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1.
EMBO J ; 36(16): 2404-2418, 2017 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-28716804

RESUMEN

Type 2 inflammation is a defining feature of infection with parasitic worms (helminths), as well as being responsible for widespread suffering in allergies. However, the precise mechanisms involved in T helper (Th) 2 polarization by dendritic cells (DCs) are currently unclear. We have identified a previously unrecognized role for type I IFN (IFN-I) in enabling this process. An IFN-I signature was evident in DCs responding to the helminth Schistosoma mansoni or the allergen house dust mite (HDM). Further, IFN-I signaling was required for optimal DC phenotypic activation in response to helminth antigen (Ag), and efficient migration to, and localization with, T cells in the draining lymph node (dLN). Importantly, DCs generated from Ifnar1-/- mice were incapable of initiating Th2 responses in vivo These data demonstrate for the first time that the influence of IFN-I is not limited to antiviral or bacterial settings but also has a central role to play in DC initiation of Th2 responses.


Asunto(s)
Células Dendríticas/inmunología , Interferón Tipo I/metabolismo , Células Th2/inmunología , Alérgenos/inmunología , Animales , Ratones , Ratones Noqueados , Pyroglyphidae/inmunología , Receptor de Interferón alfa y beta/deficiencia , Schistosoma mansoni/inmunología
2.
PLoS Pathog ; 13(3): e1006233, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-28334040

RESUMEN

Rapid reprogramming of the macrophage activation phenotype is considered important in the defense against consecutive infection with diverse infectious agents. However, in the setting of persistent, chronic infection the functional importance of macrophage-intrinsic adaptation to changing environments vs. recruitment of new macrophages remains unclear. Here we show that resident peritoneal macrophages expanded by infection with the nematode Heligmosomoides polygyrus bakeri altered their activation phenotype in response to infection with Salmonella enterica ser. Typhimurium in vitro and in vivo. The nematode-expanded resident F4/80high macrophages efficiently upregulated bacterial induced effector molecules (e.g. MHC-II, NOS2) similarly to newly recruited monocyte-derived macrophages. Nonetheless, recruitment of blood monocyte-derived macrophages to Salmonella infection occurred with equal magnitude in co-infected animals and caused displacement of the nematode-expanded, tissue resident-derived macrophages from the peritoneal cavity. Global gene expression analysis revealed that although nematode-expanded resident F4/80high macrophages made an anti-bacterial response, this was muted as compared to newly recruited F4/80low macrophages. However, the F4/80high macrophages adopted unique functional characteristics that included enhanced neutrophil-stimulating chemokine production. Thus, our data provide important evidence that plastic adaptation of MΦ activation does occur in vivo, but that cellular plasticity is outweighed by functional capabilities specific to the tissue origin of the cell.


Asunto(s)
Activación de Macrófagos/inmunología , Macrófagos/inmunología , Macrófagos/microbiología , Salmonelosis Animal/microbiología , Infecciones por Strongylida/microbiología , Animales , Coinfección , Citometría de Flujo , Ratones , Ratones Endogámicos C57BL , Nematospiroides dubius/inmunología , Análisis de Secuencia por Matrices de Oligonucleótidos , Salmonelosis Animal/inmunología , Salmonella typhi/inmunología , Infecciones por Strongylida/inmunología
3.
Eur J Immunol ; 46(10): 2311-2321, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27592711

RESUMEN

IL-33 plays an important role in the initiation of type-2 immune responses, as well as the enhancement of type 2 effector functions. Engagement of the IL-33 receptor on macrophages facilitates polarization to an alternative activation state by amplifying IL-4 and IL-13 signaling to IL-4Rα. IL-4 and IL-13 also induce macrophage proliferation but IL-33 involvement in this process has not been rigorously evaluated. As expected, in vivo delivery of IL-33 induced IL-4Rα-dependent alternative macrophage activation in the serous cavities. IL-33 delivery also induced macrophages to proliferate but, unexpectedly, this was independent of IL-4Rα signaling. In a filarial nematode infection model in which IL-4Rα-dependent alternative activation and proliferation in the pleural cavity is well described, IL-33R was essential for alternative activation but not macrophage proliferation. Similarly, during Alternaria alternata induced airway inflammation, which provokes strong IL-33 responses, we observed that both IL-4Rα and IL-33R were required for alternative activation, while macrophage proliferation in the pleural cavity was still evident in the absence of either receptor alone. Our data show that IL-33R and IL-4Rα promote macrophage proliferation independently of each other, but both are essential for induction of alternative activation.


Asunto(s)
Alternaria/inmunología , Alternariosis/inmunología , Filariasis/inmunología , Proteína 1 Similar al Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , Macrófagos/fisiología , Receptores de Superficie Celular/metabolismo , Membrana Serosa/inmunología , Animales , Proliferación Celular , Células Cultivadas , Filarioidea/inmunología , Proteína 1 Similar al Receptor de Interleucina-1/genética , Activación de Macrófagos , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Cavidad Pleural/patología , Receptores de Superficie Celular/genética , Transducción de Señal
4.
Immunol Cell Biol ; 94(4): 400-10, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26657145

RESUMEN

Dendritic cells (DCs) are the key initiators of T-helper (Th) 2 immune responses against the parasitic helminth Schistosoma mansoni. Although the liver is one of the main sites of antigen deposition during infection with this parasite, it is not yet clear how distinct DC subtypes in this tissue respond to S. mansoni antigens in vivo, or how the liver microenvironment might influence DC function during establishment of the Th2 response. In this study, we show that hepatic DC subsets undergo distinct activation processes in vivo following murine infection with S. mansoni. Conventional DCs (cDCs) from schistosome-infected mice upregulated expression of the costimulatory molecule CD40 and were capable of priming naive CD4(+) T cells, whereas plasmacytoid DCs (pDCs) upregulated expression of MHC class II, CD86 and CD40 but were unable to support the expansion of either naive or effector/memory CD4(+) T cells. Importantly, in vivo depletion of pDCs revealed that this subset was dispensable for either maintenance or regulation of the hepatic Th2 effector response during acute S. mansoni infection. Our data provides strong evidence that S. mansoni infection favors the establishment of an immunogenic, rather than tolerogenic, liver microenvironment that conditions cDCs to initiate and maintain Th2 immunity in the context of ongoing antigen exposure.


Asunto(s)
Células Dendríticas/inmunología , Hígado/inmunología , Schistosoma mansoni/inmunología , Esquistosomiasis mansoni/inmunología , Células Th2/inmunología , Animales , Antígenos Helmínticos/inmunología , Diferenciación Celular , Células Cultivadas , Células Dendríticas/parasitología , Hígado/parasitología , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL
5.
Mucosal Immunol ; 16(1): 27-38, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36690078

RESUMEN

Gastrointestinal nematode infections cause morbidity and socioeconomic loss in the most deprived communities. The shift in the context of obesity has led to spatial overlap with endemic gastrointestinal nematode regions resulting in the emergence of a novel comorbidity. Despite this, the impact of a high-fat diet (HFD) on immune-regulated protection against gastrointestinal infections remains largely unknown. We employed the murine model of nematode infection, Trichuris muris, to investigate the effect of an HFD on the immune response against chronic infection. Surprisingly, diet-induced obesity drove parasite expulsion in both single and repeated trickle low doses of T. muris eggs. Mechanistically, an HFD increased the expression of the ST2 receptor on CD4+ T cells, priming an enhanced type 2 helper T (Th2) cell cytokine production following interleukin (IL)-33 stimulation ex vivo. Despite IL-33-/- mice demonstrating that IL-33 is not critical for host protective immunity to T. muris under a conventional diet, HFD-fed T-cell deplete mice adoptively transferred with ST2-/- CD4 T cells were unable to expel a T. muris infection unlike those transferred with ST2-sufficient cells. Collectively, this study demonstrates that an HFD primes CD4+ T cells to utilize the IL-33-ST2 axis in a novel induction of type 2 immunity, providing insights into the emerging comorbidities of obesity and nematode infection.


