Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 196
Filtrar
Más filtros

Banco de datos
Tipo del documento
Intervalo de año de publicación
1.
Cell ; 184(5): 1214-1231.e16, 2021 03 04.
Artículo en Inglés | MEDLINE | ID: mdl-33636133

RESUMEN

Although enteric helminth infections modulate immunity to mucosal pathogens, their effects on systemic microbes remain less established. Here, we observe increased mortality in mice coinfected with the enteric helminth Heligmosomoides polygyrus bakeri (Hpb) and West Nile virus (WNV). This enhanced susceptibility is associated with altered gut morphology and transit, translocation of commensal bacteria, impaired WNV-specific T cell responses, and increased virus infection in the gastrointestinal tract and central nervous system. These outcomes were due to type 2 immune skewing, because coinfection in Stat6-/- mice rescues mortality, treatment of helminth-free WNV-infected mice with interleukin (IL)-4 mirrors coinfection, and IL-4 receptor signaling in intestinal epithelial cells mediates the susceptibility phenotypes. Moreover, tuft cell-deficient mice show improved outcomes with coinfection, whereas treatment of helminth-free mice with tuft cell-derived cytokine IL-25 or ligand succinate worsens WNV disease. Thus, helminth activation of tuft cell-IL-4-receptor circuits in the gut exacerbates infection and disease of a neurotropic flavivirus.


Asunto(s)
Coinfección , Nematospiroides dubius/fisiología , Transducción de Señal , Infecciones por Strongylida/patología , Virus del Nilo Occidental/fisiología , Animales , Linfocitos T CD8-positivos/inmunología , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Mucosa Intestinal/parasitología , Mucosa Intestinal/virología , Ratones , Ratones Endogámicos C57BL , Neuronas/parasitología , Neuronas/virología , Receptores de Interleucina-4/metabolismo , Factor de Transcripción STAT6/genética , Índice de Severidad de la Enfermedad , Infecciones por Strongylida/parasitología
2.
Nat Immunol ; 24(8): 1256-1264, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37400674

RESUMEN

Innate lymphoid cells (ILCs) can quickly switch from a quiescent state to an active state and rapidly produce effector molecules that provide critical early immune protection. How the post-transcriptional machinery processes different stimuli and initiates robust gene expression in ILCs is poorly understood. Here, we show that deletion of the N6-methyladenosine (m6A) writer protein METTL3 has little impact on ILC homeostasis or cytokine-induced ILC1 or ILC3 responses but significantly diminishes ILC2 proliferation, migration and effector cytokine production and results in impaired antihelminth immunity. m6A RNA modification supports an increase in cell size and transcriptional activity in activated ILC2s but not in ILC1s or ILC3s. Among other transcripts, the gene encoding the transcription factor GATA3 is highly m6A methylated in ILC2s. Targeted m6A demethylation destabilizes nascent Gata3 mRNA and abolishes the upregulation of GATA3 and ILC2 activation. Our study suggests a lineage-specific requirement of m6A for ILC2 responses.


Asunto(s)
Inmunidad Innata , Linfocitos , Citocinas/metabolismo , Homeostasis , Inmunidad Innata/genética , Inmunidad Innata/inmunología , Linfocitos/inmunología , ARN/metabolismo , Animales , Ratones
3.
Nat Immunol ; 20(6): 687-700, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-31061528

RESUMEN

Most tissue-resident macrophage populations develop during embryogenesis, self-renew in the steady state and expand during type 2 immunity. Whether shared mechanisms regulate the proliferation of macrophages in homeostasis and disease is unclear. Here we found that the transcription factor Bhlhe40 was required in a cell-intrinsic manner for the self-renewal and maintenance of large peritoneal macrophages (LPMs), but not that of other tissue-resident macrophages. Bhlhe40 was necessary for the proliferation, but not the polarization, of LPMs in response to the cytokine IL-4. During infection with the helminth Heligmosomoides polygyrus bakeri, Bhlhe40 was required for cell cycling of LPMs. Bhlhe40 repressed the expression of genes encoding the transcription factors c-Maf and Mafb and directly promoted expression of transcripts encoding cell cycle-related proteins to enable the proliferation of LPMs. In LPMs, Bhlhe40 bound to genomic sites co-bound by the macrophage lineage-determining factor PU.1 and to unique sites, including Maf and loci encoding cell-cycle-related proteins. Our findings demonstrate a tissue-specific control mechanism that regulates the proliferation of resident macrophages in homeostasis and type 2 immunity.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Proteínas de Homeodominio/genética , Homeostasis/genética , Homeostasis/inmunología , Inmunidad/genética , Macrófagos/inmunología , Macrófagos/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Biomarcadores , Ciclo Celular/genética , Ciclo Celular/inmunología , Proliferación Celular , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Técnicas de Inactivación de Genes , Infecciones por Helicobacter/genética , Infecciones por Helicobacter/inmunología , Helicobacter pylori/inmunología , Proteínas de Homeodominio/metabolismo , Inmunofenotipificación , Macrófagos Peritoneales/inmunología , Macrófagos Peritoneales/metabolismo , Ratones , Ratones Transgénicos , Monocitos/inmunología , Monocitos/metabolismo , Especificidad de Órganos/genética , Especificidad de Órganos/inmunología , Transcriptoma
4.
Cell ; 165(5): 1120-1133, 2016 May 19.
Artículo en Inglés | MEDLINE | ID: mdl-27156451

RESUMEN

Innate lymphoid cells (ILCs) play key roles in host defense, barrier integrity, and homeostasis and mirror adaptive CD4(+) T helper (Th) cell subtypes in both usage of effector molecules and transcription factors. To better understand the relationship between ILC subsets and their Th cell counterparts, we measured genome-wide chromatin accessibility. We find that chromatin in proximity to effector genes is selectively accessible in ILCs prior to high-level transcription upon activation. Accessibility of these regions is acquired in a stepwise manner during development and changes little after in vitro or in vivo activation. Conversely, dramatic chromatin remodeling occurs in naive CD4(+) T cells during Th cell differentiation using a type-2-infection model. This alteration results in a substantial convergence of Th2 cells toward ILC2 regulomes. Our data indicate extensive sharing of regulatory circuitry across the innate and adaptive compartments of the immune system, in spite of their divergent developing pathways.


Asunto(s)
Redes Reguladoras de Genes , Linfocitos/citología , Linfocitos/inmunología , Animales , Linaje de la Célula , Femenino , Regulación de la Expresión Génica , Linfocitos/metabolismo , Ratones , Ratones Endogámicos C57BL , Transcriptoma
5.
Immunity ; 54(1): 151-163.e6, 2021 01 12.
Artículo en Inglés | MEDLINE | ID: mdl-33220232

RESUMEN

The gastrointestinal tract is known as the largest endocrine organ that encounters and integrates various immune stimulations and neuronal responses due to constant environmental challenges. Enterochromaffin (EC) cells, which function as chemosensors on the gut epithelium, are known to translate environmental cues into serotonin (5-HT) production, contributing to intestinal physiology. However, how immune signals participate in gut sensation and neuroendocrine response remains unclear. Interleukin-33 (IL-33) acts as an alarmin cytokine by alerting the system of potential environmental stresses. We here demonstrate that IL-33 induced instantaneous peristaltic movement and facilitated Trichuris muris expulsion. We found that IL-33 could be sensed by EC cells, inducing release of 5-HT. IL-33-mediated 5-HT release activated enteric neurons, subsequently promoting gut motility. Mechanistically, IL-33 triggered calcium influx via a non-canonical signaling pathway specifically in EC cells to induce 5-HT secretion. Our data establish an immune-neuroendocrine axis in calibrating rapid 5-HT release for intestinal homeostasis.


Asunto(s)
Células Enterocromafines/fisiología , Interleucina-33/metabolismo , Intestinos/fisiología , Neuronas/fisiología , Serotonina/metabolismo , Tricuriasis/inmunología , Trichuris/fisiología , Animales , Señalización del Calcio , Homeostasis , Interleucina-33/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuroinmunomodulación , Peristaltismo
6.
Nat Immunol ; 17(5): 538-44, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-27043413

RESUMEN

Acidic mammalian chitinase (AMCase) is known to be induced by allergens and helminths, yet its role in immunity is unclear. Using AMCase-deficient mice, we show that AMCase deficiency reduced the number of group 2 innate lymphoid cells during allergen challenge but was not required for establishment of type 2 inflammation in the lung in response to allergens or helminths. In contrast, AMCase-deficient mice showed a profound defect in type 2 immunity following infection with the chitin-containing gastrointestinal nematodes Nippostrongylus brasiliensis and Heligmosomoides polygyrus bakeri. The impaired immunity was associated with reduced mucus production and decreased intestinal expression of the signature type 2 response genes Il13, Chil3, Retnlb, and Clca1. CD103(+) dendritic cells, which regulate T cell homing, were also reduced in mesenteric lymph nodes of infected AMCase-deficient mice. Thus, AMCase functions as a critical initiator of protective type 2 responses to intestinal nematodes but is largely dispensable for allergic responses in the lung.


Asunto(s)
Quitinasas/inmunología , Tracto Gastrointestinal/inmunología , Inmunidad/inmunología , Infecciones por Strongylida/inmunología , Animales , Quitinasas/genética , Quitinasas/metabolismo , Canales de Cloruro/genética , Canales de Cloruro/inmunología , Canales de Cloruro/metabolismo , Citometría de Flujo , Tracto Gastrointestinal/metabolismo , Tracto Gastrointestinal/parasitología , Expresión Génica/inmunología , Hormonas Ectópicas/genética , Hormonas Ectópicas/inmunología , Hormonas Ectópicas/metabolismo , Interacciones Huésped-Parásitos/inmunología , Hipersensibilidad/genética , Hipersensibilidad/inmunología , Hipersensibilidad/metabolismo , Inmunidad/genética , Péptidos y Proteínas de Señalización Intercelular , Interleucina-13/genética , Interleucina-13/inmunología , Interleucina-13/metabolismo , Lectinas/genética , Lectinas/inmunología , Lectinas/metabolismo , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Fluorescente , Nematospiroides dubius/inmunología , Nematospiroides dubius/fisiología , Nippostrongylus/inmunología , Nippostrongylus/fisiología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Infecciones por Strongylida/metabolismo , Infecciones por Strongylida/parasitología , beta-N-Acetilhexosaminidasas/genética , beta-N-Acetilhexosaminidasas/inmunología , beta-N-Acetilhexosaminidasas/metabolismo
7.
Immunity ; 50(5): 1188-1201.e6, 2019 05 21.
Artículo en Inglés | MEDLINE | ID: mdl-31053504

RESUMEN

Lymph nodes (LNs) play critical roles in adaptive immunity by concentrating in one location the antigens, antigen-presenting cells, and antigen-responsive lymphocytes involved in such responses. Recent studies have revealed nonrandom localization of innate and adaptive immune cells within these organs, suggesting that microanatomical positioning optimizes responses involving sparse cooperating cells. Here, we report that the peripheral localization of LN cDC2 dendritic cells specialized for MHC-II antigen presentation is matched by a similarly biased paracortical distribution of CD4+ T cells directed by the chemoattractant receptor Ebi2. In the absence of Ebi2, CD4+ T cells lose their location bias and are delayed in antigen recognition, proliferative expansion, differentiation, direct effector activity, and provision of help for CD8+ T cell-mediated memory responses, limiting host defense and vaccine responses. These findings demonstrate evolutionary selection for distinct niches within the LN that promote cellular responses, emphasizing the critical link between fine-grained tissue organization and host defense.


Asunto(s)
Inmunidad Adaptativa/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Células Dendríticas/inmunología , Receptores Acoplados a Proteínas G/metabolismo , Animales , Presentación de Antígeno/inmunología , Antígenos/inmunología , Diferenciación Celular/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores Acoplados a Proteínas G/genética
8.
Immunity ; 51(4): 682-695.e6, 2019 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-31353223

RESUMEN

Innate lymphocytes maintain tissue homeostasis at mucosal barriers, with group 2 innate lymphoid cells (ILC2s) producing type 2 cytokines and controlling helminth infection. While the molecular understanding of ILC2 responses has advanced, the complexity of microenvironmental factors impacting ILC2s is becoming increasingly apparent. Herein, we used single-cell analysis to explore the diversity of gene expression among lung lymphocytes during helminth infection. Following infection, we identified a subset of ILC2s that preferentially expressed Il5-encoding interleukin (IL)-5, together with Calca-encoding calcitonin gene-related peptide (CGRP) and its cognate receptor components. CGRP in concert with IL-33 and neuromedin U (NMU) supported IL-5 but constrained IL-13 expression and ILC2 proliferation. Without CGRP signaling, ILC2 responses and worm expulsion were enhanced. Collectively, these data point to CGRP as a context-dependent negative regulatory factor that shapes innate lymphocyte responses to alarmins and neuropeptides during type 2 innate immune responses.


Asunto(s)
Inflamación/inmunología , Linfocitos/inmunología , Nippostrongylus/fisiología , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Infecciones por Strongylida/inmunología , Animales , Células Cultivadas , Citocinas/metabolismo , Inmunidad Innata , Interleucina-33/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuropéptidos/metabolismo , Receptores de Péptido Relacionado con el Gen de Calcitonina/genética , Análisis de la Célula Individual , Células Th2/inmunología , Quimera por Trasplante
9.
Nat Immunol ; 16(10): 1051-9, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26322482

RESUMEN

Type 2 helper T cells (TH2 cells) produce interleukin 13 (IL-13) when stimulated by papain or house dust mite extract (HDM) and induce eosinophilic inflammation. This innate response is dependent on IL-33 but not T cell antigen receptors (TCRs). While type 2 innate lymphoid cells (ILC2 cells) are the dominant innate producers of IL-13 in naive mice, we found here that helminth-infected mice had more TH2 cells compared to uninfected mice, and thes e cells became major mediators of innate type 2 responses. TH2 cells made important contributions to HDM-induced antigen-nonspecific eosinophilic inflammation and protected mice recovering from infection with Ascaris suum against subsequent infection with the phylogenetically distant nematode Nippostrongylus brasiliensis. Our findings reveal a previously unappreciated role for effector TH2 cells during TCR-independent innate-like immune responses.


Asunto(s)
Inmunidad Innata , Células Th2/inmunología , Animales , Citometría de Flujo , Helmintiasis/inmunología , Helmintos/inmunología , Pulmón/citología , Pulmón/inmunología , Linfocitos/inmunología , Ratones , Reacción en Cadena de la Polimerasa
10.
Nat Immunol ; 16(2): 161-9, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25531830

RESUMEN

Innate lymphoid cells (ILCs) are lymphocyte-like cells that lack T cell or B cell antigen receptors and mediate protective and repair functions through cytokine secretion. Among these, type 2 ILCs (ILC2 cells) are able to produce type 2 cytokines. We report the existence of an inflammatory ILC2 (iILC2) population responsive to interleukin 25 (IL-25) that complemented IL-33-responsive natural ILC2 (nILC2) cells. iILC2 cells developed into nILC2-like cells in vitro and in vivo and contributed to the expulsion of Nippostrongylus brasiliensis. They also acquired IL-17-producing ability and provided partial protection against Candida albicans. We propose that iILC2 cells are transient progenitors of ILCs mobilized by inflammation and infection that develop into nILC2-like cells or ILC3-like cells and contribute to immunity to both helminths and fungi.


Asunto(s)
Interleucina-17/metabolismo , Linfocitos/inmunología , Receptores Inmunológicos/metabolismo , Animales , Animales Modificados Genéticamente , Candida albicans/inmunología , Candidiasis/inmunología , Linaje de la Célula , Eliminación de Gen , Inflamación/inmunología , Lectinas Tipo C , Leucocitos/inmunología , Pulmón/inmunología , Pulmón/patología , Linfocitos/citología , Ratones , Nippostrongylus/inmunología , Receptores Inmunológicos/genética , Receptores de Interleucina-7/metabolismo , Infecciones por Strongylida/inmunología
11.
Immunity ; 49(5): 915-928.e5, 2018 11 20.
Artículo en Inglés | MEDLINE | ID: mdl-30446384

RESUMEN

Innate lymphoid cells (ILCs) are important for mucosal immunity. The intestine harbors all ILC subsets, but how these cells are balanced to achieve immune homeostasis and mount appropriate responses during infection remains elusive. Here, we show that aryl hydrocarbon receptor (Ahr) expression in the gut regulates ILC balance. Among ILCs, Ahr is most highly expressed by gut ILC2s and controls chromatin accessibility at the Ahr locus via positive feedback. Ahr signaling suppresses Gfi1 transcription-factor-mediated expression of the interleukin-33 (IL-33) receptor ST2 in ILC2s and expression of ILC2 effector molecules IL-5, IL-13, and amphiregulin in a cell-intrinsic manner. Ablation of Ahr enhances anti-helminth immunity in the gut, whereas genetic or pharmacological activation of Ahr suppresses ILC2 function but enhances ILC3 maintenance to protect the host from Citrobacter rodentium infection. Thus, the host regulates the gut ILC2-ILC3 balance by engaging the Ahr pathway to mount appropriate immunity against various pathogens.


Asunto(s)
Inmunidad Innata , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Receptores de Hidrocarburo de Aril/metabolismo , Animales , Biomarcadores , Cromatina/genética , Cromatina/metabolismo , Citrobacter rodentium/inmunología , Infecciones por Enterobacteriaceae/inmunología , Infecciones por Enterobacteriaceae/microbiología , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Sitios Genéticos , Interacciones Huésped-Parásitos/inmunología , Inmunidad Mucosa/genética , Inmunofenotipificación , Proteína 1 Similar al Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Ratones , Ratones Noqueados , Receptores de Hidrocarburo de Aril/genética , Transcriptoma
12.
Nat Immunol ; 15(10): 938-46, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25173346

RESUMEN

We examined the role of innate cells in acquired resistance to the natural murine parasitic nematode, Nippostrongylus brasiliensis. Macrophages obtained from lungs as late as 45 d after N. brasiliensis inoculation were able to transfer accelerated parasite clearance to naive recipients. Primed macrophages adhered to larvae in vitro and triggered increased mortality of parasites. Neutrophil depletion in primed mice abrogated the protective effects of transferred macrophages and inhibited their in vitro binding to larvae. Neutrophils in parasite-infected mice showed a distinct transcriptional profile and promoted alternatively activated M2 macrophage polarization through secretory factors including IL-13. Differentially activated neutrophils in the context of a type 2 immune response therefore prime a long-lived effector macrophage phenotype that directly mediates rapid nematode damage and clearance.


Asunto(s)
Inmunidad Adaptativa/inmunología , Macrófagos/inmunología , Neutrófilos/inmunología , Nippostrongylus/inmunología , Infecciones por Strongylida/inmunología , Animales , Adhesión Celular/inmunología , Adhesión Celular/fisiología , Células Cultivadas , Citocinas/genética , Citocinas/inmunología , Citocinas/metabolismo , Resistencia a la Enfermedad/inmunología , Femenino , Citometría de Flujo , Interacciones Huésped-Parásitos/inmunología , Interleucina-13/genética , Interleucina-13/inmunología , Interleucina-13/metabolismo , Subunidad alfa del Receptor de Interleucina-4/genética , Subunidad alfa del Receptor de Interleucina-4/inmunología , Subunidad alfa del Receptor de Interleucina-4/metabolismo , Larva/inmunología , Larva/fisiología , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/parasitología , Macrófagos/metabolismo , Ratones Endogámicos BALB C , Ratones Noqueados , Neutrófilos/metabolismo , Nippostrongylus/fisiología , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Infecciones por Strongylida/genética , Infecciones por Strongylida/parasitología , Transcriptoma/inmunología
13.
Nat Immunol ; 15(9): 846-55, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25086775

RESUMEN

Alternative (M2) activation of macrophages driven via the α-chain of the receptor for interleukin 4 (IL-4Rα) is important for immunity to parasites, wound healing, the prevention of atherosclerosis and metabolic homeostasis. M2 polarization is dependent on fatty acid oxidation (FAO), but the source of the fatty acids that support this metabolic program has not been clear. We found that the uptake of triacylglycerol substrates via the scavenger receptor CD36 and their subsequent lipolysis by lysosomal acid lipase (LAL) was important for the engagement of elevated oxidative phosphorylation, enhanced spare respiratory capacity (SRC), prolonged survival and expression of genes that together define M2 activation. Inhibition of lipolysis suppressed M2 activation during infection with a parasitic helminth and blocked protective responses to this pathogen. Our findings delineate a critical role for cell-intrinsic lysosomal lipolysis in M2 activation.


Asunto(s)
Antígenos CD36/inmunología , Ácidos Grasos/metabolismo , Interleucina-4/inmunología , Lipólisis/inmunología , Lisosomas/inmunología , Activación de Macrófagos/inmunología , Macrófagos/inmunología , Fosforilación Oxidativa , Transducción de Señal/inmunología , Esterol Esterasa/inmunología , Animales , Respiración de la Célula , Helmintiasis Animal/inmunología , Humanos , Ratones , Consumo de Oxígeno , Receptores de Interleucina-4/inmunología , Transcriptoma
14.
J Immunol ; 211(3): 389-402, 2023 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-37272847

RESUMEN

The impact of endemic parasitic infection on vaccine efficacy is an important consideration for vaccine development and deployment. We have examined whether intestinal infection with the natural murine helminth Heligmosomoides polygyrus bakeri alters Ag-specific Ab and cellular immune responses to oral and parenteral vaccination in mice. Oral vaccination of mice with a clinically relevant, live, attenuated, recombinant Salmonella vaccine expressing chicken egg OVA (Salmonella-OVA) induced the accumulation of activated, OVA-specific T effector cells rather than OVA-specific regulatory T cells in the GALT. Intestinal helminth infection significantly reduced Th1-skewed Ab responses to oral vaccination with Salmonella-OVA. Activated, adoptively transferred, OVA-specific CD4+ T cells accumulated in draining mesenteric lymph nodes of vaccinated mice, regardless of their helminth infection status. However, helminth infection increased the frequencies of adoptively transferred OVA-specific CD4+ T cells producing IL-4 and IL-10 in the mesenteric lymph node. Ab responses to the oral Salmonella-OVA vaccine were reduced in helminth-free mice adoptively transferred with OVA-specific CD4+ T cells harvested from mice with intestinal helminth infection. Intestinal helminth infection also significantly reduced Th2-skewed Ab responses to parenteral vaccination with OVA adsorbed to alum. These findings suggest that vaccine-specific CD4+ T cells induced in the context of helminth infection retain durable immunomodulatory properties and may promote blunted Ab responses to vaccination. They also underscore the potential need to treat parasitic infection before mass vaccination campaigns in helminth-endemic areas.


Asunto(s)
Helmintiasis , Parasitosis Intestinales , Ratones , Animales , Eficacia de las Vacunas , Linfocitos T CD4-Positivos , Vacunas Sintéticas , Ovalbúmina , Ratones Endogámicos BALB C
15.
J Immunol ; 208(8): 2008-2018, 2022 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-35354611

RESUMEN

IL-27 is a heterodimeric IL-12 family cytokine formed by noncovalent association of the promiscuous EBI3 subunit and selective p28 subunit. IL-27 is produced by mononuclear phagocytes and unfolds pleiotropic immune-modulatory functions through ligation to IL-27 receptor α (IL-27RA). Although IL-27 is known to contribute to immunity and to limit inflammation after various infections, its relevance for host defense against multicellular parasites is still poorly defined. Here, we investigated the role of IL-27 during infection with the soil-transmitted hookworm, Nippostrongylus brasiliensis, in its early host intrapulmonary life cycle. IL-27(p28) was detectable in bronchoalveolar lavage fluid of C57BL/6J wild-type mice on day 1 after s.c. inoculation. IL-27RA expression was most abundant on lung-invading γδ T cells. Il27ra-/- mice showed increased lung parasite burden together with aggravated pulmonary hemorrhage and higher alveolar total protein leakage as a surrogate for epithelial-vascular barrier disruption. Conversely, injections of recombinant mouse (rm)IL-27 into wild-type mice reduced lung injury and parasite burden. In multiplex screens, higher airway accumulations of IL-6, TNF-α, and MCP-3 (CCL7) were observed in Il27ra-/- mice, whereas rmIL-27 treatment showed a reciprocal effect. Importantly, γδ T cell numbers in airways were enhanced by endogenous or administered IL-27. Further analysis revealed a direct antihelminthic function of IL-27 on γδ T cells as adoptive intratracheal transfer of rmIL-27-treated γδ T cells during primary N. brasiliensis lung infection conferred protection in mice. In summary, this report demonstrates protective functions of IL-27 to control the early lung larval stage of hookworm infection.


Asunto(s)
Infecciones por Uncinaria , Interleucina-27 , Animales , Interleucinas , Pulmón , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Antígenos de Linfocitos T gamma-delta
16.
Proc Natl Acad Sci U S A ; 118(30)2021 07 27.
Artículo en Inglés | MEDLINE | ID: mdl-34290141

RESUMEN

"Taste-like" tuft cells in the intestine trigger type 2 immunity in response to worm infection. The secretion of interleukin-13 (IL-13) from type 2 innate lymphoid cells (ILC2) represents a key step in the tuft cell-ILC2 cell-intestinal epithelial cell circuit that drives the clearance of worms from the gut via type 2 immune responses. Hallmark features of type 2 responses include tissue remodeling, such as tuft and goblet cell expansion, and villus atrophy, yet it remains unclear if additional molecular changes in the gut epithelium facilitate the clearance of worms from the gut. Using gut organoids, we demonstrated that IL-4 and IL-13, two type 2 cytokines with similar functions, not only induced the classical type 2 responses (e.g., tuft cell expansion) but also drastically up-regulated the expression of gasdermin C genes (Gsdmcs). Using an in vivo worm-induced type 2 immunity model, we confirmed the up-regulation of Gsdmcs in Nippostrongylus brasiliensis-infected wild-type C57BL/6 mice. Consistent with gasdermin family members being principal effectors of pyroptosis, overexpression of Gsdmc2 in human embryonic kidney 293 (HEK293) cells triggered pyroptosis and lytic cell death. Moreover, in intestinal organoids treated with IL-4 or IL-13, or in wild-type mice infected with N. brasiliensis, lytic cell death increased, which may account for villus atrophy observed in worm-infected mice. Thus, we propose that the up-regulated Gsdmc family may be major effectors for type 2 responses in the gut and that Gsdmc-mediated pyroptosis may provide a conduit for the release of antiparasitic factors from enterocytes to facilitate the clearance of worms.


Asunto(s)
Muerte Celular , Proteínas de Unión al ADN/metabolismo , Enterocitos/patología , Inmunidad Innata/inmunología , Intestino Delgado/patología , Infecciones por Strongylida/complicaciones , Células Th2/inmunología , Animales , Proliferación Celular , Proteínas de Unión al ADN/genética , Enterocitos/inmunología , Enterocitos/metabolismo , Enterocitos/parasitología , Femenino , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Intestino Delgado/inmunología , Intestino Delgado/metabolismo , Intestino Delgado/parasitología , Masculino , Ratones , Ratones Endogámicos C57BL , Nippostrongylus/fisiología , Transducción de Señal , Infecciones por Strongylida/inmunología , Infecciones por Strongylida/metabolismo , Infecciones por Strongylida/parasitología
17.
Eur J Immunol ; 51(2): 433-444, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33067820

RESUMEN

Infection with parasitic worms (helminths) alters host immune responses and can inhibit pathogenic inflammation. Helminth infection promotes a strong Th2 and T regulatory response while suppressing Th1 and Th17 function. Th2 responses are largely dependent on transcriptional programs directed by Stat6-signaling. We examined the importance of intact T cell Stat6 signaling on helminth-induced suppression of murine colitis that results from T cell transfer into immune-deficient mice. Colonization with the intestinal nematode Heligmosomoides polygyrus bakeri resolves WT T cell transfer colitis. However, if the transferred T cells lack intact Stat6 then helminth exposure failed to attenuate colitis or suppress MLN T cell IFN-γ or IL17 production. Loss of Stat6 signaling resulted in decreased IL10 and increased IFN-γ co-expression by IL-17+ T cells. We also transferred T cells from mice with constitutive T cell expression of activated Stat6 (Stat6VT). These mice developed a severe eosinophilic colitis that also was not attenuated by helminth infection. These results show that T cell expression of intact but regulated Stat6 signaling is required for helminth infection-associated regulation of pathogenic intestinal inflammation.


Asunto(s)
Colitis/inmunología , Nematospiroides dubius/inmunología , Factor de Transcripción STAT6/inmunología , Transducción de Señal/inmunología , Infecciones por Strongylida/inmunología , Linfocitos T Reguladores/inmunología , Animales , Colitis/parasitología , Interferón gamma/inmunología , Interleucina-10/inmunología , Interleucina-17/inmunología , Mucosa Intestinal/inmunología , Mucosa Intestinal/parasitología , Ratones , Ratones Endogámicos C57BL , Células TH1/inmunología , Células TH1/parasitología , Células Th17/inmunología , Células Th17/parasitología , Células Th2/inmunología , Células Th2/parasitología
18.
Cell Immunol ; 374: 104498, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35334276

RESUMEN

Basophils and mast cells play a critical role in allergic inflammation and provide protective immunity against certain types of parasitic infections. Expansion of basophils and mast cells to the critical numbers is believed to be an essential step in enabling basophils and mast cells to carry out their protective functions. However, factors that drive basophil and mast cell expansion are still incompletely understood. We tested the roles of cytokines and growth factors IL-3, TSLP, GM-CSF, IL-5, SCF, IL-7, IL-25, and IL-33 in promoting the differentiation of pre-basophil and mast cell progenitors (pre-BMPs)in vitro.We found that while GM-CSF only expanded basophils, IL-3 promoted the differentiation of pre-BMPs into both basophils and mast cells. We found that IL-3 expanded the number of pre-BMPsin vivo. We showed that IL-3 upregulatedIl3ramRNA and protein expression on pre-BMPs, supporting that IL-3 expands pre-BMPs in part by upregulating the IL-3 receptor expression. Although Gata2 mRNA expression was upregulated by IL-3 treatment in pre-BMPs, it is dispensable for IL-3-mediated upregulation of IL-3 receptor expression. Our study reveals a novel mechanism through which IL-3 expands basophil and mast cells.


Asunto(s)
Basófilos , Receptores de Interleucina-3 , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Interleucina-3 , Mastocitos
19.
J Immunol ; 204(4): 923-932, 2020 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-31900338

RESUMEN

The transcription factor BHLHE40 is an emerging regulator of the immune system. Recent studies suggest that BHLHE40 regulates type 2 immunity, but this has not been demonstrated in vivo. We found that BHLHE40 is required in T cells for a protective TH2 cell response in mice infected with the helminth Heligmosomoides polygyrus bakeri H. polygyrus elicited changes in gene and cytokine expression by lamina propria CD4+ T cells, many of which were BHLHE40 dependent, including production of the common ß (CSF2RB) chain family cytokines GM-CSF and IL-5. In contrast to deficiency in GM-CSF or IL-5 alone, loss of both GM-CSF and IL-5 signaling impaired protection against H. polygyrus Overall, we show that BHLHE40 regulates the TH2 cell transcriptional program during helminth infection to support normal expression of Csf2, Il5, and other genes required for protection and reveal unexpected redundancy of common ß chain-dependent cytokines previously thought to possess substantially divergent functions.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Proteínas de Homeodominio/metabolismo , Interleucina-5/metabolismo , Nematospiroides dubius/inmunología , Infecciones por Strongylida/inmunología , Células Th2/inmunología , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Subunidad beta Común de los Receptores de Citocinas/genética , Subunidad beta Común de los Receptores de Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Proteínas de Homeodominio/genética , Inmunidad Celular/efectos de los fármacos , Inmunidad Celular/genética , Interleucina-5/antagonistas & inhibidores , Interleucina-5/genética , Interleucina-5/inmunología , Ratones , Ratones Noqueados , Membrana Mucosa/citología , Membrana Mucosa/inmunología , Membrana Mucosa/metabolismo , Infecciones por Strongylida/parasitología , Células Th2/efectos de los fármacos , Transcripción Genética/inmunología
20.
Artículo en Inglés | MEDLINE | ID: mdl-33318013

RESUMEN

Gastrointestinal nematodes (GINs) of humans, e.g., hookworms, negatively impact childhood growth, cognition, nutrition, educational attainment, income, productivity, and pregnancy. Hundreds of millions of people are targeted with mass drug administration (MDA) of donated benzimidazole anthelmintics. However, benzimidazole efficacy against GINs is suboptimal, and reduced/low efficacy has been seen. Developing an anthelmintic for human MDA is daunting: it must be safe, effective, inexpensive, stable without a cold chain, and massively scalable. Bacillus thuringiensis crystal protein 5B (Cry5B) has anthelmintic properties that could fill this void. Here, we developed an active pharmaceutical ingredient (API) containing B. thuringiensis Cry5B compatible with MDA. We expressed Cry5B in asporogenous B. thuringiensis during vegetative phase, forming cytosolic crystals. These bacteria with cytosolic crystals (BaCC) were rendered inviable (inactivated BaCC [IBaCC]) with food-grade essential oils. IBaCC potency was validated in vitro against nematodes. IBaCC was also potent in vivo against human hookworm infections in hamsters. IBaCC production was successfully scaled to 350 liters at a contract manufacturing facility. A simple fit-for-purpose formulation to protect against stomach digestion and powdered IBaCC were successfully made and used against GINs in hamsters and mice. A pilot histopathology study and blood chemistry workup showed that five daily consecutive doses of 200 mg/kg body weight Cry5B IBaCC (the curative single dose is 40 mg/kg) was nontoxic to hamsters and completely safe. IBaCC is a safe, inexpensive, highly effective, easy-to-manufacture, and scalable anthelmintic that is practical for MDA and represents a new paradigm for treating human GINs.


Asunto(s)
Antihelmínticos , Infecciones por Uncinaria , Nematodos , Parásitos , Animales , Antihelmínticos/uso terapéutico , Proteínas Bacterianas , Niño , Cricetinae , Infecciones por Uncinaria/tratamiento farmacológico , Humanos , Ratones
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA