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1.
Physiol Rev ; 99(2): 1047-1078, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30648461

RESUMO

Cellular senescence is a permanent state of cell cycle arrest that occurs in proliferating cells subjected to different stresses. Senescence is, therefore, a cellular defense mechanism that prevents the cells to acquire an unnecessary damage. The senescent state is accompanied by a failure to re-enter the cell cycle in response to mitogenic stimuli, an enhanced secretory phenotype and resistance to cell death. Senescence takes place in several tissues during different physiological and pathological processes such as tissue remodeling, injury, cancer, and aging. Although senescence is one of the causative processes of aging and it is responsible of aging-related disorders, senescent cells can also play a positive role. In embryogenesis and tissue remodeling, senescent cells are required for the proper development of the embryo and tissue repair. In cancer, senescence works as a potent barrier to prevent tumorigenesis. Therefore, the identification and characterization of key features of senescence, the induction of senescence in cancer cells, or the elimination of senescent cells by pharmacological interventions in aging tissues is gaining consideration in several fields of research. Here, we describe the known key features of senescence, the cell-autonomous, and noncell-autonomous regulators of senescence, and we attempt to discuss the functional role of this fundamental process in different contexts in light of the development of novel therapeutic targets.


Assuntos
Envelhecimento/fisiologia , Transformação Celular Neoplásica/metabolismo , Senescência Celular/fisiologia , Neoplasias/metabolismo , Cicatrização/fisiologia , Envelhecimento/metabolismo , Animais , Proliferação de Células/fisiologia , Humanos
2.
Immunity ; 43(3): 527-40, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26362264

RESUMO

The interrelationship between IgAs and microbiota diversity is still unclear. Here we show that BALB/c mice had higher abundance and diversity of IgAs than C57BL/6 mice and that this correlated with increased microbiota diversity. We show that polyreactive IgAs mediated the entrance of non-invasive bacteria to Peyer's patches, independently of CX3CR1(+) phagocytes. This allowed the induction of bacteria-specific IgA and the establishment of a positive feedback loop of IgA production. Cohousing of mice or fecal transplantation had little or no influence on IgA production and had only partial impact on microbiota composition. Germ-free BALB/c, but not C57BL/6, mice already had polyreactive IgAs that influenced microbiota diversity and selection after colonization. Together, these data suggest that genetic predisposition to produce polyreactive IgAs has a strong impact on the generation of antigen-specific IgAs and the selection and maintenance of microbiota diversity.


Assuntos
Antígenos de Bactérias/imunologia , Variação Genética/imunologia , Imunoglobulina A/imunologia , Microbiota/imunologia , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/imunologia , DNA Bacteriano/química , DNA Bacteriano/genética , Fezes/microbiologia , Citometria de Fluxo , Interações Hospedeiro-Patógeno/imunologia , Imunização , Imunoglobulina A/sangue , Imunoglobulina A/metabolismo , Metagenômica/métodos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Microbiota/genética , Nódulos Linfáticos Agregados/imunologia , Nódulos Linfáticos Agregados/metabolismo , Nódulos Linfáticos Agregados/microbiologia , Filogenia , RNA Ribossômico 16S/genética , Salmonella typhimurium/genética , Salmonella typhimurium/imunologia , Salmonella typhimurium/fisiologia , Especificidade da Espécie
3.
Nature ; 559(7714): 363-369, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29950727

RESUMO

Patients with prostate cancer frequently show resistance to androgen-deprivation therapy, a condition known as castration-resistant prostate cancer (CRPC). Acquiring a better understanding of the mechanisms that control the development of CRPC remains an unmet clinical need. The well-established dependency of cancer cells on the tumour microenvironment indicates that the microenvironment might control the emergence of CRPC. Here we identify IL-23 produced by myeloid-derived suppressor cells (MDSCs) as a driver of CRPC in mice and patients with CRPC. Mechanistically, IL-23 secreted by MDSCs can activate the androgen receptor pathway in prostate tumour cells, promoting cell survival and proliferation in androgen-deprived conditions. Intra-tumour MDSC infiltration and IL-23 concentration are increased in blood and tumour samples from patients with CRPC. Antibody-mediated inactivation of IL-23 restored sensitivity to androgen-deprivation therapy in mice. Taken together, these results reveal that MDSCs promote CRPC by acting in a non-cell autonomous manner. Treatments that block IL-23 can oppose MDSC-mediated resistance to castration in prostate cancer and synergize with standard therapies.


Assuntos
Interleucina-23/antagonistas & inibidores , Interleucina-23/metabolismo , Células Supressoras Mieloides/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/terapia , Antagonistas de Receptores de Andrógenos/farmacologia , Antagonistas de Receptores de Andrógenos/uso terapêutico , Androgênios/deficiência , Animais , Benzamidas , Proliferação de Células , Sobrevivência Celular , Humanos , Interleucina-23/sangue , Interleucina-23/imunologia , Masculino , Camundongos , Células Supressoras Mieloides/citologia , Células Supressoras Mieloides/imunologia , Nitrilas , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Feniltioidantoína/análogos & derivados , Feniltioidantoína/farmacologia , Feniltioidantoína/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptores Androgênicos/metabolismo , Receptores de Interleucina/metabolismo , Transdução de Sinais
4.
Cancer Cell ; 41(3): 602-619.e11, 2023 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-36868226

RESUMO

Tumor cells promote the recruitment of immunosuppressive neutrophils, a subset of myeloid cells driving immune suppression, tumor proliferation, and treatment resistance. Physiologically, neutrophils are known to have a short half-life. Here, we report the identification of a subset of neutrophils that have upregulated expression of cellular senescence markers and persist in the tumor microenvironment. Senescent-like neutrophils express the triggering receptor expressed on myeloid cells 2 (TREM2) and are more immunosuppressive and tumor-promoting than canonical immunosuppressive neutrophils. Genetic and pharmacological elimination of senescent-like neutrophils decreases tumor progression in different mouse models of prostate cancer. Mechanistically, we have found that apolipoprotein E (APOE) secreted by prostate tumor cells binds TREM2 on neutrophils, promoting their senescence. APOE and TREM2 expression increases in prostate cancers and correlates with poor prognosis. Collectively, these results reveal an alternative mechanism of tumor immune evasion and support the development of immune senolytics targeting senescent-like neutrophils for cancer therapy.


Assuntos
Apolipoproteínas E , Neoplasias da Próstata , Animais , Humanos , Masculino , Camundongos , Apolipoproteínas E/metabolismo , Senescência Celular/genética , Glicoproteínas de Membrana/genética , Células Mieloides/metabolismo , Neoplasias da Próstata/metabolismo , Receptores Imunológicos/metabolismo , Microambiente Tumoral
5.
Front Immunol ; 13: 873195, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35757699

RESUMO

COVID-19 has proven to be particularly serious and life-threatening for patients presenting with pre-existing pathologies. Patients affected by rheumatic musculoskeletal disease (RMD) are likely to have impaired immune responses against SARS-CoV-2 infection due to their compromised immune system and the prolonged use of disease-modifying anti-rheumatic drugs (DMARDs), which include conventional synthetic (cs) DMARDs or biologic and targeted synthetic (b/ts) DMARDs. To provide an integrated analysis of the immune response following SARS-CoV-2 infection in RMD patients treated with different classes of DMARDs we carried out an immunological analysis of the antibody responses toward SARS-CoV-2 nucleocapsid and RBD proteins and an extensive immunophenotypic analysis of the major immune cell populations. We showed that RMD individuals under most DMARD treatments mount a sustained antibody response to the virus, with neutralizing activity. In addition, they displayed a sizable percentage of effector T and B lymphocytes. Among b-DMARDs, we found that anti-TNFα treatments are more favorable drugs to elicit humoral and cellular immune responses as compared to CTLA4-Ig and anti-IL6R inhibitors. This study provides a whole picture of the humoral and cellular immune responses in RMD patients by reassuring the use of DMARD treatments during COVID-19. The study points to TNF-α inhibitors as those DMARDs permitting elicitation of functional antibodies to SARS-CoV-2 and adaptive effector populations available to counteract possible re-infections.


Assuntos
Antirreumáticos , Tratamento Farmacológico da COVID-19 , Doenças Reumáticas , Antirreumáticos/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Doenças Reumáticas/tratamento farmacológico , SARS-CoV-2
6.
Sci Immunol ; 6(62)2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376481

RESUMO

To understand how a protective immune response against SARS-CoV-2 develops over time, we integrated phenotypic, transcriptional and repertoire analyses on PBMCs from mild and severe COVID-19 patients during and after infection, and compared them to healthy donors (HD). A type I IFN-response signature marked all the immune populations from severe patients during the infection. Humoral immunity was dominated by IgG production primarily against the RBD and N proteins, with neutralizing antibody titers increasing post infection and with disease severity. Memory B cells, including an atypical FCRL5+ T-BET+ memory subset, increased during the infection, especially in patients with mild disease. A significant reduction of effector memory, CD8+ T cells frequency characterized patients with severe disease. Despite such impairment, we observed robust clonal expansion of CD8+ T lymphocytes, while CD4+ T cells were less expanded and skewed toward TCM and TH2-like phenotypes. MAIT cells were also expanded, but only in patients with mild disease. Terminally differentiated CD8+ GZMB+ effector cells were clonally expanded both during the infection and post-infection, while CD8+ GZMK+ lymphocytes were more expanded post-infection and represented bona fide memory precursor effector cells. TCR repertoire analysis revealed that only highly proliferating T cell clonotypes, which included SARS-CoV-2-specific cells, were maintained post-infection and shared between the CD8+ GZMB+ and GZMK+ subsets. Overall, this study describes the development of immunity against SARS-CoV-2 and identifies an effector CD8+ T cell population with memory precursor-like features.


Assuntos
COVID-19/genética , COVID-19/imunologia , Interações Hospedeiro-Patógeno/imunologia , Imunofenotipagem , SARS-CoV-2/imunologia , Transcriptoma , Adulto , Idoso , Anticorpos Antivirais/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Biomarcadores , COVID-19/virologia , Plasticidade Celular/genética , Plasticidade Celular/imunologia , Evolução Clonal/imunologia , Feminino , Perfilação da Expressão Gênica , Humanos , Isotipos de Imunoglobulinas/imunologia , Memória Imunológica , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
7.
Science ; 374(6564): 216-224, 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34618582

RESUMO

The microbiota comprises the microorganisms that live in close contact with the host, with mutual benefit for both counterparts. The contribution of the gut microbiota to the emergence of castration-resistant prostate cancer (CRPC) has not yet been addressed. We found that androgen deprivation in mice and humans promotes the expansion of defined commensal microbiota that contributes to the onset of castration resistance in mice. Specifically, the intestinal microbial community in mice and patients with CRPC was enriched for species capable of converting androgen precursors into active androgens. Ablation of the gut microbiota by antibiotic therapy delayed the emergence of castration resistance even in immunodeficient mice. Fecal microbiota transplantation (FMT) from CRPC mice and patients rendered mice harboring prostate cancer resistant to castration. In contrast, tumor growth was controlled by FMT from hormone-sensitive prostate cancer patients and Prevotella stercorea administration. These results reveal that the commensal gut microbiota contributes to endocrine resistance in CRPC by providing an alternative source of androgens.


Assuntos
Androgênios/biossíntese , Bactérias/metabolismo , Microbioma Gastrointestinal/fisiologia , Interações entre Hospedeiro e Microrganismos , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/microbiologia , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Androgênios/uso terapêutico , Animais , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Bactérias/genética , Linhagem Celular Tumoral , Transplante de Microbiota Fecal , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Neoplasias Experimentais , Prevotella/metabolismo , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Simbiose , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Nat Microbiol ; 5(3): 511-524, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31988379

RESUMO

The microbiota has been shown to promote intestinal tumourigenesis, but a possible anti-tumourigenic effect has also been postulated. Here, we demonstrate that changes in the microbiota and mucus composition are concomitant with tumourigenesis. We identified two anti-tumourigenic strains of the microbiota-Faecalibaculum rodentium and its human homologue, Holdemanella biformis-that are strongly under-represented during tumourigenesis. Reconstitution of ApcMin/+ or azoxymethane- and dextran sulfate sodium-treated mice with an isolate of F. rodentium (F. PB1) or its metabolic products reduced tumour growth. Both F. PB1 and H. biformis produced short-chain fatty acids that contributed to control protein acetylation and tumour cell proliferation by inhibiting calcineurin and NFATc3 activation in mouse and human settings. We have thus identified endogenous anti-tumourigenic bacterial strains with strong diagnostic, therapeutic and translational potential.


Assuntos
Firmicutes/fisiologia , Microbioma Gastrointestinal/fisiologia , Neoplasias Intestinais/microbiologia , Intestinos/microbiologia , Adulto , Idoso , Animais , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/microbiologia , Neoplasias do Colo/terapia , DNA Bacteriano/genética , DNA Bacteriano/isolamento & purificação , Ácidos Graxos Voláteis/metabolismo , Feminino , Firmicutes/isolamento & purificação , Humanos , Hibridização in Situ Fluorescente , Neoplasias Intestinais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Pessoa de Meia-Idade , RNA Bacteriano/genética , RNA Bacteriano/isolamento & purificação
9.
Cell Rep ; 28(8): 2156-2168.e5, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31433989

RESUMO

Tumor-associated macrophages (TAMs) represent a major component of the tumor microenvironment supporting tumorigenesis. TAMs re-education has been proposed as a strategy to promote tumor inhibition. However, whether this approach may work in prostate cancer is unknown. Here we find that Pten-null prostate tumors are strongly infiltrated by TAMs expressing C-X-C chemokine receptor type 2 (CXCR2), and activation of this receptor through CXCL2 polarizes macrophages toward an anti-inflammatory phenotype. Notably, pharmacological blockade of CXCR2 receptor by a selective antagonist promoted the re-education of TAMs toward a pro-inflammatory phenotype. Strikingly, CXCR2 knockout monocytes infused in Ptenpc-/-; Trp53pc-/- mice differentiated in tumor necrosis factor alpha (TNF-α)-releasing pro-inflammatory macrophages, leading to senescence and tumor inhibition. Mechanistically, PTEN-deficient tumor cells are vulnerable to TNF-α-induced senescence, because of an increase of TNFR1. Our results identify TAMs as targets in prostate cancer and describe a therapeutic strategy based on CXCR2 blockade to harness anti-tumorigenic potential of macrophages against this disease.


Assuntos
Senescência Celular , Macrófagos/patologia , Neoplasias da Próstata/patologia , Receptores de Interleucina-8B/antagonistas & inibidores , Animais , Carcinogênese/metabolismo , Carcinogênese/patologia , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Polaridade Celular , Quimiocina CXCL2/administração & dosagem , Quimiocina CXCL2/farmacologia , Humanos , Inflamação/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estadiamento de Neoplasias , Testes de Neutralização , PTEN Fosfo-Hidrolase/metabolismo , Receptores de Interleucina-8B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Proteína Supressora de Tumor p53/metabolismo
10.
Immunol Lett ; 178: 45-9, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27091478

RESUMO

Although immunoglobulins (Ig) of the A isotype were discovered more than 50 years ago, their homeostatic function, production and specificity has only lately started to be unravelled. We have recently described that the level of IgAs is genetically determined and contributes to microbiota diversification via establishing a positive feedback loop of IgA production. Here we show that the amount of both fecal and serum IgAs is intermediate in a F1 BALB/c x C57BL/6 mixed background. Naïve mice that have never been exposed to certain bacterial strains but that carry innate IgAs that react towards those bacteria undergo de novo differentiation of antigen-specific responses, indicating that there is not just a recall of a pre-existing innate IgA response. We also demonstrate that, differently from pathogenic bacteria, a commensal does not induce systemic IgG response but only a mucosal IgA response. Thus IgAs come into different flavours and can potentiate their own production, but also drive the development of new specificities.


Assuntos
Imunoglobulina A/imunologia , Animais , Antígenos de Bactérias/imunologia , Bactérias/imunologia , Epitopos de Linfócito B/imunologia , Feminino , Patrimônio Genético , Imunidade nas Mucosas , Imunoglobulina A/sangue , Imunoglobulina A Secretora/imunologia , Imunoglobulina G/imunologia , Memória Imunológica , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Microbiota/imunologia , Mucosa/imunologia , Mucosa/metabolismo , Mucosa/microbiologia
11.
Nat Commun ; 7: 11037, 2016 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-26996437

RESUMO

Excessive activation of blood coagulation and neutrophil accumulation have been described in several human cancers. However, whether hypercoagulation and neutrophilia are linked and involved in cancer development is currently unknown. Here we show that spontaneous intestinal tumorigenesis correlates with the accumulation of low-density neutrophils with a pro-tumorigenic N2 phenotype and unprompted neutrophil extracellular traps (NET) formation. We find that increased circulating lipopolysaccharide induces upregulation of complement C3a receptor on neutrophils and activation of the complement cascade. This leads to NETosis, induction of coagulation and N2 polarization, which prompts tumorigenesis, showing a novel link between coagulation, neutrophilia and complement activation. Finally, in a cohort of patients with small but not large intestinal cancer, we find a correlation between neutrophilia and hypercoagulation. This study provides a mechanistic explanation for the tumour-promoting effects of hypercoagulation, which could be used as a new biomarker or as a therapeutic target.


Assuntos
Coagulação Sanguínea , Carcinogênese/imunologia , Carcinogênese/patologia , Armadilhas Extracelulares/metabolismo , Intestino Delgado/patologia , Neutrófilos/metabolismo , Receptores de Complemento/metabolismo , Polipose Adenomatosa do Colo/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Coagulação Sanguínea/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Ativação do Complemento/efeitos dos fármacos , Via Alternativa do Complemento/efeitos dos fármacos , Progressão da Doença , Armadilhas Extracelulares/efeitos dos fármacos , Hematopoese/efeitos dos fármacos , Hemostasia/efeitos dos fármacos , Heparina de Baixo Peso Molecular/farmacologia , Humanos , Neoplasias Intestinais/patologia , Intestino Delgado/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Modelos Biológicos , Neutrófilos/efeitos dos fármacos , Fenótipo
12.
Science ; 350(6262): 830-4, 2015 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-26564856

RESUMO

In healthy individuals, the intestinal microbiota cannot access the liver, spleen, or other peripheral tissues. Some pathogenic bacteria can reach these sites, however, and can induce a systemic immune response. How such compartmentalization is achieved is unknown. We identify a gut-vascular barrier (GVB) in mice and humans that controls the translocation of antigens into the blood stream and prohibits entry of the microbiota. Salmonella typhimurium can penetrate the GVB in a manner dependent on its pathogenicity island (Spi) 2-encoded type III secretion system and on decreased ß-catenin-dependent signaling in gut endothelial cells. The GVB is modified in celiac disease patients with elevated serum transaminases, which indicates that GVB dismantling may be responsible for liver damage in these patients. Understanding the GVB may provide new insights into the regulation of the gut-liver axis.


Assuntos
Permeabilidade Capilar/imunologia , Intestinos/imunologia , Intestinos/microbiologia , Microbiota/imunologia , Infecções por Salmonella/imunologia , Salmonella typhimurium/imunologia , Animais , Antígenos de Bactérias/sangue , Antígenos de Bactérias/imunologia , Doença Celíaca/sangue , Doença Celíaca/imunologia , Doença Celíaca/microbiologia , Ilhas Genômicas/genética , Ilhas Genômicas/imunologia , Humanos , Íleo/irrigação sanguínea , Íleo/imunologia , Íleo/microbiologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Intestinos/irrigação sanguínea , Fígado/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Salmonella typhimurium/genética , Salmonella typhimurium/patogenicidade , Transdução de Sinais , Baço/imunologia , Transaminases/sangue , Sistemas de Secreção Tipo III/genética , Sistemas de Secreção Tipo III/imunologia , Via de Sinalização Wnt , beta Catenina/metabolismo
13.
PLoS One ; 9(2): e87615, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24520333

RESUMO

The rapid expansion of commercially available fermented food products raises important safety issues particularly when infant food is concerned. In many cases, the activity of the microorganisms used for fermentation as well as what will be the immunological outcome of fermented food intake is not known. In this manuscript we used complex in vitro, ex-vivo and in vivo systems to study the immunomodulatory properties of probiotic-fermented products (culture supernatant and fermented milk without live bacteria to be used in infant formula). We found in vitro and ex-vivo that fermented products of Lactobacillus paracasei CBA L74 act via the inhibition of proinflammatory cytokine release leaving anti-inflammatory cytokines either unaffected or even increased in response to Salmonella typhimurium. These activities are not dependent on the inactivated bacteria but to metabolic products released during the fermentation process. We also show that our in vitro systems are predictive of an in vivo efficacy by the fermented products. Indeed CBA L74 fermented products (both culture medium and fermented milk) could protect against colitis and against an enteric pathogen infection (Salmonella typhimurium). Hence we found that fermented products can act via the inhibition of immune cell inflammation and can protect the host from pathobionts and enteric pathogens. These results open new perspectives in infant nutrition and suggest that L. paracasei CBA L74 fermented formula can provide immune benefits to formula-fed infants, without carrying live bacteria that may be potentially dangerous to an immature infant immune system.


Assuntos
Anti-Inflamatórios/farmacologia , Colite/prevenção & controle , Células Dendríticas/metabolismo , Fermentação/efeitos dos fármacos , Fórmulas Infantis/farmacologia , Lactobacillus/metabolismo , Leite/metabolismo , Salmonella typhimurium/efeitos dos fármacos , Administração Oral , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/uso terapêutico , Colite/tratamento farmacológico , Colite/microbiologia , Células Dendríticas/efeitos dos fármacos , Humanos , Lactente , Fórmulas Infantis/administração & dosagem , Mediadores da Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Salmonelose Animal/microbiologia , Salmonelose Animal/prevenção & controle , Salmonella typhimurium/fisiologia
14.
PLoS One ; 7(11): e50667, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23209805

RESUMO

BACKGROUND: The bacterial pathogen Salmonella causes worldwide disease. A major route of intestinal entry involves M cells, providing access to B cell-rich Peyer's Patches. Primary human B cells phagocytose Salmonella typhimurium upon recognition by the specific surface Ig receptor (BCR). As it is unclear how Salmonella disseminates systemically, we studied whether Salmonella can use B cells as a transport device for spreading. METHODOLOGY/PRINCIPAL FINDINGS: Human primary B cells or Ramos cell line were incubated with GFP-expressing Salmonella. Intracellular survival and escape was studied in vitro by live cell imaging, flow cytometry and flow imaging. HEL-specific B cells were transferred into C57BL/6 mice and HEL-expressing Salmonella spreading in vivo was analyzed investigating mesenteric lymph nodes, spleen and blood. After phagocytosis by B cells, Salmonella survives intracellularly in a non-replicative state which is actively maintained by the B cell. Salmonella is later excreted followed by reproductive infection of other cell types. Salmonella-specific B cells thus act both as a survival niche and a reservoir for reinfection. Adoptive transfer of antigen-specific B cells before oral infection of mice showed that these B cells mediate in vivo systemic spreading of Salmonella to spleen and blood. CONCLUSIONS/SIGNIFICANCE: This is a first example of a pathogenic bacterium that abuses the antigen-specific cells of the adaptive immune system for systemic spreading for dissemination of infection.


Assuntos
Linfócitos B/imunologia , Linfócitos B/microbiologia , Infecções por Salmonella/imunologia , Salmonella typhimurium/imunologia , Salmonella typhimurium/patogenicidade , Imunidade Adaptativa/fisiologia , Animais , Linhagem Celular , Células Cultivadas , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Fagocitose/fisiologia
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