Asunto(s)
Helmintos , Tricuriasis , Ratones , Animales , Interleucina-33 , Dieta Alta en Grasa , Proteína 1 Similar al Receptor de Interleucina-1 , Trichuris , Citocinas/metabolismo
6.
Front Immunol ; 14: 1139329, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37033932

RESUMEN

Introduction: Vaccination with Vi capsular polysaccharide (Vi-PS) or protein-Vi typhoid conjugate vaccine (TCV) can protect adults against Salmonella Typhi infections. TCVs offer better protection than Vi-PS in infants and may offer better protection in adults. Potential reasons for why TCV may be superior in adults are not fully understood. Methods and results: Here, we immunized wild-type (WT) mice and mice deficient in IgG or IgM with Vi-PS or TCVs (Vi conjugated to tetanus toxoid or CRM197) for up to seven months, with and without subsequent challenge with Vi-expressing Salmonella Typhimurium. Unexpectedly, IgM or IgG alone were similarly able to reduce bacterial burdens in tissues, and this was observed in response to conjugated or unconjugated Vi vaccines and was independent of antibody being of high affinity. Only in the longer-term after immunization (>5 months) were differences observed in tissue bacterial burdens of mice immunized with Vi-PS or TCV. These differences related to the maintenance of antibody responses at higher levels in mice boosted with TCV, with the rate of fall in IgG titres induced to Vi-PS being greater than for TCV. Discussion: Therefore, Vi-specific IgM or IgG are independently capable of protecting from infection and any superior protection from vaccination with TCV in adults may relate to responses being able to persist better rather than from differences in the antibody isotypes induced. These findings suggest that enhancing our understanding of how responses to vaccines are maintained may inform on how to maximize protection afforded by conjugate vaccines against encapsulated pathogens such as S. Typhi.


Asunto(s)
Fiebre Tifoidea , Vacunas Tifoides-Paratifoides , Animales , Ratones , Salmonella typhi , Vacunas Conjugadas , Fiebre Tifoidea/prevención & control , Polisacáridos Bacterianos , Inmunoglobulina G , Formación de Anticuerpos , Inmunoglobulina M
7.
Immunohorizons ; 5(8): 721-732, 2021 08 30.
Artículo en Inglés | MEDLINE | ID: mdl-34462311

RESUMEN

Plasmacytoid dendritic cells (pDCs) are potent producers of type I IFN (IFN-I) during viral infection and respond to IFN-I in a positive feedback loop that promotes their function. IFN-I shapes dendritic cell responses during helminth infection, impacting their ability to support Th2 responses. However, the role of pDCs in type 2 inflammation is unclear. Previous studies have shown that pDCs are dispensable for hepatic or splenic Th2 responses during the early stages of murine infection with the trematode Schistosoma mansoni at the onset of parasite egg laying. However, during S. mansoni infection, an ongoing Th2 response against mature parasite eggs is required to protect the liver and intestine from acute damage and how pDCs participate in immune responses to eggs and adult worms in various tissues beyond acute infection remains unclear. We now show that pDCs are required for optimal Th2 cytokine production in response to S. mansoni eggs in the intestinal-draining mesenteric lymph nodes throughout infection and for egg-specific IFN-γ at later time points of infection. Further, pDC depletion at chronic stages of infection led to increased hepatic and splenic pathology as well as abrogated Th2 cell cytokine production and activation in the liver. In vitro, mesenteric lymph node pDCs supported Th2 cell responses from infection-experienced CD4+ T cells, a process dependent on pDC IFN-I responsiveness, yet independent of Ag. Together, these data highlight a previously unappreciated role for pDCs and IFN-I in maintaining and reinforcing type 2 immunity in the lymph nodes and inflamed tissue during helminth infection.


Asunto(s)
Citocinas/inmunología , Células Dendríticas/inmunología , Activación de Linfocitos/inmunología , Schistosoma mansoni/inmunología , Esquistosomiasis mansoni/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/parasitología , Citocinas/metabolismo , Células Dendríticas/parasitología , Femenino , Citometría de Flujo/métodos , Interacciones Huésped-Parásitos/inmunología , Recuento de Linfocitos , Ratones Endogámicos C57BL , Ratones Noqueados , Schistosoma mansoni/fisiología , Esquistosomiasis mansoni/metabolismo , Esquistosomiasis mansoni/parasitología , Linfocitos T Colaboradores-Inductores/metabolismo , Linfocitos T Colaboradores-Inductores/parasitología , Células Th2/inmunología , Células Th2/metabolismo , Células Th2/parasitología
8.
iScience ; 24(9): 102941, 2021 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-34368648

RESUMEN

Global deployment of an effective and safe vaccine is necessary to curtail the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we evaluated a Newcastle disease virus (NDV)-based vectored-vaccine in mice and hamsters for its immunogenicity, safety, and protective efficacy against SARS-CoV-2. Intranasal administration of recombinant (r)NDV-S vaccine expressing spike (S) protein of SARS-CoV-2 to mice induced high levels of SARS-CoV-2-specific neutralizing immunoglobulin A (IgA) and IgG2a antibodies and T-cell-mediated immunity. Hamsters immunized with two doses of vaccine showed complete protection from lung infection, inflammation, and pathological lesions following SARS-CoV-2 challenge. Importantly, administration of two doses of intranasal rNDV-S vaccine significantly reduced the SARS-CoV-2 shedding in nasal turbinate and lungs in hamsters. Collectively, intranasal vaccination has the potential to control infection at the site of inoculation, which should prevent both clinical disease and virus transmission to halt the spread of the COVID-19 pandemic.

9.
Curr Opin Immunol ; 64: 42-49, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32353646

RESUMEN

The serous cavities contain specialised adipose tissues which house small clusters of immune cells known as fat-associated lymphoid clusters (FALCs). The continuous flow of fluid from the serous cavities through FALCs makes them unique niches for the clearance of fluid phase contaminants and initiation of locally protective immune responses during infection and inflammation. Development, and activation of FALCs both at homeostasis and following inflammation are co-ordinated by the close interaction of mesothelial and fibroblastic stromal cell populations with immune cells. In this review we discuss recent developments in FALC stromal cell biology and highlight key interactions that occur between FALC stroma and immune cells.


Asunto(s)
Inflamación , Células del Estroma , Tejido Adiposo , Humanos , Inmunidad
10.
Curr Opin Immunol ; 50: 9-13, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29078198

RESUMEN

Natural IgM are crucial for early protection against infection and play an important homeostatic function by clearing dead cells. The production of IgM is ensured by a population of B cells with innate-like properties: their response is rapidly activated by innate signals early during the onset of infection. The main reservoir of innate-like B cells (IBCs) are the serous cavities, but their maintenance and activation depends on their relocation to a variety of lymphoid tissues. Recent advances indicate that fat-associated lymphoid clusters (FALCs) and milky spots contribute to local IgM secretion and play a central role in the localisation and regulation of IBC function.


Asunto(s)
Formación de Anticuerpos/inmunología , Subgrupos de Linfocitos B/inmunología , Inmunidad Innata , Inmunoglobulina M/inmunología , Activación de Linfocitos/inmunología , Animales , Subgrupos de Linfocitos B/metabolismo , Humanos
11.
Hypertension ; 2017 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-28739975

