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1.
mBio ; : e0133224, 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38940553

RESUMO

Transposon sequencing (Tn-seq) is a powerful genome-wide technique to assess bacterial fitness under varying growth conditions. However, screening via Tn-seq in vivo is challenging. Dose limitations and host restrictions create bottlenecks that diminish the transposon mutant pool being screened. Here, we have developed a murine model with a disruption in Akr1c13 that renders the resulting RECON-/- mouse resistant to high-dose infection. We leveraged this model to perform a Tn-seq screen of the human pathogen Listeria monocytogenes in vivo. We identified 135 genes which were required for L. monocytogenes growth in mice including novel genes not previously identified for host survival. We identified organ-specific requirements for L. monocytogenes survival and investigated the role of the folate enzyme FolD in L. monocytogenes liver pathogenesis. A mutant lacking folD was impaired for growth in murine livers by 2.5-log10 compared to wild type and failed to spread cell-to-cell in fibroblasts. In contrast, a mutant in alsR, which encodes a transcription factor that represses an operon involved in D-allose catabolism, was attenuated in both livers and spleens of mice by 4-log10 and 3-log10, respectively, but showed modest phenotypes in in vitro models. We confirmed that dysregulation of the D-allose catabolism operon is responsible for the in vivo growth defect, as deletion of the operon in the ∆alsR background rescued virulence. By undertaking an unbiased, genome-wide screen in mice, we have identified novel fitness determinants for L. monocytogenes host infection, which highlights the utility of the RECON-/- mouse model for future screening efforts. IMPORTANCE: Listeria monocytogenes is the gram-positive bacterium responsible for the food-borne disease listeriosis. Although infections with L. monocytogenes are limiting in healthy hosts, vulnerable populations, including pregnant and elderly people, can experience high rates of mortality. Thus, understanding the breadth of genetic requirements for L. monocytogenes in vivo survival will present new opportunities for treatment and prevention of listeriosis. We developed a murine model of infection using a RECON-/- mouse that is restrictive to systemic L. monocytogenes infection. We utilized this model to screen for L. monocytogenes genes required in vivo via transposon sequencing. We identified the liver-specific gene folD and a repressor, alsR, that only exhibits an in vivo growth defect. AlsR controls the expression of the D-allose operon which is a marker in diagnostic techniques to identify pathogenic Listeria. A better understanding of the role of the D-allose operon in human disease may further inform diagnostic and prevention measures.

2.
Int J Food Microbiol ; 382: 109906, 2022 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-36108483

RESUMO

Listeriosis is a foodborne disease caused by the Gram-positive bacterium Listeria monocytogenes, a pathogen that modulates its intracellular survival via vacuolar escape and cytosolic replication. In the present study, we examined the ability of 58 L. monocytogenes isolates recovered in Brazil (beef, clinical and environmental samples, from 1978 to 2013) to invade, replicate and spread in a human intestinal epithelial cell line (Caco-2). Premature stop codons were common in the inlA gene of serotype 1/2c strains from beef and environment samples, associated with decreased Caco-2 cell invasion when compared to other serotypes. The isolates varied widely in their intracellular doubling times, and there was no clear relationship between serotypes and samples origin. Serotype 1/2a isolates were generally impaired in their ability to spread between Caco-2 cells, with an average 30 % smaller focus area than the 10403S reference strain. However, most isolates of serotype 1/2b exhibited enhanced cell-to-cell spread, with an average 35 % increase in focus area. Our findings are consistent with serotype being a better predictors of cell invasion potential and cell spread compared with sample origin of isolates, although the most invasive isolates were primarily isolated from beef. Additionally, we have identified isolates that could provide novel insight into the pathogenicity of L. monocytogenes that may not be revealed by studying common laboratory reference strains.


Assuntos
Listeria monocytogenes , Listeriose , Animais , Proteínas de Bactérias/genética , Células CACO-2 , Bovinos , Códon sem Sentido , Microbiologia de Alimentos , Humanos , Listeriose/microbiologia , Sorogrupo
3.
Cell Host Microbe ; 30(7): 961-974.e6, 2022 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-35439435

RESUMO

Antimicrobials can impact bacterial physiology and host immunity with negative treatment outcomes. Extensive exposure to antifolate antibiotics promotes thymidine-dependent Staphylococcus aureus small colony variants (TD-SCVs), commonly associated with worse clinical outcomes. We show that antibiotic-mediated disruption of thymidine synthesis promotes elevated levels of the bacterial second messenger cyclic di-AMP (c-di-AMP), consequently inducing host STING activation and inflammation. An initial antibiotic screen in Firmicutes revealed that c-di-AMP production was largely driven by antifolate antibiotics targeting dihydrofolate reductase (DHFR), which promotes folate regeneration required for thymidine biosynthesis. Additionally, TD-SCVs exhibited excessive c-di-AMP production and STING activation in a thymidine-dependent manner. Murine lung infection with TD-SCVs revealed STING-dependent elevation of proinflammatory cytokines, causing higher airway neutrophil infiltration and activation compared with normal-colony S. aureus and hemin-dependent SCVs. Collectively, our results suggest that thymidine metabolism disruption in Firmicutes leads to elevated c-di-AMP-mediated STING-dependent inflammation, with potential impacts on antibiotic usage and infection outcomes.


Assuntos
Antagonistas do Ácido Fólico , Infecções Estafilocócicas , Animais , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Proteínas de Bactérias/metabolismo , AMP Cíclico/metabolismo , Fosfatos de Dinucleosídeos , Antagonistas do Ácido Fólico/metabolismo , Inflamação , Camundongos , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/metabolismo , Timidina/metabolismo
4.
Elife ; 102021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-33955352

RESUMO

Pathogens encounter numerous antimicrobial responses during infection, including the reactive oxygen species (ROS) burst. ROS-mediated oxidation of host membrane poly-unsaturated fatty acids (PUFAs) generates the toxic alpha-beta carbonyl 4-hydroxy-2-nonenal (4-HNE). Although studied extensively in the context of sterile inflammation, research into 4-HNE's role during infection remains limited. Here, we found that 4-HNE is generated during bacterial infection, that it impacts growth and survival in a range of bacteria, and that the intracellular pathogen Listeria monocytogenes induces many genes in response to 4-HNE exposure. A component of the L. monocytogenes 4-HNE response is the expression of the genes lmo0103 and lmo0613, deemed rha1 and rha2 (reductase of host alkenals), respectively, which code for two NADPH-dependent oxidoreductases that convert 4-HNE to the product 4-hydroxynonanal (4-HNA). Loss of these genes had no impact on L. monocytogenes bacterial burdens during murine or tissue culture infection. However, heterologous expression of rha1/2 in Bacillus subtilis significantly increased bacterial resistance to 4-HNE in vitro and promoted bacterial survival following phagocytosis by murine macrophages in an ROS-dependent manner. Thus, Rha1 and Rha2 are not necessary for 4-HNE resistance in L. monocytogenes but are sufficient to confer resistance to an otherwise sensitive organism in vitro and in host cells. Our work demonstrates that 4-HNE is a previously unappreciated component of ROS-mediated toxicity encountered by bacteria within eukaryotic hosts.


Assuntos
Aldeídos/metabolismo , Interações Hospedeiro-Patógeno , Listeria monocytogenes/genética , Listeria monocytogenes/patogenicidade , Animais , Bacillus subtilis/genética , Linhagem Celular , Feminino , Concentração de Íons de Hidrogênio , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Fagocitose
5.
Immunity ; 54(6): 1320-1337.e4, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-33945787

RESUMO

Natural killer (NK) cells and type 1 innate lymphoid cells (ILC1s) are heterogenous innate lymphocytes broadly defined in mice as Lin-NK1.1+NKp46+ cells that express the transcription factor T-BET and produce interferon-γ. The ILC1 definition primarily stems from studies on liver and small intestinal populations. However, NK1.1+NKp46+ cells in the salivary glands, uterus, adipose, and other tissues exhibit nonuniform programs that differ from those of liver or intestinal ILC1s or NK cells. Here, we performed single-cell RNA sequencing on murine NK1.1+NKp46+ cells from blood, spleen, various tissues, and solid tumors. We identified gene expression programs of tissue-specific ILC1s, tissue-specific NK cells, and non-tissue-specific populations in blood, spleen, and other tissues largely corresponding to circulating cells. Moreover, we found that circulating NK cell programs were reshaped in tumor-bearing mice. Core programs of circulating and tumor NK cells paralleled conserved human NK cells signatures, advancing our understanding of the human NK-ILC1 spectrum.


Assuntos
Imunidade Inata/imunologia , Células Matadoras Naturais/imunologia , Linfócitos/imunologia , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Subfamília B de Receptores Semelhantes a Lectina de Células NK/imunologia , Receptor 1 Desencadeador da Citotoxicidade Natural/imunologia , Neoplasias/imunologia , Análise de Célula Única/métodos , Fatores de Transcrição/imunologia
6.
Curr Opin Immunol ; 62: 9-14, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31825814

RESUMO

Tissue-resident lymphocytes that lack expression of rearranged antigen receptors and are lineage negative for classical T and B cell markers are collectively known as innate lymphoid cells (ILCs). The ILC family is remarkably heterogeneous and exhibits plasticity; however, mature ILCs can be grouped based on their steady state expression of distinct surface receptors and transcription factors as well as production of signature cytokines following activation. The study of ILC subsets in mouse and human tissues has revealed that the elicitation and magnitude of their effector functions are determined by a combination of extrinsic cues specific to the niches in which they reside. In this short review, we will summarize some recent findings related to tissue-specific signals that govern ILC responses and localization.


Assuntos
Imunidade Inata/imunologia , Linfócitos/imunologia , Animais , Humanos
7.
Environ Microbiol ; 21(12): 4478-4487, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31251828

RESUMO

Advances in whole-genome sequencing (WGS) technologies have documented genetic diversity and epidemiology of the major foodborne pathogen Listeria monocytogenes (Lm) in Europe and North America, but data concerning South America are scarce. Here, we examined the population structure and genetic diversity of this major foodborne pathogen collected in Brazil. Based on core genome multilocus sequence typing (cgMLST), isolates from lineages I (n = 22; 63%) and II (n = 13; 37%) were distributed into 10 different sublineages (SLs) and represented 31 new cgMLST types (CTs). The most prevalent SLs were SL9 (n = 9; 26%), SL3 (n = 6; 17%) and SL2 and SL218 (n = 5; 14%). Isolates belonging to CTs L2-SL9-ST9-CT4420 and L1-SL315-ST520-CT4429 were collected 3 and 9 years apart, respectively, revealing long-term persistence of Lm in Brazil. Genetic elements associated with stress survival were present in 60% of isolates (57% SSI-1 and 3% SSI-2). Pathogenic islands were present in 100% (LIPI-1), 43% (LIPI-3) and 6% (LIPI-4) of the isolates. Mutations leading to premature stop codons were detected in the prfA and inlA virulence genes. This study is an important contribution to understanding the genomic diversity and epidemiology of Lm in South America. In addition, the results highlight the importance of using WGS to reveal Lm long-term persistence.


Assuntos
Listeria monocytogenes/genética , Listeriose/microbiologia , Brasil/epidemiologia , Microbiologia de Alimentos , Variação Genética , Genoma Bacteriano , Humanos , Listeriose/epidemiologia , Carne/microbiologia , Tipagem de Sequências Multilocus , Virulência/genética , Sequenciamento Completo do Genoma
8.
mBio ; 9(3)2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29764944

RESUMO

The oxidoreductase RECON is a high-affinity cytosolic sensor of bacterium-derived cyclic dinucleotides (CDNs). CDN binding inhibits RECON's enzymatic activity and subsequently promotes inflammation. In this study, we sought to characterize the effects of RECON on the infection cycle of the intracellular bacterium Listeria monocytogenes, which secretes cyclic di-AMP (c-di-AMP) into the cytosol of infected host cells. Here, we report that during infection of RECON-deficient hepatocytes, which exhibit hyperinflammatory responses, L. monocytogenes exhibits significantly enhanced cell-to-cell spread. Enhanced bacterial spread could not be attributed to alterations in PrfA or ActA, two virulence factors critical for intracellular motility and intercellular spread. Detailed microscopic analyses revealed that in the absence of RECON, L. monocytogenes actin tail lengths were significantly longer and there was a larger number of faster-moving bacteria. Complementation experiments demonstrated that the effects of RECON on L. monocytogenes spread and actin tail lengths were linked to its enzymatic activity. RECON enzyme activity suppresses NF-κB activation and is inhibited by c-di-AMP. Consistent with these previous findings, we found that augmented NF-κB activation in the absence of RECON caused enhanced L. monocytogenes cell-to-cell spread and that L. monocytogenes spread correlated with c-di-AMP secretion. Finally, we discovered that, remarkably, increased NF-κB-dependent inducible nitric oxide synthase expression and nitric oxide production were responsible for promoting L. monocytogenes cell-to-cell spread. The work presented here supports a model whereby L. monocytogenes secretion of c-di-AMP inhibits RECON's enzymatic activity, drives augmented NF-κB activation and nitric oxide production, and ultimately enhances intercellular spread.IMPORTANCE To date, bacterial CDNs in eukaryotes are solely appreciated for their capacity to activate cytosolic sensing pathways in innate immunity. However, it remains unclear whether pathogens that actively secrete CDNs benefit from this process. Here, we provide evidence that secretion of CDNs leads to enhancement of L. monocytogenes cell-to-cell spread. This is a heretofore-unknown role of these molecules and suggests L. monocytogenes may benefit from their secretion in certain contexts. Molecular characterization revealed that, surprisingly, nitric oxide was responsible for the enhanced spread. Pathogens act to prevent nitric oxide production or, like L. monocytogenes, they have evolved to resist its direct antimicrobial effects. This study provides evidence that intracellular bacterial pathogens not only tolerate nitric oxide, which is inevitably encountered during infection, but can also capitalize on the changes this pleiotropic molecule enacts on the host cell.


Assuntos
Estradiol Desidrogenases/imunologia , Hepatócitos/enzimologia , Listeria monocytogenes/fisiologia , Listeriose/enzimologia , Oxirredutases/metabolismo , Animais , AMP Cíclico/metabolismo , Estradiol Desidrogenases/genética , Hepatócitos/imunologia , Hepatócitos/microbiologia , Humanos , Listeria monocytogenes/genética , Listeriose/imunologia , Listeriose/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/genética , NF-kappa B/imunologia , Oxirredutases/genética
9.
Immunity ; 46(3): 433-445, 2017 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-28329705

RESUMO

Bacterial and host cyclic dinucleotides (cdNs) mediate cytosolic immune responses through the STING signaling pathway, although evidence suggests that alternative pathways exist. We used cdN-conjugated beads to biochemically isolate host receptors for bacterial cdNs, and we identified the oxidoreductase RECON. High-affinity cdN binding inhibited RECON enzyme activity by simultaneously blocking the substrate and cosubstrate sites, as revealed by structural analyses. During bacterial infection of macrophages, RECON antagonized STING activation by acting as a molecular sink for cdNs. Bacterial infection of hepatocytes, which do not express STING, revealed that RECON negatively regulates NF-κB activation. Loss of RECON activity, via genetic ablation or inhibition by cdNs, increased NF-κB activation and reduced bacterial survival, suggesting that cdN inhibition of RECON promotes a proinflammatory, antibacterial state that is distinct from the antiviral state associated with STING activation. Thus, RECON functions as a cytosolic sensor for bacterial cdNs, shaping inflammatory gene activation via its effects on STING and NF-κB.


Assuntos
Infecções Bacterianas/imunologia , Proteínas de Bactérias/imunologia , Estradiol Desidrogenases/imunologia , Inflamação/imunologia , NF-kappa B/imunologia , Animais , Ativação Enzimática/imunologia , Macrófagos/imunologia , Camundongos , Camundongos Knockout , NF-kappa B/metabolismo , Reação em Cadeia da Polimerase em Tempo Real
10.
Nat Med ; 22(12): 1475-1481, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27841874

RESUMO

Hepatitis C virus (HCV) infects 200 million people globally, and 60-80% of cases persist as a chronic infection that will progress to cirrhosis and liver cancer in 2-10% of patients. We recently demonstrated that HCV induces aberrant expression of two host microRNAs (miRNAs), miR-208b and miR-499a-5p, encoded by myosin genes in infected hepatocytes. These miRNAs, along with AU-rich-element-mediated decay, suppress IFNL2 and IFNL3, members of the type III interferon (IFN) gene family, to support viral persistence. In this study, we show that miR-208b and miR-499a-5p also dampen type I IFN signaling in HCV-infected hepatocytes by directly down-regulating expression of the type I IFN receptor chain, IFNAR1. Inhibition of these miRNAs by using miRNA inhibitors during HCV infection increased expression of IFNAR1. Additionally, inhibition rescued the antiviral response to exogenous type I IFN, as measured by a marked increase in IFN-stimulated genes and a decrease in HCV load. Treatment of HCV-infected hepatocytes with type I IFN increased expression of myosins over HCV infection alone. Since these miRNAs can suppress type III IFN family members, these data collectively define a novel cross-regulation between type I and III IFNs during HCV infection.


Assuntos
Regulação da Expressão Gênica/imunologia , Hepacivirus/imunologia , Hepatite C Crônica/imunologia , Hepatócitos/imunologia , Interferon Tipo I/imunologia , MicroRNAs/imunologia , Sistemas CRISPR-Cas , Regulação para Baixo , Técnicas de Inativação de Genes , Células Hep G2 , Hepatite C/imunologia , Humanos , Interferons , Interleucinas/imunologia , Miosinas/metabolismo , Receptor de Interferon alfa e beta/genética
11.
Cell Host Microbe ; 20(1): 4-6, 2016 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-27414494

RESUMO

Type I IFN production is an important host defense mechanism against Gram-positive Streptococci. In this issue of Cell Host & Microbe, Andrade et al. (2016) report that Group B Streptococcus limits type I IFN by expressing a surface phosphodiesterase that degrades extracellular bacterial cyclic dinucleotides, thereby promoting virulence.


Assuntos
Evasão da Resposta Imune , Streptococcus agalactiae/imunologia , Streptococcus , Virulência
12.
Nat Immunol ; 15(1): 72-9, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24241692

RESUMO

IFNL3, which encodes interferon-λ3 (IFN-λ3), has received considerable attention in the hepatitis C virus (HCV) field, as many independent genome-wide association studies have identified a strong association between polymorphisms near IFNL3 and clearance of HCV. However, the mechanism underlying this association has remained elusive. In this study, we report the identification of a functional polymorphism (rs4803217) in the 3' untranslated region (UTR) of IFNL3 mRNA that dictated transcript stability. We found that this polymorphism influenced AU-rich element (ARE)-mediated decay (AMD) of IFNL3 mRNA, as well as the binding of HCV-induced microRNAs during infection. Together these pathways mediated robust repression of the unfavorable IFNL3 polymorphism. Our data reveal a previously unknown mechanism by which HCV attenuates the antiviral response and indicate new potential therapeutic targets for HCV treatment.


Assuntos
Elementos Ricos em Adenilato e Uridilato/genética , Interleucinas/genética , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único , Estabilidade de RNA/genética , Regiões 3' não Traduzidas/genética , Sequência de Bases , Linhagem Celular Tumoral , Citometria de Fluxo , Genótipo , Células Hep G2 , Hepacivirus/fisiologia , Hepatite C/genética , Hepatite C/virologia , Interações Hospedeiro-Patógeno , Humanos , Interferons , Interleucinas/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Dados de Sequência Molecular , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Homologia de Sequência do Ácido Nucleico
13.
Eur J Immunol ; 43(7): 1896-906, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23616277

RESUMO

Synthetic oligonucleotides (ODN) expressing CpG motifs mimic the ability of bacterial DNA to trigger the innate immune system via TLR9. Plasmacytoid dendritic cells (pDCs) make a critical contribution to the ensuing immune response. This work examines the induction of antiviral (IFN-ß) and pro-inflammatory (IL-6) cytokines by CpG-stimulated human pDCs and the human CAL-1 pDC cell line. Results show that interferon regulatory factor-5 (IRF-5) and NF-κB p50 are key co-regulators of IFN-ß and IL-6 expression following TLR9-mediated activation of human pDCs. The nuclear accumulation of IRF-1 was also observed, but this was a late event that was dependant on type 1 IFN and unrelated to the initiation of gene expression. IRF-8 was identified as a novel negative regulator of gene activation in CpG-stimulated pDCs. As variants of IRF-5 and IRF-8 were recently found to correlate with susceptibility to certain autoimmune diseases, these findings are relevant to our understanding of the pharmacologic effects of "K" ODN and the role of TLR9 ligation under physiologic, pathologic, and therapeutic conditions.


Assuntos
Células Dendríticas/imunologia , Fatores Reguladores de Interferon/imunologia , Interferon beta/biossíntese , Interleucina-6/biossíntese , Subunidade p50 de NF-kappa B/imunologia , Linhagem Celular , Células Dendríticas/metabolismo , Imunofluorescência , Regulação da Expressão Gênica/imunologia , Humanos , Immunoblotting , Imunoprecipitação , Fatores Reguladores de Interferon/metabolismo , Interferon beta/imunologia , Interleucina-6/imunologia , Subunidade p50 de NF-kappa B/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Receptor Toll-Like 9/imunologia
14.
PLoS One ; 6(2): e16967, 2011 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-21365015

RESUMO

BACKGROUND: There have been conflicting reports of the role of Type I interferons (IFN) in inflammatory bowel disease (IBD). Clinical trials have shown potent efficacy of systemic interferon-beta (IFN-ß) in inducing remission of ulcerative colitis. Likewise, IFNAR1(-/-) mice display an increased sensitivity to dextran sulfate sodium (DSS)-induced colitis, suggesting Type I IFN play a protective role during inflammation of the gut. Curiously, however, there have also been reports detailing the spontaneous development of IBD in patients receiving systemic IFN-ß therapy for multiple sclerosis or hepatitis. METHODOLOGY/PRINCIPAL FINDINGS: To investigate the effects of local administration of IFN-ß on a murine model of colitis, we developed a transgenic Lactobacillus acidophilus strain that constitutively expresses IFN-ß (La-IFN-ß). While pretreatment of mice with control Lactobacillus (La-EV) provided slight protective benefits, La-IFN-ß increased sensitivity to DSS. Analysis showed colitic mice pretreated with La-IFN-ß had increased production of TNF-α, IFN-γ, IL-17A and IL-13 by intestinal tissues and decreased regulatory T cells (Tregs) in their small intestine. Examination of CD103(+) dendritic cells (DCs) in the Peyer's patches revealed that IFNAR1 expression was dramatically reduced by La-IFN-ß. Similarly, bone marrow-derived DCs matured with La-IFN-ß experienced a 3-fold reduction of IFNAR1 and were impaired in their ability to induce Tregs. CONCLUSIONS/SIGNIFICANCE: Our IFNAR1 expression data identifies a correlation between the loss/downregulation of IFNAR1 on DCs and exacerbation of colitis. Our data show that Lactobacillus secreting IFN-ß has an immunological effect that in our model results in the exacerbation of colitis. This study underscores that the selection of therapeutics delivered by a bacterial vehicle must take into consideration the simultaneous effects of the vehicle itself.


Assuntos
Colite/genética , Técnicas de Transferência de Genes , Interferon Tipo I/efeitos adversos , Interferon Tipo I/genética , Lactobacillus acidophilus/genética , Animais , Células Cultivadas , Colite/induzido quimicamente , Colite/microbiologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Sulfato de Dextrana , Modelos Animais de Doenças , Progressão da Doença , Predisposição Genética para Doença , Vetores Genéticos , Interferon Tipo I/metabolismo , Lactobacillus acidophilus/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Organismos Geneticamente Modificados , Receptor de Interferon alfa e beta/genética , Proteínas Recombinantes
15.
Blood ; 117(2): 575-84, 2011 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-20971950

RESUMO

The interleukin (IL)-22R1 chain of the heterodimeric IL-22 receptor is not expressed on normal leukocytes, but this receptor is expressed on T cells from anaplastic lymphoma kinase-positive (ALK(+)) anaplastic large cell lymphoma (ALCL) patients. To investigate the consequences of aberrant expression of this receptor on lymphocytes, we generated transgenic mice that express IL-22R1 on lymphocytes. The health of these animals progressively deteriorated at 8 to 12 weeks of age, as they displayed respiratory distress, rough coat and sluggish movement, and subsequent lethality due to multiorgan inflammation. The IL-22R1 transgenic animals developed neutrophilia that correlated with increased levels of circulating IL-17 and granulocyte colony-stimulating factor. In addition, these mice had increased serum IL-22 levels, suggesting that T cells expressing IL-22R1 generate IL-22 in a positive autoregulatory loop. As a result of the mouse model findings, we analyzed circulating cytokine levels in ALK(+)ALCL patients and detected elevated levels of IL-22, IL-17, and IL-8 in untreated patient samples. Importantly, IL-22 and IL-17 were undetectable in all patients who were in complete remission after chemotherapy. This study documents a previously unknown role of IL-22R1 in inflammation and identifies the involvement of IL-22R1/IL-22 in ALK(+)ALCL.


Assuntos
Inflamação/metabolismo , Interleucinas/metabolismo , Linfoma Anaplásico de Células Grandes/metabolismo , Receptores de Interleucina/metabolismo , Quinase do Linfoma Anaplásico , Animais , Western Blotting , Separação Celular , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Inflamação/genética , Interleucina-17/metabolismo , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Tirosina Quinases/metabolismo , Receptores Proteína Tirosina Quinases , Receptores de Interleucina/genética , Interleucina 22
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