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1.
Zhonghua Yi Xue Za Zhi ; 102(2): 141-146, 2022 Jan 11.
Artigo em Chinês | MEDLINE | ID: mdl-35012304

RESUMO

Objective: To investigate the change of innate lymphoid cells (ILC) subsets in peripheral blood and ascites in liver cirrhotic patients complicated with spontaneous bacterial peritonitis (SBP). Methods: The data of 62 patients with liver cirrhosis admited to the Zhumadian Central Hospital from November 2019 to November 2020 were analyzed. Among them, 41 cases were complicated with untainted ascites (untainted ascites group), while the other 21 cases were complicated with SBP (SBP group). Meanwhile, 20 cases of controls who received healthy examination in the same period were also enrolled (control group). Peripheral blood mononuclear cell (PBMC) was isolated from peripheral blood of all patients and controls. Mononuclear cell in ascites was isolated from patients with liver cirrhosis. The percentage of ILC1, ILC2, and ILC3 subsets in PBMC and mononuclear cell in ascites were measured by flow cytometry. CD3-CD19-CD20-CD14- cells (lin-cells) were purified from ascites and were stimulated with lipopolysaccharide (LPS) for 24 h. The transcription factor T-bet, GATA3, and RORγt mRNA relative level in lin-cells was semi-quantified by real-time PCR. Cytokine level in the supernatants was measured by enzyme linked immunosorbent assay. Differences of ILC subsets in peripheral blood and ascites were compared among groups. Results: There were twenty-nine males and twelve females in untainted ascites group, aged M(Q1,Q3) 49(33, 78) years. There were twelve males and nine females in SBP group, aged 50(37, 76) years. There were eleven males and nine females in control group, aged 48(32, 69) years. lin-CD45+CD161+CD127+ ILC cells could be detected in both peripheral blood and ascites. There was no significant difference in total ILC percentage within PBMC among untainted ascites group, SBP group, and control group (P=0.235). There was also no significant difference of total ILC percentage within mononuclear cells in ascites between untainted ascites group and SBP group (P=0.232). The differences were not statistically significant of peripheral CD117-CRTh2-ILC1, CRTh2+ILC2, or CD117+CRTh2-ILC3 within peripheral ILC among untainted ascites group, SBP group, and control group (all P>0.05). ILC1 percentage in ascites was up-regulated in SBP group compared with untainted ascites group (35.69%±3.39% vs 26.40%±3.85%, P<0.001), while ILC2 in ascites was down-regulated in SBP group (36.83%±7.70% vs 48.35%±9.45%, P<0.001). There was no statistical difference in ILC3 percentage in ascites between the two groups (P=0.230). T-bet mRNA relative level and IFN-γ production by lin- cells from ascites were elevated in response to LPS stimulation in SBP group compared with untainted ascites group (both P<0.001). GATA3 mRNA relative level and IL-5/IL-13 secretion by lin-cells from ascites were reduced in SBP group compared with untainted ascites group (both P<0.05). There was no significant difference of RORγt mRNA relative level or IL-17/IL-22 expression between the two groups (both P>0.05). Conclusion: Peripheral ILC subsets do not change in liver cirrhosis patients with SBP. ILC1 percentage is up-regulated, and ILC2 percentage is down-regulated in ascites in liver cirrhosis patients with SBP.


Assuntos
Imunidade Inata , Peritonite , Ascite/patologia , Feminino , Humanos , Leucócitos Mononucleares , Cirrose Hepática , Linfócitos/patologia , Masculino , Peritonite/patologia
2.
Int J Biol Sci ; 18(1): 386-408, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34975340

RESUMO

Responding to the coronavirus disease 2019 (COVID-19) pandemic has been an unexpected and unprecedented global challenge for humanity in this century. During this crisis, specialists from the laboratories and frontline clinical personnel have made great efforts to prevent and treat COVID-19 by revealing the molecular biological characteristics and epidemic characteristics of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Currently, SARS-CoV-2 has severe consequences for public health, including human respiratory system, immune system, blood circulation system, nervous system, motor system, urinary system, reproductive system and digestive system. In the review, we summarize the physiological and pathological damage of SARS-CoV-2 to these systems and its molecular mechanisms followed by clinical manifestation. Concurrently, the prevention and treatment strategies of COVID-19 will be discussed in preclinical and clinical studies. With constantly unfolding and expanding scientific understanding about COVID-19, the updated information can help applied researchers understand the disease to build potential antiviral drugs or vaccines, and formulate creative therapeutic ideas for combating COVID-19 at speed.


Assuntos
COVID-19/patologia , COVID-19/terapia , Imunoterapia/métodos , SARS-CoV-2 , Animais , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Vacinas contra COVID-19 , Citocinas/metabolismo , Feminino , Humanos , Sistema Imunitário , Imunidade Inata , Memória Imunológica , Masculino , Camundongos
5.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 53(1): 1-6, 2022 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-35048592

RESUMO

Coronavirus disease 2019 (COVID-19), an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a global pandemic since its outbreak in 2019, presenting serious threats to public health and the health of the people. As one of the main components of the host innate immune system, type-Ⅰ interferon (IFN) plays a critical role in the defense against viral infections. The battle between the virus and the host innate immune system determines the disease progression. It has been reported that SARS-CoV-2 inhibits IFN production and suppresses the activation of IFN signaling pathway through its interactions with the host innate immune system. Then, the weakened or delayed response of type-Ⅰ interferon causes the disturbance of host immune responses, which is one of the important reasons why SARS-CoV-2 causes such high morbidity and mortality. Herein, we reviewed and discussed the interaction between SARS-CoV-2 viral proteins and the host innate immune system, especially the interaction with type-Ⅰ IFN pathway, to provide new insights into the mechanisms of viral evasion of host immune response and new perspectives and strategies for treating COVID-19 with IFN.


Assuntos
COVID-19 , Interferon Tipo I , Humanos , Imunidade Inata , Pandemias , SARS-CoV-2
6.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 53(1): 15-19, 2022 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-35048594

RESUMO

The circadian rhythm is a widely-recognized phenomenon, according to which the life activities of organisms change periodically, synchronizing with the day and night cycles. The activities of the immune system are also regulated by the circadian rhythm. Group 3 innate lymphoid cells (ILC3s) and T helper 17 (Th17) cells (ILC3/Th17) are the innate and adaptive subsets of immune cells mediating type 17 immune response, which is featured by the expression of transcription factor retinoid orphan receptor gamma t (RORγt) and the production of interleukin (IL)-17 and IL-22. The processes of type 17 immune response are completed mainly through the participation of ILC3/Th17 and are closely associated with the intestinal immune response. Recent studies have found that the immune response mediated by ILC3/Th17 is intricately regulated by the circadian rhythm through molecular mechanisms controlling the circadian rhythm, or through other external factors that change according to the light-darkness cycle, for example the food intake rhythm. The secretion of cytokines changes along with the regulatory effect of circadian rhythm on ILC3/Th17, which in turn impacts, to a certain degree, on the onset and development of intestinal inflammatory diseases, including bacterial infection and autoimmune diseases. The understanding of mechanisms regulating ILC3/Th17 responses by the circadian rhythm may promote better understanding of the course of action of the immune system and facilitate the development and discovery of potential targets for treatment of intestinal inflammatory diseases.


Assuntos
Ritmo Circadiano , Imunidade Inata , Citocinas , Intestinos , Linfócitos , Células Th17
7.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 53(1): 20-27, 2022 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-35048595

RESUMO

The innate immune system is critical to the elimination and control of infections. However, uncontrolled immune responses can cause indirect host-mediated tissue damage. The regulation of immune homeostasis is a complex but finely regulated process. ncRNAs have been increasingly identified as important regulators of a variety of biological processes. Recent research findings suggest that microRNAs and long non-coding RNAs participate in antiviral responses, tumor immunity, and autoimmune diseases by regulating gene expression in the innate immune pathways. MicroRNAs regulate gene expression at the post-transcriptional level by binding to the 3' untranslated regions of mRNA, while long non-coding RNAs act as endogenous competing RNAs for microRNAs, inhibiting the binding of microRNAs and mRNAs. In this review, we summarized the regulatory role of non-coding RNAs in innate immunity and its mechanism to provide references for research in the regulation of innate immunity and immune-related diseases. In addition, we also reported discussions on the future research directions in the field, including the expression and maturation regulation mechanism of new non-coding RNAs, and the conservation of non-coding RNAs in evolution.


Assuntos
MicroRNAs , RNA Longo não Codificante , Imunidade Inata/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , RNA Mensageiro , RNA não Traduzido/genética
8.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 53(1): 28-34, 2022 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-35048596

RESUMO

Gut microbiota-derived metabolites play vital roles in the regulation of host-gut microbiota mutualism, gut homeostasis and the pathogenesis of multiple human diseases. Fermentation of indigestible dietary fibers by gut microbiota produces a variety of short-chain fatty acids (SCFAs) consisting mainly of acetate, propionate and butyrate. Despite high concentrations of SCFAs in the gut, it has been reported in a large number of studies that SCFAs are involved in the onset and development of multiple diseases, including colitis, diabetes mellitus, hepatic steatosis, and obesity. Recent studies including our work found that SCFAs regulates allergic immune reactions and the pathogenesis of allergic diseases via their action on allergic effector immune cells, including T helper 2 (Th2) cells, type 2 innate lymphoid cells (ILC2), eosinophils, mast cells and basophils. Herein, we reviewed the association of SCFAs with human allergic diseases, their role in regulating the animal model of allergic diseases and the effects of different SCFAs in regulating the functions of allergic effectors cells and the underlying mechanisms, aiming to provide research clues for in-depth investigation in the role played by SCFAs in regulating various allergic diseases.


Assuntos
Hipersensibilidade , Imunidade Inata , Animais , Butiratos , Ácidos Graxos Voláteis , Humanos , Linfócitos
9.
J Int Med Res ; 50(1): 3000605211053156, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35048721

RESUMO

The prevalence rate of allergic diseases, such as asthma, atopic rhinitis (AR), and atopic dermatitis (AD), has been significantly increasing over the years because of environmental changes. Type 2 immunity is mediated by allergic inflammation initiated by an innate immune response. This response is orchestrated by type 2 cytokines (interleukin [IL]-4, IL-5, IL-9, and IL-13) together with other cells. The dendritic cell [DC]-T helper 2 (Th2) cell axis is the conventional type 2 immune pathway, and is currently known as the group 2 innate lymphoid cell (ILC2)-DC-Th2 axis that mediates type 2 inflammation. ILC2s strongly mediate type 2 inflammation in allergic diseases. ILC2s are activated by epithelial cell-derived cytokines, such as IL-25 and IL-33, and thymic stromal lymphopoietin. Additionally, ILC2s are activated by mast cell lipid inflammatory mediators, such as cysteinyl leukotrienes and prostaglandin D2. ILC2s produce a large amount of type 2 cytokines. The important role of ILC2s in the pathogenesis of type 2-mediated disease has resulted in ILC2-derived cytokines being a target for therapeutic development. In this review, we discuss type 2 immunity, mainly the ILC2-DC-Th2 axis, and other immune cells, the dominant role of ILC2s in asthma, AR, and AD, and therapeutic targets against type 2 cytokines.


Assuntos
Asma , Rinite Alérgica , Asma/tratamento farmacológico , Citocinas , Humanos , Imunidade Inata , Linfócitos , Células Th2
10.
Nat Commun ; 13(1): 17, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35013162

RESUMO

Defense against intracellular infection has been extensively studied in vertebrate hosts, but less is known about invertebrate hosts; specifically, the transcription factors that induce defense against intracellular intestinal infection in the model nematode Caenorhabditis elegans remain understudied. Two different types of intracellular pathogens that naturally infect the C. elegans intestine are the Orsay virus, which is an RNA virus, and microsporidia, which comprise a phylum of fungal pathogens. Despite their molecular differences, these pathogens induce a common host transcriptional response called the intracellular pathogen response (IPR). Here we show that zip-1 is an IPR regulator that functions downstream of all known IPR-activating and regulatory pathways. zip-1 encodes a putative bZIP transcription factor, and we show that zip-1 controls induction of a subset of genes upon IPR activation. ZIP-1 protein is expressed in the nuclei of intestinal cells, and is at least partially required in the intestine to upregulate IPR gene expression. Importantly, zip-1 promotes resistance to infection by the Orsay virus and by microsporidia in intestinal cells. Altogether, our results indicate that zip-1 represents a central hub for triggers of the IPR, and that this transcription factor has a protective function against intracellular pathogen infection in C. elegans.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica , Caenorhabditis elegans , Enterócitos , Interações Hospedeiro-Patógeno/fisiologia , Animais , Fatores de Transcrição de Zíper de Leucina Básica/imunologia , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Caenorhabditis elegans/imunologia , Caenorhabditis elegans/microbiologia , Caenorhabditis elegans/virologia , Proteínas de Caenorhabditis elegans/imunologia , Proteínas de Caenorhabditis elegans/metabolismo , Enterócitos/imunologia , Enterócitos/microbiologia , Enterócitos/virologia , Imunidade Inata/fisiologia , Intestinos/microbiologia , Intestinos/virologia , Invertebrados/imunologia , Microsporídios/patogenicidade , Vírus de RNA/patogenicidade
11.
Nat Commun ; 13(1): 14, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35013241

RESUMO

Type I interferons (IFNs) are critical for anti-viral responses, and also drive autoimmunity when dysregulated. Upon viral sensing, monocytes elicit a sequential cascade of IFNß and IFNα production involving feedback amplification, but how exactly this cascade is regulated in human cells is incompletely understood. Here we show that the PYHIN protein myeloid cell nuclear differentiation antigen (MNDA) is required for IFNα induction in monocytes. Unlike other PYHINs, this is not due to a pathogen sensing role, but rather MNDA regulated expression of IRF7, a transcription factor essential for IFNα induction. Mechanistically, MNDA is required for recruitment of STAT2 and RNA polymerase II to the IRF7 gene promoter, and in fact MNDA is itself recruited to the IRF7 promoter after type I IFN stimulation. These data implicate MNDA as a critical regulator of the type I IFN cascade in human myeloid cells and reveal a new role for human PYHINs in innate immune gene induction.


Assuntos
Antígenos de Diferenciação Mielomonocítica/metabolismo , Imunidade Inata , Interferon Tipo I/metabolismo , Células Mieloides/metabolismo , Fatores de Transcrição/metabolismo , Linhagem Celular , Regulação da Expressão Gênica , Humanos , Imunidade Inata/genética , Imunidade Inata/fisiologia , Monócitos/metabolismo
12.
Gut ; 71(1): 163-175, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-33431576

RESUMO

OBJECTIVE: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) pathophysiology remains unclear. This study aims to characterise the molecular basis of HBV-ACLF using transcriptomics. METHODS: Four hundred subjects with HBV-ACLF, acute-on-chronic hepatic dysfunction (ACHD), liver cirrhosis (LC) or chronic hepatitis B (CHB) and normal controls (NC) from a prospective multicentre cohort were studied, and 65 subjects (ACLF, 20; ACHD, 10; LC, 10; CHB, 10; NC, 15) among them underwent mRNA sequencing using peripheral blood mononuclear cells (PBMCs). RESULTS: The functional synergy analysis focusing on seven bioprocesses related to the PBMC response and the top 500 differentially expressed genes (DEGs) showed that viral processes were associated with all disease stages. Immune dysregulation, as the most prominent change and disorder triggered by HBV exacerbation, drove CHB or LC to ACHD and ACLF. Metabolic disruption was significant in ACHD and severe in ACLF. The analysis of 62 overlapping DEGs further linked the HBV-based immune-metabolism disorder to ACLF progression. The signatures of interferon-related, neutrophil-related and monocyte-related pathways related to the innate immune response were significantly upregulated. Signatures linked to the adaptive immune response were downregulated. Disruptions of lipid and fatty acid metabolism were observed during ACLF development. External validation of four DEGs underlying the aforementioned molecular mechanism in patients and experimental rats confirmed their specificity and potential as biomarkers for HBV-ACLF pathogenesis. CONCLUSIONS: This study highlights immune-metabolism disorder triggered by HBV exacerbation as a potential mechanism of HBV-ACLF and may indicate a novel diagnostic and treatment target to reduce HBV-ACLF-related mortality.


Assuntos
Insuficiência Hepática Crônica Agudizada/patologia , Hepatite B Crônica/complicações , Leucócitos Mononucleares/imunologia , Insuficiência Hepática Crônica Agudizada/virologia , Imunidade Adaptativa , Adulto , Animais , Estudos de Casos e Controles , DNA Viral/sangue , Feminino , Vírus da Hepatite B , Humanos , Imunidade Inata , Masculino , Metaboloma , Pessoa de Meia-Idade , Estudos Prospectivos , Ratos , Transcriptoma
13.
Chem Biol Interact ; 352: 109777, 2022 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-34896122

RESUMO

OBJECTIVE: To determine the differences in the immune response against SARS-CoV-2 infection of patients based on sex and disease severity. METHODS: We used an analytical framework of 382 transcriptional modules and multi-omics analyses to discriminate COVID-19 patients based on sex and disease severity. RESULTS: Male and female patients overexpressed modules related to the innate immune response. The expression of modules related to the adaptive immune response showed lower enrichment levels in males than females. Inflammation modules showed ascending overexpression in male and female patients, while a higher level was observed in severe female patients. Moderate female patients demonstrated significant overexpression to interferon, cytolytic lymphocyte, T & B cells, and erythrocytes modules. Moderate female patients showed a higher adaptive immune response than males matched group. Pathways involved in metabolism dysregulation and Hippo signaling were upregulated in females than in male patients. Females and moderate cases showed higher levels of metabolic dysregulation. CONCLUSIONS: The immune landscape in COVID-19 patients was noticeably different between the sexes, and these differences may highlight disease vulnerability in males. This study suggested that certain treatments that increase or decrease the immune responses to SARS-CoV-2 might be necessary for male and female patients at certain disease stages.


Assuntos
COVID-19/imunologia , COVID-19/metabolismo , Imunidade Adaptativa/imunologia , Adulto , Idoso , COVID-19/patologia , Feminino , Humanos , Imunidade Inata/imunologia , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Linfócitos/imunologia , Linfócitos/metabolismo , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Caracteres Sexuais
14.
Chem Biol Interact ; 352: 109776, 2022 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-34906553

RESUMO

Boosting or suppressing our immune system represents an attractive adjunct in the treatment of infections including SARS-CoV-2, cancer, AIDS, malnutrition, age related problems and some inflammatory disorders. Thus, there has been a growing interest in exploring and developing novel drugs, natural or synthetic, that can manipulate our defence mechanism. Many of such studies, reported till date, have been designed to explore effect of the therapeutic on function of macrophages, being a key component in innate immune system. Indeed, RAW264.7, J774A.1, THP-1 and U937 cell lines act as ideal model systems for preliminary investigation and selection of dose for in vivo studies. Several bioassays have been standardized so far where many techniques require high throughput instruments, cost effective reagents and technical assistance that may hinder many scholars to perform a method demanding compilation of available protocols. In this review, we have taken an attempt for the first time to congregate commonly used in vitro immune-modulating techniques explaining their principles. The study detected that among about 40 different assays and more than 150 sets of primers, the methods of cell proliferation by MTT, phagocytosis by neutral red, NO detection by Griess reaction and estimation of expression of TLRs, COX-2, iNOS, TNF-α, IL-6 and IL-1ß by PCR have been the most widely used to screen the therapeutics under investigation.


Assuntos
Imunidade Inata/imunologia , Imunomodulação/imunologia , Animais , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Humanos , Inflamação/imunologia , Fagocitose/imunologia
15.
Artigo em Inglês | MEDLINE | ID: mdl-34371155

RESUMO

Temperature is an important environmental factor influencing immune responses of crayfish. However, the mechanism underlying how temperature affects immune responses remains unclear. Here, we identified an ortholog of the transient receptor potential ankyrin subtype 1 (TRPA1), a temperature sensor of Drosophila, from Procambarus clarkii (PcTRPA1-1). Its expression was induced by high temperature and challenge with heat-killed A. hydrophila at high temperature, but not at lower temperature. PcTRPA1-1 silencing led to increased mortality of crayfish challenged with live A. hydrophila at high temperature (32 °C), but had no statistically significant effect on crayfish mortality at 24 °C. This suggests that PcTRPA1-1 is involved in the immune responses of crayfish at high temperature as a potential temperature sensor. Further assay exhibited that PcTRPA1-1 silencing affected immune responses of crayfish, including increase of lipid peroxidation, reduction of total antioxidant capacity, decreased phenoloxidase activity and disruption of circadian rhythm of total hemocyte count entrained by temperature cycles. PcTRPA1-1 silencing also decreased the expression of PcHSP70 and PcHSP90 which are responsive to heat stimuli and bacterial challenge. The results collectively indicate that TRPA1 contributes to heat sensing of crayfish and is required for crayfish defense against bacterial infection.


Assuntos
Aeromonas hydrophila , Astacoidea , Animais , Astacoidea/genética , Temperatura Alta , Imunidade Inata , Temperatura
16.
Artigo em Inglês | MEDLINE | ID: mdl-34637922

RESUMO

Toll like receptor 5 (TLR5) plays a crucial role in the innate immune response by recognizing bacterial flagellin proteins. In the present study, the genomic and 5'-flanking sequences of LcTLR5M (membrane) and LcTLR5S (soluble) were cloned from the large yellow croaker, Larimichthys crocea. Then, their promoter activities were determined in human embryonic kidney (HEK293T) cells. LcTLR5M contained 4 exons and 3 introns, and LcTLR5S contained 2 exons and 1 intron. Bioinformatic prediction of transcription factor binding sites (TFBSs) indicated that the promoter structures were different between LcTLR5M and LcTLR5S. A dual luciferase assay showed that the deletion mutant -471 to +189 of LcTLR5M promoter possessed the greatest activity with 36 times activity of the control (P < 0.05). For LcTLR5S, two deletion mutants, -1687 to +106 and - 720 to +106, showed high promoter activity. Furthermore, site-directed mutation demonstrated that a -392 to -391 AT/GG substitution in Oct-1 binding site, and a -104 to -103 GG/TT and a -98 to -97 CC/AA substitution in the NF-κB binding site of TLR5S caused a significant decline of luciferase activity (P < 0.05). Moreover, the co-transfection of an NF-κB/p65 over-expression plasmid with wild type TLR5S (-720 to +106) resulted in an extremely significant increase of promoter activity by more than 9 times compared with the NF-kB mutant (P < 0.01). Our findings suggest that the genomic organization and promoter structure may differ between LcTLR5M and LcTLR5S. Oct1 and NF-κB binding sites might be cis-regulatory elements in the LcTLR5S promoter. NF-κB/p65 plays an important role in LcTLR5S promoter activation through binding with the NF-κB binding site.


Assuntos
NF-kappa B , Perciformes , Animais , Sítios de Ligação , Proteínas de Peixes/genética , Células HEK293 , Humanos , Imunidade Inata , NF-kappa B/genética , NF-kappa B/metabolismo , Perciformes/genética , Perciformes/metabolismo
17.
Biochim Biophys Acta Mol Basis Dis ; 1868(1): 166292, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34710568

RESUMO

Tuberculosis (TB) remains a major cause of mortality and morbidity worldwide, and it is instant to discover novel anti-TB drugs due to the rapidly growing drug-resistance TB. Mycobacterium tuberculosis (Mtb) secreted effector ESAT6 plays a critical role in modulation miRNAs to regulate host defense mechanisms during Mtb infection, it can be a possible target for new tuberculosis drugs. The non-tuberculous mycobacteria Mycobacterium smegmatis (M. smegmatis) and Mtb have high gene homology but no pathogenicity. We used ESAT6 to interfere with macrophages or mice infected by M. smegmatis and determined that it enhanced the survival rate of bacteria and regulated miR-222-3p target PTEN. Expression of miR-222-3p reduced and PTEN enhanced with the progression of macrophages infected by M. smegmatis with ESAT6 co-incubation. MiR-222-3p overexpression diminished M. smegmatis survival and upregulated proinflammatory cytokines. VO-Ohpic trihydrate (PTEN inhibitor) reduced M. smegmatis survival and upregulated proinflammatory cytokines in vivo and in vitro, and VO-Ohpic trihydrate reversed the tissue damage of mouse organs caused by ESAT6. These results uncover an ESAT6 dependent role for miR-222-3p and its target PTEN in regulating host immune responses to bacterial infection and may provide a potential site for the development of anti-tuberculosis drugs that specifically antagonize the virulence of ESAT6.


Assuntos
Antígenos de Bactérias/genética , Proteínas de Bactérias/genética , MicroRNAs/genética , PTEN Fosfo-Hidrolase/genética , Tuberculose/genética , Animais , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno/genética , Humanos , Imunidade Inata/genética , Camundongos , Mycobacterium smegmatis/genética , Mycobacterium smegmatis/patogenicidade , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/patogenicidade , Tuberculose/imunologia , Tuberculose/patologia
18.
J Exp Med ; 219(1)2022 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-34757384

RESUMO

As SARS-CoV-2 continues to cause morbidity and mortality around the world, there is an urgent need for the development of effective medical countermeasures. Here, we assessed the antiviral capacity of a minimal RIG-I agonist, stem-loop RNA 14 (SLR14), in viral control, disease prevention, post-infection therapy, and cross-variant protection in mouse models of SARS-CoV-2 infection. A single dose of SLR14 prevented viral infection in the lower respiratory tract and development of severe disease in a type I interferon (IFN-I)-dependent manner. SLR14 demonstrated remarkable prophylactic protective capacity against lethal SARS-CoV-2 infection and retained considerable efficacy as a therapeutic agent. In immunodeficient mice carrying chronic SARS-CoV-2 infection, SLR14 elicited near-sterilizing innate immunity in the absence of the adaptive immune system. In the context of infection with variants of concern (VOCs), SLR14 conferred broad protection against emerging VOCs. These findings demonstrate the therapeutic potential of SLR14 as a host-directed, broad-spectrum antiviral for early post-exposure treatment and treatment of chronically infected immunosuppressed patients.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , RNA/metabolismo , SARS-CoV-2/efeitos dos fármacos , Animais , COVID-19/metabolismo , Modelos Animais de Doenças , Imunidade Inata/efeitos dos fármacos , Interferon Tipo I/metabolismo , Camundongos , Camundongos Endogâmicos BALB C
19.
Life Sci Alliance ; 5(3)2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34862272

RESUMO

Murine neural stem cells (NSCs) were recently shown to release piRNA-containing exosomes/microvesicles (Ex/Mv) for exerting antiviral immunity, but it remains unknown if these Ex/Mv could target SARS-CoV-2 and whether the PIWI-piRNA system is important for these antiviral actions. Here, using in vitro infection models, we show that hypothalamic NSCs (htNSCs) Ex/Mv provided an innate immunity protection against SARS-CoV-2. Importantly, enhanced antiviral actions were achieved by using induced Ex/Mv that were derived from induced htNSCs through twice being exposed to several RNA fragments of SARS-CoV-2 genome, a process that was designed not to involve protein translation of these RNA fragments. The increased antiviral effects of these induced Ex/Mv were associated with increased expression of piRNA species some of which could predictably target SARS-CoV-2 genome. Knockout of piRNA-interacting protein PIWIL2 in htNSCs led to reductions in both innate and induced antiviral effects of Ex/Mv in targeting SARS-CoV-2. Taken together, this study demonstrates a case suggesting Ex/Mv from certain cell types have innate and adaptive immunity against SARS-CoV-2, and the PIWI-piRNA system is important for these antiviral actions.


Assuntos
Proteínas Argonauta/metabolismo , COVID-19/imunologia , COVID-19/metabolismo , Micropartículas Derivadas de Células/metabolismo , Exossomos , RNA Interferente Pequeno/metabolismo , RNA/metabolismo , SARS-CoV-2 , Células A549 , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Genoma Viral , Humanos , Hipotálamo/metabolismo , Sistema Imunitário , Imunidade Inata , Técnicas In Vitro , Camundongos
20.
Handb Exp Pharmacol ; 268: 297-310, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34173865

RESUMO

Allergies are highly prevalent hypersensitivity responses to usually harmless substances. They are mediated by the immune system which causes pathologic responses such as type I (rhinoconjunctivitis, allergic asthma, atopy) or type IV hypersensitivity (allergic contact dermatitis). The different types of allergy are mediated by effector and memory T cells and, in the case of type I hypersensitivity, B cells. A prerequisite for the activation of these cells of the adaptive immune system is the activation of the innate immune system. The resulting inflammation is essential not only for the initiation but also for the elicitation and maintenance of allergies. Great progress has been made in the elucidation of the cellular and molecular pathomechanisms underlying allergen-induced inflammation. It is now recognized that the innate immune system in concert with tissue stress and damage responses orchestrates inflammation. This should enable the development of novel mechanism-based anti-inflammatory treatment strategies as well as of animal-free in vitro assays for the identification and potency classification of contact allergens.


Assuntos
Dermatite Alérgica de Contato , Imunidade Inata , Alérgenos , Dermatite Alérgica de Contato/tratamento farmacológico , Dermatite Alérgica de Contato/etiologia , Humanos , Inflamação , Linfócitos T
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