RESUMEN

CFB (complement factor B) is elevated in adipose tissue and serum from patients with type 2 diabetes mellitus and cardiovascular disease, but the causal relationship to disease pathogenesis is unclear. Cfb is also elevated in adipose tissue and serum of the spontaneously hypertensive rat, a well-characterized model of metabolic syndrome. To establish the role of CFB in metabolic syndrome, we knocked out the Cfb gene in the spontaneously hypertensive rat. Cfb-/- rats showed improved glucose tolerance and insulin sensitivity, redistribution of visceral to subcutaneous fat, increased adipocyte mitochondrial respiration, and marked changes in gene expression. Cfb-/- rats also had lower blood pressure, increased ejection fraction and fractional shortening, and reduced left ventricular mass. These changes in metabolism and gene expression, in adipose tissue and left ventricle, suggest new adipose tissue-intrinsic and blood pressure-independent mechanisms for insulin resistance and cardiac hypertrophy in the spontaneously hypertensive rat. In silico analysis of the human CFB locus revealed 2 cis-regulated expression quantitative trait loci for CFB expression significantly associated with visceral fat, circulating triglycerides and hypertension in genome-wide association studies. Together, these data demonstrate a key role for CFB in the development of spontaneously hypertensive rat metabolic syndrome phenotypes and of related traits in humans and indicate the potential for CFB as a novel target for treatment of cardiometabolic disease.

12.
Science ; 356(6342): 1076-1080, 2017 06 09.
Artículo en Inglés | MEDLINE | ID: mdl-28495878

RESUMEN

The type 2 immune response controls helminth infection and maintains tissue homeostasis but can lead to allergy and fibrosis if not adequately regulated. We have discovered local tissue-specific amplifiers of type 2-mediated macrophage activation. In the lung, surfactant protein A (SP-A) enhanced interleukin-4 (IL-4)-dependent macrophage proliferation and activation, accelerating parasite clearance and reducing pulmonary injury after infection with a lung-migrating helminth. In the peritoneal cavity and liver, C1q enhancement of type 2 macrophage activation was required for liver repair after bacterial infection, but resulted in fibrosis after peritoneal dialysis. IL-4 drives production of these structurally related defense collagens, SP-A and C1q, and the expression of their receptor, myosin 18A. These findings reveal the existence within different tissues of an amplification system needed for local type 2 responses.


Asunto(s)
Interleucina-4/inmunología , Activación de Macrófagos , Nippostrongylus/fisiología , Receptores de Interleucina-4/inmunología , Infecciones por Strongylida/inmunología , Animales , Complemento C1q/inmunología , Humanos , Listeria monocytogenes , Listeriosis/inmunología , Hígado/inmunología , Pulmón/inmunología , Ratones , Ratones Endogámicos C57BL , Proteína A Asociada a Surfactante Pulmonar/metabolismo , Regeneración , Infecciones por Strongylida/patología
13.
Nat Commun ; 7: 12651, 2016 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-27582256

RESUMEN

Fat-associated lymphoid clusters (FALC) are inducible structures that support rapid innate-like B-cell immune responses in the serous cavities. Little is known about the physiological cues that activate FALCs in the pleural cavity and more generally the mechanisms controlling B-cell activation in FALCs. Here we show, using separate models of pleural nematode infection with Litomosoides sigmodontis and Altenaria alternata induced acute lung inflammation, that inflammation of the pleural cavity rapidly activates mediastinal and pericardial FALCs. IL-33 produced by FALC stroma is crucial for pleural B1-cell activation and local IgM secretion. However, B1 cells are not the direct target of IL-33, which instead requires IL-5 for activation. Moreover, lung inflammation leads to increased IL-5 production by type 2 cytokine-producing innate lymphoid cells (ILC2) in the FALC. These findings reveal a link between inflammation, IL-33 release by FALC stromal cells, ILC2 activation and pleural B-cell activation in FALCs, resulting in local and antigen-specific IgM production.


Asunto(s)
Alternaria/inmunología , Filarioidea/inmunología , Inmunoglobulina M/inmunología , Interleucina-33/inmunología , Tejido Linfoide/inmunología , Neumonía/inmunología , Alternariosis/inmunología , Alternariosis/parasitología , Animales , Linfocitos B/inmunología , Células Cultivadas , Femenino , Filariasis/inmunología , Filariasis/parasitología , Inmunidad Innata/inmunología , Interleucina-5/inmunología , Activación de Linfocitos/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados
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