Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 12 de 12
Filtrar
1.
J Vasc Surg ; 71(4): 1378-1389.e3, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32035769

RESUMO

BACKGROUND: Neointimal hyperplasia is a major contributor to restenosis after arterial interventions, but the genetic and environmental mechanisms underlying the variable propensity for neointimal hyperplasia between individuals, including the role of commensal microbiota, are not well understood. We sought to characterize how shifting the microbiome using cage sharing and bedding mixing between rats with differing restenosis phenotypes after carotid artery balloon angioplasty could alter arterial remodeling. METHODS: We co-housed and mixed bedding between genetically distinct rats (Lewis [LE] and Sprague-Dawley [SD]) that harbor different commensal microbes and that are known to have different neointimal hyperplasia responses to carotid artery balloon angioplasty. Sequencing of the 16S ribosomal RNA gene was used to monitor changes in the gut microbiome. RESULTS: There were significant differences in neointimal hyperplasia between non-co-housed LE and SD rats 14 days after carotid artery angioplasty (mean intima + media [I + M] area, 0.117 ± 0.014 mm2 LE vs 0.275 ± 0.021 mm2 SD; P < .001) that were diminished by co-housing. Co-housing also altered local adventitial Ki67 immunoreactivity, local accumulation of leukocytes and macrophages (total and M2), and interleukin 17A concentration 3 days after surgery in each strain. Non-co-housed SD and LE rats had microbiomes distinguished by both weighted (P = .012) and unweighted (P < .001) UniFrac beta diversity distances, although without significant differences in alpha diversity. The difference in unweighted beta diversity between the fecal microbiota of SD and LE rats was significantly reduced by co-housing. Operational taxonomic units that significantly correlated with average I + M area include Parabacteroides distasonis, Desulfovibrio, Methanosphaera, Peptococcus, and Prevotella. Finally, serum concentrations of microbe-derived metabolites hydroxyanthranilic acid and kynurenine/tryptophan ratio were significantly associated with I + M area in both rat strains independent of co-housing. CONCLUSIONS: We describe a novel mechanism for how microbiome manipulations affect arterial remodeling and the inflammatory response after arterial injury. A greater understanding of the host inflammatory-microbe axis could uncover novel therapeutic targets for the prevention and treatment of restenosis.


Assuntos
Angioplastia com Balão , Lesões das Artérias Carótidas/patologia , Microbioma Gastrointestinal , Inflamação/patologia , Neointima/patologia , Animais , Fezes/microbiologia , Hiperplasia , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley
2.
Clin Sci (Lond) ; 132(18): 2013-2028, 2018 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-30232239

RESUMO

Inflammatory bowel diseases (IBD) are a group of chronic diseases of increasing worldwide prevalence characterized by gastrointestinal (GI) inflammation leading to debilitating symptoms and complications. The contribution of the intestinal microbiota to the pathogenesis and etiology of these diseases is an area of active research interest. Here, we discuss key mechanisms underlying the chronic inflammation seen in IBD as well as evidence implicating the intestinal microbiota in the development and potentiation of that inflammation. We also discuss recently published work in areas of interest within the field of microbial involvement in IBD pathogenesis - the importance of proper microecology within the GI tract, the evidence that the intestinal microbiota transduces environmental and genetic risk factors for IBD, and the mechanisms by which microbial products contribute to communication between microbe and host. There is an extensive body of published research on the evidence for microbial involvement in IBD; the goal of this review is to highlight the growing edges of the field where exciting and innovative research is pushing the boundaries of the conceptual framework of the role of the intestinal microbiota in IBD pathogenesis.


Assuntos
Microbioma Gastrointestinal/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Inflamação/imunologia , Doenças Inflamatórias Intestinais/imunologia , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/imunologia , Disbiose/genética , Disbiose/imunologia , Microbioma Gastrointestinal/fisiologia , Variação Genética/imunologia , Humanos , Inflamação/microbiologia , Doenças Inflamatórias Intestinais/microbiologia
3.
Cytokine ; 63(3): 230-6, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23764548

RESUMO

Enteroviruses are the most common human viral pathogens worldwide. This genus of small, non-enveloped, single stranded RNA viruses includes coxsackievirus, rhinovirus, echovirus, and poliovirus species. Infection with these viruses can induce mild symptoms that resemble the common cold, but can also be associated with more severe syndromes such as poliomyelitis, neurological diseases including aseptic meningitis and encephalitis, myocarditis, and the onset of type I diabetes. In humans, polarized epithelial cells lining the respiratory and/or digestive tracts represent the initial sites of infection by enteroviruses. Control of infection in the host is initiated through the engagement of a variety of pattern recognition receptors (PRRs). PRRs act as the sentinels of the innate immune system and serve to alert the host to the presence of a viral invader. This review assembles the available data annotating the role of PRRs in the response to enteroviral infection as well as the myriad ways by which enteroviruses both interrupt and manipulate PRR signaling to enhance their own replication, thereby inducing human disease.


Assuntos
Infecções por Enterovirus/imunologia , Enterovirus/imunologia , Evasão da Resposta Imune/imunologia , Receptores de Reconhecimento de Padrão/imunologia , Humanos , Imunidade Inata/imunologia , Receptores de Reconhecimento de Padrão/metabolismo , Transdução de Sinais/imunologia
4.
Science ; 381(6657): 502-508, 2023 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-37535745

RESUMO

The mammalian gut secretes a family of multifunctional peptides that affect appetite, intestinal secretions, and motility whereas others regulate the microbiota. We have found that peptide YY (PYY1-36), but not endocrine PYY3-36, acts as an antimicrobial peptide (AMP) expressed by gut epithelial paneth cells (PC). PC-PYY is packaged into secretory granules and is secreted into and retained by surface mucus, which optimizes PC-PYY activity. Although PC-PYY shows some antibacterial activity, it displays selective antifungal activity against virulent Candida albicans hyphae-but not the yeast form. PC-PYY is a cationic molecule that interacts with the anionic surfaces of fungal hyphae to cause membrane disruption and transcriptional reprogramming that selects for the yeast phenotype. Hence, PC-PYY is an antifungal AMP that contributes to the maintenance of gut fungal commensalism.


Assuntos
Antifúngicos , Peptídeos Antimicrobianos , Candida , Celulas de Paneth , Fragmentos de Peptídeos , Peptídeo YY , Animais , Antifúngicos/metabolismo , Peptídeos Antimicrobianos/metabolismo , Candida/efeitos dos fármacos , Candida/fisiologia , Celulas de Paneth/metabolismo , Fragmentos de Peptídeos/metabolismo , Peptídeo YY/metabolismo , Simbiose , Humanos , Camundongos
5.
Microorganisms ; 10(10)2022 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-36296342

RESUMO

Cardiovascular diseases are associated with gut dysbiosis, but the role of microbe-derived metabolites as biomarkers or modulators of cardiovascular disease are not well understood. This is a targeted metabolomics study to investigate the association of nine microbe-derived metabolites with lower extremity peripheral artery disease (PAD), a form of atherosclerosis, and major adverse cardiac events (MACE). The study cohort consists of individuals with intermittent claudication and ankle-brachial index (ABI) < 0.9 (N = 119) and controls without clinically-apparent atherosclerosis (N = 37). The primary endpoint was MACE, a composite endpoint of myocardial infarction, coronary revascularization, stroke, transient ischemic attack, or cardiac-related death. Plasma metabolite concentrations differed significantly between the PAD and control groups. After adjustment for traditional atherosclerosis risk factors, kynurenine, hippuric acid, indole-3-propionic acid (IPA), and indole-3-aldehyde (I3A) concentrations were negatively associated with PAD, whereas indoxyl sulfate and 3-hydroxyanthranilic acid were positively associated. Hippuric acid, IPA, and I3A correlated with ABI, a surrogate for atherosclerotic disease burden. Those in the highest I3A concentration quartile had significantly improved freedom from MACE during follow-up compared to those in the lowest quartile. This study identifies specific indole- and phenyl-derived species impacted by gut microbial metabolic pathways that could represent novel microbiome-related biomarkers of PAD.

