innate antiviral response remain urgent issues in the current pandemic. Here we identified that the dimerization domain of the SARS-CoV-2 nucleocapsid protein (SARS2-NP) is required for SARS2-NP to undergo liquid-liquid phase separation with RNA, which inhibits Lys63-linked poly-ubiquitination and aggregation of MAVS and thereby suppresses the innate antiviral immune response. Mice infected with an RNA virus carrying SARS2-NP exhibited reduced innate immunity, an increased viral load and high morbidity. Notably, we identified SARS2-NP acetylation at Lys375 by host acetyltransferase and reported frequently occurring acetylation-mimicking mutations of Lys375, all of which impaired SARS2-NP liquid-liquid phase separation with RNA. Importantly, a peptide targeting the dimerization domain was screened out to disrupt the SARS2-NP liquid-liquid phase separation and demonstrated to inhibit SARS-CoV-2 replication and rescue innate antiviral immunity both in vitro and in vivo.


Assuntos
Proteínas do Nucleocapsídeo/imunologia , Proteínas do Nucleocapsídeo/metabolismo , SARS-CoV-2/genética , Animais , Imunidade Inata/imunologia , Imunidade Inata/fisiologia , Camundongos , Proteínas do Nucleocapsídeo/genética , Vírus de RNA/genética , SARS-CoV-2/fisiologia
4.
Int J Mol Sci ; 22(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203170

RESUMO

Acidovorax avenae is a flagellated, pathogenic bacterium to various plant crops that has also been found in human patients with haematological malignancy, fever, and sepsis; however, the exact mechanism for infection in humans is not known. We hypothesized that the human innate immune system could be responsive to the purified flagellin isolated from A. avenae, named FLA-AA. We observed the secretion of inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and IL-8 by treating FLA-AA to human dermal fibroblasts, as well as macrophages. This response was exclusively through TLR5, which was confirmed by using TLR5-overexpression cell line, 293/hTLR5, as well as TLR5-specific inhibitor, TH1020. We also observed the secretion of inflammatory cytokine, IL-1ß, by the activation of NLRC4 with FLA-AA. Overall, our results provide a molecular basis for the inflammatory response caused by FLA-AA in cell-based assays.


Assuntos
Comamonadaceae/química , Flagelina/farmacologia , Imunidade Inata/fisiologia , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Imunidade Inata/genética , Interleucina-18/metabolismo , Interleucina-6/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
5.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201509

RESUMO

The innate immune system relies on families of pattern recognition receptors (PRRs) that detect distinct conserved molecular motifs from microbes to initiate antimicrobial responses. Activation of PRRs triggers a series of signaling cascades, leading to the release of pro-inflammatory cytokines, chemokines and antimicrobials, thereby contributing to the early host defense against microbes and regulating adaptive immunity. Additionally, PRRs can detect perturbation of cellular homeostasis caused by pathogens and fine-tune the immune responses. Among PRRs, nucleotide binding oligomerization domain (NOD)-like receptors (NLRs) have attracted particular interest in the context of cellular stress-induced inflammation during infection. Recently, mechanistic insights into the monitoring of cellular homeostasis perturbation by NLRs have been provided. We summarize the current knowledge about the disruption of cellular homeostasis by pathogens and focus on NLRs as innate immune sensors for its detection. We highlight the mechanisms employed by various pathogens to elicit cytoskeleton disruption, organelle stress as well as protein translation block, point out exemplary NLRs that guard cellular homeostasis during infection and introduce the concept of stress-associated molecular patterns (SAMPs). We postulate that integration of information about microbial patterns, danger signals, and SAMPs enables the innate immune system with adequate plasticity and precision in elaborating responses to microbes of variable virulence.


Assuntos
Interações Hospedeiro-Patógeno/fisiologia , Imunidade Inata/fisiologia , Infecções/metabolismo , Receptores de Reconhecimento de Padrão/fisiologia , Animais , Citoesqueleto/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Homeostase , Humanos , Inflamassomos/fisiologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína Adaptadora de Sinalização NOD1/metabolismo , Proteína Adaptadora de Sinalização NOD2/metabolismo , Biossíntese de Proteínas , Receptores de Reconhecimento de Padrão/química
6.
Cells ; 10(6)2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208037

RESUMO

Neutrophils are the most abundant circulating innate immune cells and comprise the first immune defense line, as they are the most rapidly recruited cells at sites of infection or inflammation. Their main microbicidal mechanisms are degranulation, phagocytosis, cytokine secretion and the formation of extracellular traps. Neutrophil extracellular traps (NETs) are a microbicidal mechanism that involves neutrophil death. Since their discovery, in vitro and in vivo neutrophils have been challenged with a range of stimuli capable of inducing or inhibiting NET formation, with the objective to understand its function and regulation in health and disease. These networks composed of DNA and granular components are capable of immobilizing and killing pathogens. They comprise enzymes such as myeloperoxidase, elastase, cathepsin G, acid hydrolases and cationic peptides, all with antimicrobial and antifungal activity. Therefore, the excessive formation of NETs can also lead to tissue damage and promote local and systemic inflammation. Based on this concept, in this review, we focus on the role of NETs in different infectious and inflammatory diseases of the mucosal epithelia and skin.


Assuntos
Armadilhas Extracelulares/fisiologia , Membrana Mucosa/imunologia , Dermatopatias/imunologia , Células Epiteliais/imunologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata/fisiologia , Neutrófilos/imunologia , Neutrófilos/fisiologia , Dermatopatias/patologia
7.
J Exp Med ; 218(8)2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34128960

RESUMO

Initial replication of SARS-CoV-2 in the upper respiratory tract is required to establish infection, and the replication level correlates with the likelihood of viral transmission. Here, we examined the role of host innate immune defenses in restricting early SARS-CoV-2 infection using transcriptomics and biomarker-based tracking in serial patient nasopharyngeal samples and experiments with airway epithelial organoids. SARS-CoV-2 initially replicated exponentially, with a doubling time of ∼6 h, and induced interferon-stimulated genes (ISGs) in the upper respiratory tract, which rose with viral replication and peaked just as viral load began to decline. Rhinovirus infection before SARS-CoV-2 exposure accelerated ISG responses and prevented SARS-CoV-2 replication. Conversely, blocking ISG induction during SARS-CoV-2 infection enhanced viral replication from a low infectious dose. These results show that the activity of ISG-mediated defenses at the time of SARS-CoV-2 exposure impacts infection progression and that the heterologous antiviral response induced by a different virus can protect against SARS-CoV-2.


Assuntos
COVID-19/imunologia , COVID-19/virologia , Imunidade Inata/fisiologia , Nasofaringe/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Enzima de Conversão de Angiotensina 2/genética , Estudos de Casos e Controles , Quimiocina CXCL10/metabolismo , Suscetibilidade a Doenças/imunologia , Feminino , Perfilação da Expressão Gênica , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Interferons/genética , Interferons/imunologia , Interferons/metabolismo , Masculino , Pessoa de Meia-Idade , Infecções por Picornaviridae/imunologia , Infecções por Picornaviridae/virologia , SARS-CoV-2/genética , SARS-CoV-2/fisiologia , Carga Viral , Replicação Viral
8.
J Exp Med ; 218(8)2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34128959

RESUMO

Our understanding of protective versus pathological immune responses to SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), is limited by inadequate profiling of patients at the extremes of the disease severity spectrum. Here, we performed multi-omic single-cell immune profiling of 64 COVID-19 patients across the full range of disease severity, from outpatients with mild disease to fatal cases. Our transcriptomic, epigenomic, and proteomic analyses revealed widespread dysfunction of peripheral innate immunity in severe and fatal COVID-19, including prominent hyperactivation signatures in neutrophils and NK cells. We also identified chromatin accessibility changes at NF-κB binding sites within cytokine gene loci as a potential mechanism for the striking lack of pro-inflammatory cytokine production observed in monocytes in severe and fatal COVID-19. We further demonstrated that emergency myelopoiesis is a prominent feature of fatal COVID-19. Collectively, our results reveal disease severity-associated immune phenotypes in COVID-19 and identify pathogenesis-associated pathways that are potential targets for therapeutic intervention.


Assuntos
COVID-19/sangue , COVID-19/imunologia , Imunidade Inata/fisiologia , Adulto , Idoso , COVID-19/genética , COVID-19/mortalidade , Estudos de Casos e Controles , Citocinas/genética , Epigênese Genética , Feminino , Hematopoese , Humanos , Células Matadoras Naturais/patologia , Células Matadoras Naturais/virologia , Masculino , Pessoa de Meia-Idade , Monócitos/patologia , Monócitos/virologia , NF-kappa B/metabolismo , Neutrófilos/patologia , Neutrófilos/virologia , Proteômica , Índice de Gravidade de Doença , Análise de Célula Única
9.
Mol Cell ; 81(15): 3171-3186.e8, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34171297

RESUMO

Accurate control of innate immune responses is required to eliminate invading pathogens and simultaneously avoid autoinflammation and autoimmune diseases. Here, we demonstrate that arginine monomethylation precisely regulates the mitochondrial antiviral-signaling protein (MAVS)-mediated antiviral response. Protein arginine methyltransferase 7 (PRMT7) forms aggregates to catalyze MAVS monomethylation at arginine residue 52 (R52), attenuating its binding to TRIM31 and RIG-I, which leads to the suppression of MAVS aggregation and subsequent activation. Upon virus infection, aggregated PRMT7 is disabled in a timely manner due to automethylation at arginine residue 32 (R32), and SMURF1 is recruited to PRMT7 by MAVS to induce proteasomal degradation of PRMT7, resulting in the relief of PRMT7 suppression of MAVS activation. Therefore, we not only reveal that arginine monomethylation by PRMT7 negatively regulates MAVS-mediated antiviral signaling in vitro and in vivo but also uncover a mechanism by which PRMT7 is tightly controlled to ensure the timely activation of antiviral defense.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Arginina/metabolismo , Interações Hospedeiro-Patógeno/fisiologia , Imunidade Inata/fisiologia , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Animais , Proteína DEAD-box 58/metabolismo , Fibroblastos/virologia , Células HEK293 , Herpes Simples/imunologia , Herpes Simples/metabolismo , Herpes Simples/virologia , Humanos , Metilação , Camundongos , Camundongos Knockout , Alcamidas Poli-Insaturadas , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/imunologia , Receptores Imunológicos/metabolismo , Infecções por Respirovirus/imunologia , Infecções por Respirovirus/metabolismo , Infecções por Respirovirus/virologia , Proteínas com Motivo Tripartido/genética , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
10.
Plant Cell ; 33(3): 750-765, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33955491

RESUMO

Systemic acquired resistance (SAR) is a mechanism that plants utilize to connect a local pathogen infection to global defense responses. N-hydroxy-pipecolic acid (NHP) and a glycosylated derivative are produced during SAR, yet their individual roles in this process are currently unclear. Here, we report that Arabidopsis thaliana UGT76B1 generated glycosylated NHP (NHP-Glc) in vitro and when transiently expressed alongside Arabidopsis NHP biosynthetic genes in two Solanaceous plants. During infection, Arabidopsis ugt76b1 mutants did not accumulate NHP-Glc and accumulated less glycosylated salicylic acid (SA-Glc) than wild-type plants. The metabolic changes in ugt76b1 plants were accompanied by enhanced defense to the bacterial pathogen Pseudomonas syringae, suggesting that glycosylation of the SAR molecules NHP and salicylic acid by UGT76B1 plays an important role in modulating defense responses. Transient expression of Arabidopsis UGT76B1 with the Arabidopsis NHP biosynthesis genes ALD1 and FMO1 in tomato (Solanum lycopersicum) increased NHP-Glc production and reduced NHP accumulation in local tissue and abolished the systemic resistance seen when expressing NHP-biosynthetic genes alone. These findings reveal that the glycosylation of NHP by UGT76B1 alters defense priming in systemic tissue and provide further evidence for the role of the NHP aglycone as the active metabolite in SAR signaling.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Arabidopsis/microbiologia , Ácidos Pipecólicos/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Regulação da Expressão Gênica de Plantas , Imunidade Inata/fisiologia , Lycopersicon esculentum/genética , Lycopersicon esculentum/metabolismo , Lycopersicon esculentum/microbiologia , Doenças das Plantas/microbiologia , Imunidade Vegetal/fisiologia , Pseudomonas syringae/patogenicidade
11.
Metabolism ; 121: 154795, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33971203

RESUMO

AIMS: Patients with diabetes have a higher incidence of infections with Candida albicans, Staphylococcus aureus and Mycobacterium tuberculosis, yet factors contributing to this increased risk are largely unknown. We hypothesize that altered innate and adaptive immune responses during diabetes contribute to an increased susceptibility to infections. MATERIALS AND METHODS: We studied cytokine responses to ex vivo pathogenic stimulations in a cohort with type 1 diabetes (n = 243) and non-diabetic healthy control subjects (n = 56) using isolated peripheral blood mononuclear cells (PBMCs). Clinical phenotypical data including BMI, duration of diabetes, and HbA1c levels were collected and related to the cytokine production capacity. RESULTS: Adjusted for age, sex and BMI, the presence of diabetes was associated with significantly lower IL-1ß, IL-6, TNF-α, and IL-17 production upon ex vivo stimulation of PBMCs with C. albicans and S. aureus (all, p < 0.05). In response to stimulation with M. tuberculosis only IL-17 (p < 0.001) was lower in patients with diabetes. Patients with the shortest diabetes duration had a significant lower IL-1ß, IL-6 and TNF-α production (all, p < 0.01) after M. tuberculosis stimulation. Older patients had a significant lower IFN-γ (p < 0.05) production after stimulation with all three pathogens. HbA1c levels and BMI had no significant impact on cytokine production. CONCLUSIONS: PBMCs of patients with type 1 diabetes demonstrate significantly lower cytokine production in response to stimulation with several pathogens, which likely explain, at least in part, the increased susceptibility for these infections.


Assuntos
Diabetes Mellitus Tipo 1/imunologia , Infecções/etiologia , Imunidade Adaptativa/fisiologia , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos de Coortes , Citocinas/metabolismo , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Controle Glicêmico/estatística & dados numéricos , Humanos , Imunidade Inata/fisiologia , Lactente , Recém-Nascido , Infecções/epidemiologia , Infecções/imunologia , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Fatores de Risco , Adulto Jovem
12.
Invest Ophthalmol Vis Sci ; 62(6): 10, 2021 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-33970198

RESUMO

Purpose: Interleukin (IL)-36 cytokines have been shown to play either beneficial or detrimental roles in the infection of mucosal tissues in a pathogen-dependent manner, but their involvement in fungal keratitis remains elusive. We herein investigated their expression and function in mediating corneal innate immunity against Candida albicans infection. Methods: Gene expression in mouse corneas with or without C. albicans infection was determined by regular RT- and real-time (q)-PCR, Western blot analysis, ELISA or proteome profile assay. The severity of C. albicans keratitis was assessed using clinical scoring, bacterial counting, and myeloperoxidase (MPO) activity as an indicator of neutrophil infiltration. IL36R knockout mice and IL-33-specific siRNA were used to assess the involvement IL-33 signaling in C. albicans-infected corneas. B6 CD11c-DTR mice and clodronate liposomes were used to define the involvement of dendritic cells (DCs) and macrophages in IL-36R signaling and C. albicans keratitis, respectively. Results: IL-36γ were up-regulated in C57BL6 mouse corneas in response to C. albicans infection. IL-36 receptor-deficient mice display increased severity of keratitis, with a higher fungal load, MPO, and IL-1ß levels, and lower soluble sIL-1Ra and calprotectin levels. Exogenous IL-36γ prevented fungal keratitis pathogenesis with lower fungal load and MPO activity, higher expression of sIL-1Ra and calprotectin, and lower expression of IL-1ß, at mRNA or protein levels. Protein array analysis revealed that the expression of IL-33 and REG3G were related to IL-36/IL36R signaling, and siRNA downregulation of IL-33 increased the severity of C. albicans keratitis. Depletion of dendritic cells or macrophages resulted in severe C. albicans keratitis and yet exhibited minimal effects on exogenous IL-36γ-induced protection against C. albicans infection in B6 mouse corneas. Conclusions: IL-36/IL36R signaling plays a protective role in fungal keratitis by promoting AMP expression and by suppressing fungal infection-induced expression of proinflammatory cytokines in a dendritic cell- and macrophage-independent manner.


Assuntos
Úlcera da Córnea/prevenção & controle , Infecções Oculares Fúngicas/prevenção & controle , Imunidade Inata/fisiologia , Interleucina-1/fisiologia , Ceratite/prevenção & controle , Receptores de Interleucina-1/fisiologia , Transdução de Sinais/fisiologia , Animais , Western Blotting , Candida albicans , Úlcera da Córnea/imunologia , Úlcera da Córnea/microbiologia , Células Dendríticas/imunologia , Ensaio de Imunoadsorção Enzimática , Infecções Oculares Fúngicas/imunologia , Infecções Oculares Fúngicas/microbiologia , Regulação da Expressão Gênica/fisiologia , Ceratite/imunologia , Ceratite/microbiologia , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real
13.
Cell Transplant ; 30: 9636897211010632, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33949207

RESUMO

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) first emerged in December 2019 in Wuhan, China, and has since spread rapidly worldwide. As researchers seek to learn more about COVID-19, the disease it causes, this novel virus continues to infect and kill. Despite the socioeconomic impacts of SARS-CoV-2 infections and likelihood of future outbreaks of other pathogenic coronaviruses, options to prevent or treat coronavirus infections remain limited. In current clinical trials, potential coronavirus treatments focusing on killing the virus or on preventing infection using vaccines largely ignore the host immune response. The relatively small body of current research on the virus indicates pathological responses by the immune system as the leading cause for much of the morbidity and mortality caused by COVID-19. In this review, we investigated the host innate and adaptive immune responses against COVID-19, collated information on recent COVID-19 experimental data, and summarized the systemic immune responses to and histopathology of SARS-CoV-2 infection. Finally, we summarized the immune-related biomarkers to define patients with high-risk and worst-case outcomes, and identified the possible usefulness of inflammatory markers as potential immunotherapeutic targets. This review provides an overview of current knowledge on COVID-19 and the symptomatological differences between healthy, convalescent, and severe cohorts, while offering research directions for alternative immunoregulation therapeutic targets.


Assuntos
Imunidade Adaptativa/fisiologia , Imunidade Inata/fisiologia , SARS-CoV-2/imunologia , Biomarcadores , Humanos
14.
Nat Commun ; 12(1): 2735, 2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-33980849

RESUMO

Inflammasomes are filamentous signaling platforms integral to innate immunity. Currently, little is known about how these structurally similar filaments recognize and distinguish one another. A cryo-EM structure of the AIM2PYD filament reveals that the architecture of the upstream filament is essentially identical to that of the adaptor ASCPYD filament. In silico simulations using Rosetta and molecular dynamics followed by biochemical and cellular experiments consistently demonstrate that individual filaments assemble bidirectionally. By contrast, the recognition between AIM2 and ASC requires at least one to be oligomeric and occurs in a head-to-tail manner. Using in silico mutagenesis as a guide, we also identify specific axial and lateral interfaces that dictate the recognition and distinction between AIM2 and ASC filaments. Together, the results here provide a robust framework for delineating the signaling specificity and order of inflammasomes.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/metabolismo , Proteínas de Ligação a DNA/metabolismo , Imunidade Inata/fisiologia , Inflamassomos/metabolismo , Proteínas Adaptadoras de Sinalização CARD/genética , Microscopia Crioeletrônica , Proteínas de Ligação a DNA/genética , Células HEK293 , Humanos , Simulação de Dinâmica Molecular , Mutação/genética , Estrutura Secundária de Proteína , Transdução de Sinais/fisiologia
15.
PLoS Pathog ; 17(5): e1009229, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34029358

RESUMO

While MERS-CoV (Middle East respiratory syndrome Coronavirus) provokes a lethal disease in humans, camelids, the main virus reservoir, are asymptomatic carriers, suggesting a crucial role for innate immune responses in controlling the infection. Experimentally infected camelids clear infectious virus within one week and mount an effective adaptive immune response. Here, transcription of immune response genes was monitored in the respiratory tract of MERS-CoV infected alpacas. Concomitant to the peak of infection, occurring at 2 days post inoculation (dpi), type I and III interferons (IFNs) were maximally transcribed only in the nasal mucosa of alpacas, while interferon stimulated genes (ISGs) were induced along the whole respiratory tract. Simultaneous to mild focal infiltration of leukocytes in nasal mucosa and submucosa, upregulation of the anti-inflammatory cytokine IL10 and dampened transcription of pro-inflammatory genes under NF-κB control were observed. In the lung, early (1 dpi) transcription of chemokines (CCL2 and CCL3) correlated with a transient accumulation of mainly mononuclear leukocytes. A tight regulation of IFNs in lungs with expression of ISGs and controlled inflammatory responses, might contribute to virus clearance without causing tissue damage. Thus, the nasal mucosa, the main target of MERS-CoV in camelids, seems central in driving an efficient innate immune response based on triggering ISGs as well as the dual anti-inflammatory effects of type III IFNs and IL10.


Assuntos
Camelídeos Americanos , Infecções por Coronavirus/imunologia , Interferon Tipo I/metabolismo , Interferons/metabolismo , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Animais , Antivirais/metabolismo , Antivirais/farmacologia , Camelídeos Americanos/imunologia , Camelídeos Americanos/metabolismo , Camelídeos Americanos/virologia , Chlorocebus aethiops , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/veterinária , Reservatórios de Doenças/veterinária , Resistência à Doença/efeitos dos fármacos , Resistência à Doença/genética , Resistência à Doença/imunologia , Regulação da Expressão Gênica , Imunidade Inata/fisiologia , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/veterinária , Inflamação/virologia , Interferon Tipo I/genética , Interferon Tipo I/farmacologia , Interferons/genética , Interferons/farmacologia , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Coronavírus da Síndrome Respiratória do Oriente Médio/fisiologia , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/imunologia , Mucosa Nasal/metabolismo , Mucosa Nasal/virologia , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/imunologia , Sistema Respiratório/metabolismo , Sistema Respiratório/virologia , Células Vero , Carga Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
16.
ACS Appl Mater Interfaces ; 13(20): 23410-23422, 2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-33978409

RESUMO

Nanomedicine is seen as a potential central player in the delivery of personalized medicine. Biocompatibility issues of nanoparticles have largely been resolved over the past decade. Despite their tremendous progress, less than 1% of applied nanosystems can hit their intended target location, such as a solid tumor, and this remains an obstacle to their full ability and potential with a high translational value. Therefore, achieving immune-tolerable, blood-compatible, and biofriendly nanoparticles remains an unmet need. The translational success of nanoformulations from bench to bedside involves a thorough assessment of their design, compatibility beyond cytotoxicity such as immune toxicity, blood compatibility, and immune-mediated destruction/rejection/clearance profile. Here, we report a one-pot process-engineered synthesis of ultrasmall gold nanoparticles (uGNPs) suitable for better body and renal clearance delivery of their payloads. We have obtained uGNP sizes of as low as 3 nm and have engineered the synthesis to allow them to be accurately sized (almost nanometer by nanometer). The synthesized uGNPs are biocompatible and can easily be functionalized to carry drugs, peptides, antibodies, and other therapeutic molecules. We have performed in vitro cell viability assays, immunotoxicity assays, inflammatory cytokine analysis, a complement activation study, and blood coagulation studies with the uGNPs to confirm their safety. These can help to set up a long-term safety-benefit framework of experimentation to reveal whether any designed nanoparticles are immune-tolerable and can be used as payload carriers for next-generation vaccines, chemotherapeutic drugs, and theranostic agents with better body clearance ability and deep tissue penetration.


Assuntos
Materiais Biocompatíveis , Ouro , Imunidade Inata , Nanopartículas Metálicas , Materiais Biocompatíveis/química , Materiais Biocompatíveis/toxicidade , Coagulação Sanguínea/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ouro/química , Ouro/toxicidade , Humanos , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/fisiologia , Teste de Materiais , Nanopartículas Metálicas/química , Nanopartículas Metálicas/toxicidade , Modelos Imunológicos , Citrato de Sódio , Células THP-1 , Taninos
17.
Fish Shellfish Immunol ; 114: 199-206, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33940173

RESUMO

Co-infection with parasites and bacteria is of frequent occurrence in aquaculture, leads to growth impedance otherwise mortality in fish depending on the varying degree of a load of primary pathogen either parasite or bacteria. The mechanistic regulation of immune response during co-infection in fish has merely documented. The aim of this study was to determine the impact of co-infection with Aeromonas hydrophila at three exposure doses of Argulus sp. on the innate immune responses and antioxidative stress enzymes of goldfish (Carassius auratus). The experimental fish were randomly distributed into eight treatment groups viz. T1 (control group without Argulus and A. hydrophila infection), T2 (fish exposed to a sub-lethal dose of A. hydrophila), T3 (low Argulus-infested fish), T4 (T3 + sub-lethal dose of A. hydrophila), T5 (moderate Argulus-infested fish), T6 (T5 + sub-lethal dose of A. hydrophila), T7 (high Argulus-infested fish) and T8 (T7+ sub-lethal dose of A. hydrophila) in duplicates. After distributing experimental fish into their respective treatment group, A. hydrophila was injected to T2, T4, T6 and T8. After the bacterial challenge, four fish from each experimental group were randomly sampled on 24, 72, and 168 h and subjected to the hematological, innate immune parameters and enzymatic analysis. In the co-infection group T8, a high degree of enhanced pathogenicity of A. hydrophila was noticed with increased mortalities (84.2%) in comparison to other groups. The current study shows a declining pattern in RBC, PCV and Hb values with the degree of parasite infestation without co-infection groups. Moreover, in the T8 group, exposure of a sub-lethal dose of bacteria resulted in a drastic reduction of the recorded parameters. Furthermore, a decreased value for WBC, monocyte and neutrophil was found in higher parasite group co-infected with a sub-lethal dose of bacteria relative to other co-infected groups during the experimental period. Also, a decrease in innate immune parameters and antioxidative stress enzymes were observed in the T8 group compared to T7 and T2 groups throughout the trial period. These findings indicate that a rise in the dose of Argulus infection improves A. hydrophila colonization in goldfish and contributes to suppression of the innate immune system and increased mortality.


Assuntos
Aeromonas hydrophila , Arguloida , Carpa Dourada , Infecções por Bactérias Gram-Negativas/veterinária , Imunidade Inata/fisiologia , Doenças Parasitárias em Animais/parasitologia , Animais , Antioxidantes , Catalase/genética , Catalase/metabolismo , Regulação Enzimológica da Expressão Gênica/imunologia , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Infecções por Bactérias Gram-Negativas/complicações , Infecções por Bactérias Gram-Negativas/imunologia , Doenças Parasitárias em Animais/complicações , Doenças Parasitárias em Animais/imunologia , Estresse Fisiológico , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
18.
Eur J Immunol ; 51(7): 1672-1685, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33837956

RESUMO

UNC93B1 is a trafficking chaperone of endosomal Toll-like receptors (TLRs) and plays an essential role in the TLR-mediated innate signaling. However, whether it is also involved in other innate immune sensing or cellular pathways remains largely unexplored. Here we investigated the role of UNC93B1 in cytosolic DNA-triggered cGAS-STING signaling in mouse and human cell lines. We showed that while UNC93B1 deficiency blunts the signal transduction by TLR3, it augments innate immune responses to cytosolic DNA stimulation and DNA virus infection. Mechanistic study reveals a distinct action of UNC93B1 upon STING, but not other parts along the cGAS-STING-TBK1 axis, through regulating the protein level of STING at both resting and cytosolic DNA-stimulated conditions. UNC93B1 can directly interact and traffic along with STING, and the disruption of this interaction causes accumulation of STING that subsequently leads to augmented signaling responses upon its activation. These findings reveal a new function of UNC93B1 in negatively regulating STING-mediated signaling responses.


Assuntos
Citosol/metabolismo , DNA/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Transdução de Sinais/fisiologia , Animais , Linhagem Celular , Endossomos/metabolismo , Células HEK293 , Humanos , Imunidade Inata/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Células THP-1
19.
Am J Physiol Endocrinol Metab ; 321(1): E24-E46, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33900849

RESUMO

Prematurity is the leading cause of neonatal morbidity and mortality worldwide. Premature infants often require extended hospital stays, with increased risk of developing infection compared with term infants. A picture is emerging of wide-ranging deleterious consequences resulting from innate immune system activation in the newborn infant. Those who survive infection have been exposed to a stimulus that can impose long-lasting alterations into later life. In this review, we discuss sepsis-driven alterations in integrated neuroendocrine and metabolic pathways and highlight current knowledge gaps in respect of neonatal sepsis. We review established biomarkers for sepsis and extend the discussion to examine emerging findings from human and animal models of neonatal sepsis that propose novel biomarkers for early identification of sepsis. Future research in this area is required to establish a greater understanding of the distinct neonatal signature of early and late-stage infection, to improve diagnosis, curtail inappropriate antibiotic use, and promote precision medicine through a biomarker-guided empirical and adjunctive treatment approach for neonatal sepsis. There is an unmet clinical need to decrease sepsis-induced morbidity in neonates, to limit and prevent adverse consequences in later life and decrease mortality.


Assuntos
Sistema Endócrino , Imunidade Inata/fisiologia , Recém-Nascido Prematuro , Redes e Vias Metabólicas , Sepse Neonatal , Animais , Biomarcadores , Gônadas , Humanos , Hidrocortisona/sangue , Sistema Hipotálamo-Hipofisário , Recém-Nascido , Sistemas Neurossecretores , Sepse , Glândula Tireoide
20.
Front Immunol ; 12: 648554, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33897696

RESUMO

Delayed wound healing can cause significant issues for immobile and ageing individuals as well as those living with co-morbid conditions such as diabetes, cardiovascular disease, and cancer. These delays increase a patient's risk for infection and, in severe cases, can result in the formation of chronic, non-healing ulcers (e.g., diabetic foot ulcers, surgical site infections, pressure ulcers and venous leg ulcers). Chronic wounds are very difficult and expensive to treat and there is an urgent need to develop more effective therapeutics that restore healing processes. Sustained innate immune activation and inflammation are common features observed across most chronic wound types. However, the factors driving this activation remain incompletely understood. Emerging evidence suggests that the composition and structure of the wound microbiome may play a central role in driving this dysregulated activation but the cellular and molecular mechanisms underlying these processes require further investigation. In this review, we will discuss the current literature on: 1) how bacterial populations and biofilms contribute to chronic wound formation, 2) the role of bacteria and biofilms in driving dysfunctional innate immune responses in chronic wounds, and 3) therapeutics currently available (or underdevelopment) that target bacteria-innate immune interactions to improve healing. We will also discuss potential issues in studying the complexity of immune-biofilm interactions in chronic wounds and explore future areas of investigation for the field.


Assuntos
Biofilmes/crescimento & desenvolvimento , Pé Diabético/imunologia , Imunidade Inata/imunologia , Microbiota/imunologia , Cicatrização/imunologia , Animais , Bactérias/classificação , Bactérias/crescimento & desenvolvimento , Bactérias/imunologia , Doença Crônica , Pé Diabético/microbiologia , Humanos , Imunidade Inata/fisiologia , Microbiota/fisiologia , Modelos Imunológicos , Cicatrização/fisiologia
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