RESUMEN
BACKGROUND: Transmaternal exposure to tobacco, microbes, nutrients, and other environmental factors shapes the fetal immune system through epigenetic processes. The gastric microbe Helicobacter pylori represents an ancestral constituent of the human microbiota that causes gastric disorders on the one hand and is inversely associated with allergies and chronic inflammatory conditions on the other. OBJECTIVE: Here we investigate the consequences of transmaternal exposure to H pylori in utero and/or during lactation for susceptibility to viral and bacterial infection, predisposition to allergic airway inflammation, and development of immune cell populations in the lungs and lymphoid organs. METHODS: We use experimental models of house dust mite- or ovalbumin-induced airway inflammation and influenza A virus or Citrobacter rodentium infection along with metagenomics analyses, multicolor flow cytometry, and bisulfite pyrosequencing, to study the effects of H pylori on allergy severity and immunologic and microbiome correlates thereof. RESULTS: Perinatal exposure to H pylori extract or its immunomodulator vacuolating cytotoxin confers robust protective effects against allergic airway inflammation not only in first- but also second-generation offspring but does not increase susceptibility to viral or bacterial infection. Immune correlates of allergy protection include skewing of regulatory over effector T cells, expansion of regulatory T-cell subsets expressing CXCR3 or retinoic acid-related orphan receptor γt, and demethylation of the forkhead box P3 (FOXP3) locus. The composition and diversity of the gastrointestinal microbiota is measurably affected by perinatal H pylori exposure. CONCLUSION: We conclude that exposure to H pylori has consequences not only for the carrier but also for subsequent generations that can be exploited for interventional purposes.
Asunto(s)
Infecciones por Helicobacter/inmunología , Efectos Tardíos de la Exposición Prenatal/inmunología , Efectos Tardíos de la Exposición Prenatal/microbiología , Hipersensibilidad Respiratoria/inmunología , Hipersensibilidad Respiratoria/microbiología , Linfocitos T Reguladores/inmunología , Animales , Femenino , Tolerancia Inmunológica/inmunología , Ratones Endogámicos C57BL , EmbarazoRESUMEN
The Gram-negative bacterium Helicobacter pylori is predominantly known for its tight association with peptic ulcer disease and gastric cancer development. However, recent epidemiological and experimental evidence suggests that chronic infection with H. pylori may at the same time be beneficial to the host by conferring protection against gastroesophageal diseases, asthma, other allergic disease manifestations and inflammatory bowel diseases (IBD). In this chapter, we summarize the epidemiological data that are available to date to support or refute a possible inverse correlation of H. pylori infection with various extragastric diseases. We further examine and discuss the experimental evidence, generated mostly in mouse models of allergic diseases and IBD, showing that these disorders fail to develop in the presence of H. pylori. The proposed mechanisms of the protective effects of H. pylori, which appear to involve the induction of regulatory T-cells (Tregs) with highly suppressive activity, are presented and explained.
Asunto(s)
Asma/inmunología , Infecciones por Helicobacter/microbiología , Helicobacter pylori/fisiología , Hipersensibilidad/inmunología , Enfermedades Inflamatorias del Intestino/inmunología , Animales , Asma/prevención & control , Protección Cruzada , Infecciones por Helicobacter/inmunología , Helicobacter pylori/genética , Humanos , Hipersensibilidad/prevención & control , Enfermedades Inflamatorias del Intestino/prevención & control , RatonesRESUMEN
The prevalence of allergic asthma and other atopic diseases has reached epidemic proportions in large parts of the developed world. The gradual loss of the human indigenous microbiota has been held responsible for this trend. The bacterial pathogen Helicobacter pylori is a constituent of the normal gastric microbiota whose presence has been inversely linked to allergy and asthma in humans and experimental models. Here we show that oral or i.p. tolerization with H. pylori extract prevents the airway hyperresponsiveness, bronchoalveolar eosinophilia, pulmonary inflammation, and Th2 cytokine production that are hallmarks of allergen-induced asthma in mice. Asthma protection is not conferred by extracts from other enteropathogens and requires a heat-sensitive H. pylori component and the DC-intrinsic production of IL-10. The basic leucine zipper ATF-like 3 (BATF3)-dependent CD103(+)CD11b(-) dendritic cell lineage is enriched in the lungs of protected mice and strictly required for protection. Two H. pylori persistence determinants, the γ-glutamyl-transpeptidase GGT and the vacuolating cytotoxin VacA, are required and sufficient for asthma protection and can be administered in purified form to prevent asthma. In conclusion, we provide preclinical evidence for the concept that the immunomodulatory properties of H. pylori can be exploited for tolerization strategies aiming to prevent allergen-induced asthma.
Asunto(s)
Asma/microbiología , Asma/terapia , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/inmunología , Células Dendríticas/inmunología , Helicobacter pylori/inmunología , Helicobacter pylori/patogenicidad , Factores Inmunológicos/uso terapéutico , Interleucina-10/inmunología , Proteínas Represoras/inmunología , Alérgenos/administración & dosificación , Animales , Antígenos Bacterianos/administración & dosificación , Asma/inmunología , Proteínas Bacterianas/inmunología , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/deficiencia , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Modelos Animales de Enfermedad , Humanos , Tolerancia Inmunológica , Interleucina-18/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Represoras/deficiencia , Proteínas Represoras/genética , Linfocitos T Reguladores/inmunología , gamma-Glutamiltransferasa/inmunologíaRESUMEN
The gastrointestinal (GI) tract microbiota is required for optimal digestion of foods, for the development of resistance against pathogens (termed colonization resistance), for the development of mucosa-associated lymphoid tissue, and for local as well as systemic immune homeostasis. Certain constituents of the GI tract microbiota are widely recognized as critical regulators and modulators of their host's immune response. These include bacterial members of the microbiota as well as parasitic nematodes. Immune regulation by immunomodulatory members of the GI microbiota primarily serves to subvert host antimicrobial immune defenses and promote persistent colonization, but as a side effect may prevent or suppress immunological disorders resulting from inappropriate responses to harmless antigens, such as allergy, colitis or autoimmunity. Many of the best understood GI-resident immunomodulatory species have co-evolved with their mammalian hosts for tens of thousands of years and masterfully manipulate host immune responses. In this review, we discuss the epidemiological evidence for the role of the GI tract microbiota as a whole, and of specific members, in protection against allergic and other immunological disorders. We then focus on the mechanistic basis of microbial immunomodulation, which is presented using several well-understood paradigmatic examples, that is, helminths, Helicobacter pylori, Bifidobacteria and Lactobacilli. In a final chapter, we highlight past and ongoing attempts at harnessing the immunomodulatory properties of GI microbiota species and their secreted products for intervention studies and describe the promises and limitations of these experimental approaches. The effects of pro- and prebiotics, bacterial lysates, as well as of fecal microbiota transplantation are presented and compared.
Asunto(s)
Microbioma Gastrointestinal , Hipersensibilidad/microbiología , Animales , Ensayos Clínicos como Asunto , Microbioma Gastrointestinal/efectos de los fármacos , Humanos , Hipersensibilidad/inmunología , Tolerancia Inmunológica/efectos de los fármacos , Factores Inmunológicos/farmacología , Factores Inmunológicos/uso terapéutico , Factores de RiesgoRESUMEN
Eosinophils are predominantly known for their contribution to allergy. Here, we have examined the function and regulation of gastrointestinal eosinophils in the steady-state and during infection with Helicobacter pylori or Citrobacter rodentium We find that eosinophils are recruited to sites of infection, directly encounter live bacteria, and activate a signature transcriptional program; this applies also to human gastrointestinal eosinophils in humanized mice. The genetic or anti-IL-5-mediated depletion of eosinophils results in improved control of the infection, increased inflammation, and more pronounced Th1 responses. Eosinophils control Th1 responses via the IFN-γ-dependent up-regulation of PD-L1. Furthermore, we find that the conditional loss of IFN-γR in eosinophils phenocopies the effects of eosinophil depletion. Eosinophils further possess bactericidal properties that require their degranulation and the deployment of extracellular traps. Our results highlight two novel functions of this elusive cell type and link it to gastrointestinal homeostasis and anti-bacterial defense.
Asunto(s)
Citrobacter rodentium/fisiología , Eosinófilos/inmunología , Tracto Gastrointestinal/microbiología , Tracto Gastrointestinal/patología , Helicobacter pylori/fisiología , Inflamación/inmunología , Inflamación/microbiología , Células TH1/inmunología , Enfermedad Aguda , Animales , Anticuerpos Antibacterianos/inmunología , Infecciones Bacterianas/inmunología , Infecciones Bacterianas/microbiología , Infecciones Bacterianas/patología , Degranulación de la Célula , Proliferación Celular , Colitis/inmunología , Colitis/microbiología , Colitis/patología , Citocinas/biosíntesis , Modelos Animales de Enfermedad , Eosinófilos/fisiología , Trampas Extracelulares/metabolismo , Tracto Gastrointestinal/inmunología , Homeostasis , Inmunidad Innata , Inmunidad Mucosa , Inflamación/patología , Interferón gamma/metabolismo , Ratones Endogámicos C57BL , Transducción de Señal , Células Th17/inmunologíaRESUMEN
BACKGROUND: The Gram-negative bacterium Helicobacter pylori is a constituent of the human gastric microbiota. Chronic infection with H. pylori causes gastritis and predisposes to gastric carcinoma but has also been inversely linked to various allergic and chronic inflammatory conditions. In particular, large meta-analyses have documented an inverse association between H. pylori infection and the risk of developing ulcerative colitis and Crohn's disease. METHODS: We investigated possible protective effects of experimental H. pylori infection and of regular treatment with H. pylori extract in 2 mouse models of colitis and in mouse models of type I diabetes and multiple sclerosis. The mechanism of protection was examined in mouse strains lacking specific innate immune recognition pathways and cytokines. RESULTS: We show here that experimental infection with H. pylori and administration of regular doses of H. pylori extract both alleviate the clinical and histopathological features of dextran sodium sulfate-induced chronic colitis and of T-cell transfer-induced colitis. High resolution endoscopy of the protected animals revealed the accumulation of large amounts of colonic mucus upon H. pylori exposure, which could be attributed to transcriptional activation of the mucin 2 gene. The protection against dextran sodium sulfate-induced colitis was dependent on the NLRP3 inflammasome and interleukin-18 signaling. Other autoimmune diseases, i.e., experimental autoimmune encephalomyelitis and type I diabetes, were not controlled by H. pylori. CONCLUSIONS: In summary, we propose here that the immunomodulatory activity of an ancient constituent of the gut microbiota, H. pylori, may be exploited for the prevention and/or treatment of inflammatory bowel diseases.
Asunto(s)
Proteínas Portadoras/metabolismo , Colitis/prevención & control , Infecciones por Helicobacter/inmunología , Helicobacter pylori/inmunología , Interleucina-18/metabolismo , Animales , Colitis/inducido químicamente , Colitis/microbiología , Sulfato de Dextran/toxicidad , Diabetes Mellitus Experimental/microbiología , Diabetes Mellitus Experimental/prevención & control , Diabetes Mellitus Tipo 1/prevención & control , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/microbiología , Encefalomielitis Autoinmune Experimental/prevención & control , Infecciones por Helicobacter/inducido químicamente , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Mucina 2/genética , Mucina 2/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR , Transducción de Señal , Linfocitos T/inmunología , Activación Transcripcional , Regulación hacia ArribaRESUMEN
Inflammasome activation and caspase-1-dependent (CASP1-dependent) processing and secretion of IL-1ß and IL-18 are critical events at the interface of the bacterial pathogen Helicobacter pylori with its host. Whereas IL-1ß promotes Th1 and Th17 responses and gastric immunopathology, IL-18 is required for Treg differentiation, H. pylori persistence, and protection against allergic asthma, which is a hallmark of H. pylori-infected mice and humans. Here, we show that inflammasome activation in DCs requires the cytoplasmic sensor NLRP3 as well as induction of TLR2 signaling by H. pylori. Screening of an H. pylori transposon mutant library revealed that pro-IL-1ß expression is induced by LPS from H. pylori, while the urease B subunit (UreB) is required for NLRP3 inflammasome licensing. UreB activates the TLR2-dependent expression of NLRP3, which represents a rate-limiting step in NLRP3 inflammasome assembly. ureB-deficient H. pylori mutants were defective for CASP1 activation in murine bone marrow-derived DCs, splenic DCs, and human blood-derived DCs. Despite colonizing the murine stomach, ureB mutants failed to induce IL-1ß and IL-18 secretion and to promote Treg responses. Unlike WT H. pylori, ureB mutants were incapable of conferring protection against allergen-induced asthma in murine models. Together, these results indicate that the TLR2/NLRP3/CASP1/IL-18 axis is critical to H. pylori-specific immune regulation.
Asunto(s)
Asma/prevención & control , Proteínas Bacterianas/inmunología , Proteínas Portadoras/inmunología , Helicobacter pylori/inmunología , Péptidos y Proteínas de Señalización Intercelular/inmunología , Receptor Toll-Like 2/inmunología , Ureasa/inmunología , Animales , Asma/genética , Asma/inmunología , Proteínas Bacterianas/genética , Proteínas Portadoras/genética , Células Dendríticas/inmunología , Regulación de la Expresión Génica/efectos de los fármacos , Helicobacter pylori/genética , Humanos , Inflamasomas/genética , Inflamasomas/inmunología , Péptidos y Proteínas de Señalización Intercelular/genética , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Ratones , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR , Receptor Toll-Like 2/genética , Ureasa/genéticaRESUMEN
Light-dependent gene regulation systems are advantageous as they allow for precise spatio-temporal control of target gene expression. In this paper, we present a novel UV-A and blue-light-inducible gene control system that is based on the light-dependent heterodimerization of the CRY2 and C1BN domains. Upon their interaction, a transcription factor is released from the cell membrane and initiates target gene expression. Capitalizing on that, sun cream UV-A protection properties were measured intracellularly.