6.
J Exp Med ; 217(5)2020 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-32142585

RESUMO

Most studies focus on how intestinal microbiota influence cancer immunotherapy through activating gut immunity. However, immunotherapies related to innate responses such as CD47 blockade rely on the rapid immune responses within the tumor microenvironment. Using one defined anaerobic gut microbiota to track whether microbiota interact with host immunity, we observed that Bifidobacterium facilitates local anti-CD47 immunotherapy on tumor tissues through the capacity to accumulate within the tumor microenvironment. Systemic administration of Bifidobacterium leads to its accumulation within the tumor and converts the nonresponder mice into responders to anti-CD47 immunotherapy in a stimulator of interferon genes (STING)- and interferon-dependent fashion. Local delivery of Bifidobacterium potently stimulates STING signaling and increases cross-priming of dendritic cells after anti-CD47 treatment. Our study identifies the mechanism by which gut microbiota preferentially colonize in tumor sites and facilitate immunotherapy via STING signaling.


Assuntos
Antígeno CD47/metabolismo , Neoplasias do Colo/microbiologia , Neoplasias do Colo/terapia , Microbioma Gastrointestinal , Imunoterapia , Proteínas de Membrana/metabolismo , Transdução de Sinais , Animais , Bifidobacterium/fisiologia , Linhagem Celular Tumoral , Sobrevivência Celular/imunologia , Neoplasias do Colo/imunologia , Células Dendríticas/metabolismo , Feminino , Interferon Tipo I/metabolismo , Camundongos Endogâmicos C57BL , Microambiente Tumoral/imunologia
7.
J Am Heart Assoc ; 9(5): e013496, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32089055

RESUMO

Background The potential role of the gut microbiome in cardiovascular diseases is increasingly evident. Arterial restenosis attributable to neointimal hyperplasia after cardiovascular procedures such as balloon angioplasty, stenting, and bypass surgery is a common cause of treatment failure, yet whether gut microbiota participate in the development of neointimal hyperplasia remains largely unknown. Methods and Results We performed fecal microbial transplantation from conventionally raised male C57BL/6 mice to age-, sex-, and strain-matched germ-free mice. Five weeks after inoculation, all mice underwent unilateral carotid ligation. Neointimal hyperplasia development was quantified after 4 weeks. Conventionally raised and germ-free cohorts served as comparison groups. Conclusions Germ-free mice have significantly attenuated neointimal hyperplasia development compared with conventionally raised mice. The arterial remodeling response is restored by fecal transplantation. Our results describe a causative role of gut microbiota in contributing to the pathogenesis of neointimal hyperplasia.


Assuntos
Artérias Carótidas/patologia , Lesões das Artérias Carótidas/microbiologia , Lesões das Artérias Carótidas/patologia , Transplante de Microbiota Fecal , Microbioma Gastrointestinal , Neointima , Animais , Modelos Animais de Doenças , Vida Livre de Germes , Hiperplasia , Masculino , Camundongos Endogâmicos C57BL
8.
Nat Commun ; 11(1): 2354, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32393794

RESUMO

Death due to sepsis remains a persistent threat to critically ill patients confined to the intensive care unit and is characterized by colonization with multi-drug-resistant healthcare-associated pathogens. Here we report that sepsis in mice caused by a defined four-member pathogen community isolated from a patient with lethal sepsis is associated with the systemic suppression of key elements of the host transcriptome required for pathogen clearance and decreased butyrate expression. More specifically, these pathogens directly suppress interferon regulatory factor 3. Fecal microbiota transplant (FMT) reverses the course of otherwise lethal sepsis by enhancing pathogen clearance via the restoration of host immunity in an interferon regulatory factor 3-dependent manner. This protective effect is linked to the expansion of butyrate-producing Bacteroidetes. Taken together these results suggest that fecal microbiota transplantation may be a treatment option in sepsis associated with immunosuppression.


Assuntos
Transplante de Microbiota Fecal , Imunidade , Sepse/imunologia , Sepse/terapia , Animais , Ácido Butírico/metabolismo , Fezes/química , Microbioma Gastrointestinal , Trato Gastrointestinal/patologia , Inibidores de Histona Desacetilases/farmacologia , Humanos , Fator Regulador 3 de Interferon/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Sepse/microbiologia , Transdução de Sinais , Transcrição Gênica
9.
PLoS One ; 13(12): e0208426, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30521585

RESUMO

BACKGROUND: The microbiome has a functional role in a number of inflammatory processes and disease states. While neointimal hyperplasia development has been linked to inflammation, a direct role of the microbiota in neointimal hyperplasia has not yet been established. Germ-free (GF) mice are an invaluable model for studying causative links between commensal organisms and the host. We hypothesized that GF mice would exhibit altered neointimal hyperplasia following carotid ligation compared to conventionally raised (CONV-R) mice. METHODS: Twenty-week-old male C57BL/6 GF mice underwent left carotid ligation under sterile conditions. Maintenance of sterility was assessed by cultivation and 16S rRNA qPCR of stool. Neointimal hyperplasia was assessed by morphometric and histologic analysis of arterial sections after 28 days. Local arterial cell proliferation and inflammation was assessed by immunofluorescence for Ki67 and inflammatory cell markers at five days. Systemic inflammation was assessed by multiplex immunoassays of serum. CONV-R mice treated in the same manner served as the control cohort. GF and CONV-R mice were compared using standard statistical methods. RESULTS: All GF mice remained sterile during the entire study period. Twenty-eight days after carotid ligation, CONV-R mice had significantly more neointimal hyperplasia development compared to GF mice, as assessed by intima area, media area, intima+media area, and intima area/(intima+media) area. The collagen content of the neointimal lesions appeared qualitatively similar on Masson's trichrome staining. There was significantly reduced Ki67 immunoreactivity in the media and adventitia of GF carotid arteries 5 days after ligation. GF mice also had increased arterial infiltration of anti-inflammatory M2 macrophages compared to CONV-R mouse arteries and a reduced proportion of mature neutrophils. GF mice had significantly reduced serum IFN-γ-inducible protein (IP)-10 and MIP-2 5 days after carotid ligation, suggesting a reduced systemic inflammatory response. CONCLUSIONS: GF mice have attenuated neointimal hyperplasia development compared to CONV-R mice, which is likely related to altered kinetics of wound healing and acute inflammation. Recognizing the role of commensals in the regulation of arterial remodeling will provide a deeper understanding of the pathophysiology of restenosis and support strategies to treat or reduce restenosis risk by manipulating microbiota.


Assuntos
Arterite/microbiologia , Bactérias/classificação , Lesões das Artérias Carótidas/complicações , Neointima/patologia , Animais , Bactérias/genética , Bactérias/isolamento & purificação , DNA Bacteriano/genética , DNA Ribossômico/genética , Modelos Animais de Doenças , Vida Livre de Germes , Humanos , Hiperplasia , Antígeno Ki-67/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microbiota , Neointima/microbiologia , RNA Ribossômico 16S/genética
10.
PLoS One ; 10(10): e0141383, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26509685

RESUMO

Unc93b is an endoplasmic reticulum (ER)-resident transmembrane protein that serves to bind and traffic toll-like receptors (TLRs) from the ER to their appropriate subcellular locations for ligand sensing. Because of its role in TLR trafficking, Unc93b is necessary for an effective innate immune response to coxsackievirus B3 (CVB), a positive-sense single stranded RNA virus belonging to the enterovirus family. Here, we show that Unc93b is cleaved by a CVB-encoded cysteine protease (3Cpro) during viral replication. Further, we define a role for Unc93b in the induction of apoptotic cell death and show that expression of wild-type Unc93b, but not a mutant incapable of binding TLRs or exiting the ER (H412R), induces apoptosis. Furthermore, we show that cellular caspases activated during apoptosis directly cleave Unc93b. Interestingly, we show that the 3Cpro- and caspase-mediated cleavage of Unc93b both occur within ten amino acids in the distal N-terminus of Unc93b. Mechanistically, neither caspase-mediated nor 3Cpro-mediated cleavage of Unc93b altered its trafficking function, inhibited its role in facilitating TLR3 or TLR8 signaling, or altered its apoptosis-inducing effects. Taken together, our studies show that Unc93b is targeted by both viral- and host cell-specific proteases and identify a function of Unc93b in the induction of apoptotic cell death.


Assuntos
Apoptose/genética , Enterovirus/enzimologia , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Peptídeo Hidrolases/metabolismo , Proteases Virais 3C , Caspases/metabolismo , Linhagem Celular , Células Cultivadas , Cisteína Endopeptidases/metabolismo , Infecções por Enterovirus/genética , Infecções por Enterovirus/metabolismo , Infecções por Enterovirus/virologia , Expressão Gênica , Humanos , Mutação , Transporte Proteico , Proteólise , Transdução de Sinais , Receptores Toll-Like/metabolismo , Proteínas Virais/metabolismo
11.
Cell Host Microbe ; 18(2): 221-32, 2015 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-26269957

RESUMO

Receptor interacting protein kinase-3 (RIP3) is an essential kinase for necroptotic cell death signaling and has been implicated in antiviral cell death signaling upon DNA virus infection. Here, we performed high-throughput RNAi screening and identified RIP3 as a positive regulator of coxsackievirus B3 (CVB) replication in intestinal epithelial cells (IECs). RIP3 regulates autophagy, a process utilized by CVB for viral replication factory assembly, and depletion of RIP3 inhibits autophagic flux and leads to the accumulation of autophagosomes and amphisomes. Additionally, later in infection, RIP3 is cleaved by the CVB-encoded cysteine protease 3C(pro), which serves to abrogate RIP3-mediated necrotic signaling and induce a nonnecrotic form of cell death. Taken together, our results show that temporal targeting of RIP3 allows CVB to benefit from its roles in regulating autophagy while inhibiting the induction of necroptotic cell death.


Assuntos
Autofagia , Cisteína Endopeptidases/metabolismo , Enterovirus Humano B/fisiologia , Células Epiteliais/virologia , Interações Hospedeiro-Patógeno , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Proteínas Virais/metabolismo , Replicação Viral , Proteases Virais 3C , Células CACO-2 , Enterovirus Humano B/metabolismo , Inativação Gênica , Testes Genéticos , Humanos , Interferência de RNA
12.
Cytokine Growth Factor Rev ; 25(5): 587-96, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25172372

RESUMO

Enteroviruses (EVs) are the most common human viral pathogens. They cause a variety of pathologies, including myocarditis and meningoencephalopathies, and have been linked to the onset of type I diabetes. These pathologies result from the death of cells in the myocardium, central nervous system, and pancreas, respectively. Understanding the role of EVs in inducing cell death is crucial to understanding the etiologies of these diverse pathologies. EVs both induce and delay host cell death, and their exquisite control of this balance is crucial for their success as human viral pathogens. Thus, EVs are tightly involved with cell death signaling pathways and interact with host cell signaling at multiple points. Here, we review the literature detailing the mechanisms of EV-induced cell death. We discuss the mechanisms by which EVs induce cell death, the signaling pathways involved in these pathways, and the strategies by which EVs antagonize cell death pathways. We also discuss the role of cell death in both the resulting pathology in the host and in the facilitation of viral spread.


Assuntos
Apoptose/fisiologia , Infecções por Enterovirus/fisiopatologia , Enterovirus/fisiologia , Animais , Morte Celular/fisiologia , Infecções por Enterovirus/virologia , Humanos , Transdução de Sinais
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA