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1.
Front Immunol ; 13: 773276, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35211114

RESUMO

Cystic echinococcosis (CE) is a zoonotic parasitic disease spread worldwide caused by Echinococcus granulosus (Eg), which sometimes causes serious damage; however, in many cases, people are not aware that they are infected. A number of recombinant vaccines based on Eg are used to evaluate their effectiveness against the infection. Our previous report showed that recombinant Eg.P29 (rEg.P29) has a marvelous immunoprotection and can induce Th1 immune response. Furthermore, data of miRNA microarray in mice spleen CD4+ T cells showed that miR-126a-5p was significantly elevated 1 week after immunization by using rEg.P29. Therefore, in this perspective, we discussed the role of miR-126a-5p in the differentiation of naive CD4+ T cells into Th1/Th2 under rEg.P29 immunization and determined the mechanisms associated with delta-like 1 homolog (DLK1) and Notch1 signaling pathway. One week after P29 immunization of mice, we found that miR-126a-5p was significantly increased and DLK1 expression was decreased, while Notch1 pathway activation was enhanced and Th1 response was significantly stronger. The identical conclusion was obtained by overexpression of mmu-miR-126a-5p in primary naive CD4+ T cells in mice. Intriguingly, mmu-miR-126a-5p was significantly raised in serum from mice infected with protoscolex in the early stages of infection and markedly declined in the late stages of infection, while has-miR-126-5p expression was dramatically reduced in serum from CE patients. Taken together, we show that miR-126a-5p functions as a positive regulator of Notch1-mediated differentiation of CD4+ T cells into Th1 through downregulating DLK1 in vivo and in vitro. Hsa-miR-126-5p is potentially a very promising diagnostic biomarker for CE.


Assuntos
Antígenos de Helmintos/imunologia , Linfócitos T CD4-Positivos/imunologia , Equinococose/imunologia , Echinococcus granulosus/imunologia , MicroRNAs/imunologia , Zoonoses/imunologia , Adulto , Animais , Antígenos de Helmintos/genética , Linfócitos T CD4-Positivos/parasitologia , Proteínas de Ligação ao Cálcio/metabolismo , Estudos de Casos e Controles , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Equinococose/genética , Equinococose/parasitologia , Echinococcus granulosus/genética , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , MicroRNAs/genética , Pessoa de Meia-Idade , Receptor Notch1/metabolismo , Transdução de Sinais/imunologia , Células Th1/imunologia , Células Th1/parasitologia , Células Th2/imunologia , Células Th2/parasitologia , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia , Zoonoses/genética , Zoonoses/parasitologia
2.
Sci Rep ; 11(1): 22082, 2021 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-34764345

RESUMO

Intestinal nematode infections common during pregnancy have recently been shown to have impacts that extend to their uninfected offspring including altered brain gene expression. If maternal immune signals reach the neonatal brain, they might alter neuroimmune development. We explored expression of genes associated with four distinct types of T cells (Th1, Th2, Th17, Treg) and with leukocyte transendothelial migration and endocytosis transport across the blood-brain barrier (BBB) in the postnatal brain of offspring of nematode-infected mice, through secondary analysis of a whole brain gene expression database. Th1/Th17 expression was lowered by maternal infection as evidenced by down-regulated expression of IL1ß, Th1 receptors and related proteins, and of IL22 and several Th17 genes associated with immunopathology. In contrast, Th2/Treg related pathways were upregulated as shown by higher expression of IL4 and TGF-ß family genes. Maternal infection also upregulated expression of pathways and integrin genes involved in transport of leukocytes in between endothelial cells but downregulated endosome vesicle formation related genes that are necessary for endocytosis of immunoglobulins across the BBB. Taken together, pup brain gene expression indicates that maternal nematode infection enhanced movement of leukocytes across the neonatal BBB and promoted a Th2/Treg environment that presumably minimizes the proinflammatory Th1 response in the pup brain.


Assuntos
Encéfalo , Infecções por Nematoides/genética , Complicações Parasitárias na Gravidez/genética , Linfócitos T Reguladores , Células Th2 , Animais , Animais Recém-Nascidos , Encéfalo/crescimento & desenvolvimento , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/parasitologia , Feminino , Regulação da Expressão Gênica , Humanos , Imunidade Inata , Camundongos , Infecções por Nematoides/complicações , Infecções por Nematoides/imunologia , Infecções por Nematoides/parasitologia , Gravidez , Complicações Parasitárias na Gravidez/etiologia , Complicações Parasitárias na Gravidez/imunologia , Complicações Parasitárias na Gravidez/parasitologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/parasitologia , Células Th2/imunologia , Células Th2/metabolismo , Células Th2/parasitologia , Transcriptoma , Migração Transendotelial e Transepitelial , Regulação para Cima
3.
Front Immunol ; 12: 696734, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34413850

RESUMO

Bronchial asthma is one of the most chronic pulmonary diseases and major public health problems. In general, asthma prevails in developed countries than developing countries, and its prevalence is increasing in the latter. For instance, the hygiene hypothesis demonstrated that this phenomenon resulted from higher household hygienic standards that decreased the chances of infections, which would subsequently increase the occurrence of allergy. In this review, we attempted to integrate our knowledge with the hygiene hypothesis into beneficial preventive approaches for allergic asthma. Therefore, we highlighted the studies that investigated the correlation between allergic asthma and the two different types of infections that induce the two major antagonizing arms of T cells. This elucidation reflects the association between various types of natural infections and the immune system, which is predicted to support the main objective of the current research on investigating of the benefits of natural infections, regardless their immune pathways for the prevention of allergic asthma. We demonstrated that natural infection with Mycobacterium tuberculosis (Mtb) prevents the development of allergic asthma, thus Bacille Calmette-Guérin (BCG) vaccine is suggested at early age to mediate the same prevention particularly with increasing its efficiency through genetic engineering-based modifications. Likewise, natural helminth infections might inhabit the allergic asthma development. Therefore, helminth-derived proteins at early age are good candidates for designing vaccines for allergic asthma and it requires further investigation. Finally, we recommend imitation of natural infections as a general strategy for preventing allergic asthma that increased dramatically over the past decades.


Assuntos
Asma/prevenção & controle , Vacina BCG/uso terapêutico , Proteínas de Helminto/uso terapêutico , Helmintíase/imunologia , Hipótese da Higiene , Imunoterapia , Células Th1/imunologia , Células Th2/imunologia , Tuberculose/imunologia , Animais , Asma/imunologia , Asma/microbiologia , Asma/parasitologia , Vacina BCG/efeitos adversos , Proteínas de Helminto/efeitos adversos , Helmintíase/parasitologia , Humanos , Imunoterapia/efeitos adversos , Células Th1/metabolismo , Células Th1/microbiologia , Células Th2/metabolismo , Células Th2/parasitologia , Tuberculose/microbiologia
4.
Immunohorizons ; 5(8): 721-732, 2021 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-34462311

RESUMO

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.


Assuntos
Citocinas/imunologia , Células Dendríticas/imunologia , Ativação Linfocitária/imunologia , Schistosoma mansoni/imunologia , Esquistossomose mansoni/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/parasitologia , Citocinas/metabolismo , Células Dendríticas/parasitologia , Feminino , Citometria de Fluxo/métodos , Interações Hospedeiro-Parasita/imunologia , Contagem de Linfócitos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Schistosoma mansoni/fisiologia , Esquistossomose mansoni/metabolismo , Esquistossomose mansoni/parasitologia , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Auxiliares-Indutores/parasitologia , Células Th2/imunologia , Células Th2/metabolismo , Células Th2/parasitologia
5.
Front Immunol ; 12: 624191, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33777004

RESUMO

In spite of several decades of research, an effective vaccine against schistosomiasis remains elusive. The radiation-attenuated (RA) cercarial vaccine is still the best model eliciting high protection levels, although the immune mechanisms have not yet been fully characterized. In order to identify genes and pathways underlying protection we investigated patterns of gene expression in PBMC and skin draining Lymph Nodes (LN) from mice using two exposure comparisons: vaccination with 500 attenuated cercariae versus infection with 500 normal cercariae; one versus three doses. Vaccinated mice were challenged with 120 normal parasites. Integration of PBMC and LN data from the infected group revealed early up-regulation of pathways associated with Th2 skewing and polarization of IgG antibody profiles. Additionally, hemostasis pathways were downregulated in infected mice, correlating with platelet reduction, potentially a mechanism to assist parasite migration through capillary beds. Conversely, up regulation of such mechanisms after vaccination may explain parasite blockade in the lungs. In contrast, a single exposure to attenuated parasites revealed early establishment of a Th1 bias (signaling of IL-1, IFN-γ; and Leishmania infection). Genes encoding chemokines and their receptors were more prominent in vaccinated mice, indicating an enhanced capacity for inflammation, potentially augmenting the inhibition of intravascular migration. Increasing the vaccinations from one to three did not dramatically elevate protection, but there was a clear shift towards antibody-mediated effectors. However, elements of the Th1 bias were still evident. Notable features after three vaccinations were markers of cytotoxicity (including IL-6 and NK cells) together with growth factors and their receptors (FGFR/VEGF/EGF) and the apoptosis pathway. Indeed, there is evidence for the development of anergy after three vaccinations, borne out by the limited responses detected in samples after challenge. We infer that persistence of a Th1 response puts a limit on expression of antibody-mediated mechanisms. This feature may explain the failure of multiple doses to drive protection towards sterile immunity. We suggest that the secretions of lung stage parasites would make a novel cohort of antigens for testing in protection experiments.


Assuntos
Hemostasia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Vacinas Protozoárias/administração & dosagem , Schistosoma mansoni/imunologia , Esquistossomose mansoni/prevenção & controle , Biologia de Sistemas , Animais , Cercárias/imunologia , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Hemostasia/genética , Interações Hospedeiro-Parasita , Peptídeos e Proteínas de Sinalização Intercelular/genética , Linfonodos/imunologia , Linfonodos/metabolismo , Linfonodos/parasitologia , Camundongos Endogâmicos C57BL , Análise em Microsséries , Vacinas Protozoárias/imunologia , Schistosoma mansoni/patogenicidade , Esquistossomose mansoni/imunologia , Esquistossomose mansoni/metabolismo , Esquistossomose mansoni/parasitologia , Células Th1/imunologia , Células Th1/metabolismo , Células Th1/parasitologia , Equilíbrio Th1-Th2 , Células Th2/imunologia , Células Th2/metabolismo , Células Th2/parasitologia , Fatores de Tempo , Transcriptoma , Vacinação , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/imunologia
6.
Eur J Immunol ; 51(2): 433-444, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33067820

RESUMO

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.


Assuntos
Colite/imunologia , Nematospiroides dubius/imunologia , Fator de Transcrição STAT6/imunologia , Transdução de Sinais/imunologia , Infecções por Strongylida/imunologia , Linfócitos T Reguladores/imunologia , Animais , Colite/parasitologia , Interferon gama/imunologia , Interleucina-10/imunologia , Interleucina-17/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/parasitologia , Camundongos , Camundongos Endogâmicos C57BL , Células Th1/imunologia , Células Th1/parasitologia , Células Th17/imunologia , Células Th17/parasitologia , Células Th2/imunologia , Células Th2/parasitologia
7.
Immunology ; 162(3): 328-338, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33283278

RESUMO

Schistosomiasis is a neglected tropical disease with over 250 million people infected worldwide. The main clinically important species Schistosoma mansoni (S. mansoni) and Schistosoma japonicum (S. japonicum) cause inflammatory responses against tissue-trapped eggs, resulting in formation of granulomas mainly in host liver. Persistent granulomatous response results in severe fibrosis in the liver, leading to irreversible impairment of the liver and even death of the host. CD1d, a highly conserved MHC class I-like molecule, is expressed by both haematopoietic and non-haematopoietic cells. CD1d on antigen-presenting cells (APCs) of haematopoietic origin presents pathogen-derived lipid antigens to natural killer T (NKT) cells, which enables them to rapidly produce large amounts of various cytokines and facilitate CD4+ T helper (Th) cell differentiation upon invading pathogens. Noteworthy, hepatocytes of non-haematopoietic origin have recently been shown to be involved in maintaining liver NKT cell homeostasis through a CD1d-dependent manner. However, whether hepatocyte CD1d-dependent regulation of NKT cell homeostasis also modulates CD4+ Th cell responses and liver immunopathology in murine schistosomiasis remains to be addressed. Here, we show in mice that CD1d expression on hepatocytes was decreased dramatically upon S. japonicum infection, accompanied by increased NKT cells, as well as upregulated Th1 and Th2 responses. Overexpression of CD1d in hepatocytes significantly decreased local NKT numbers and cytokines (IFN-γ, IL-4, IL-13), concomitantly with downregulation of both Th1 and Th2 responses and alleviation in pathological damage in livers of S. japonicum-infected mice. These findings highlight the potential of hepatocyte CD1d-targeted therapies for liver immunopathology control in schistosomiasis.


Assuntos
Antígenos CD1d/metabolismo , Hepatócitos/imunologia , Fígado/imunologia , Schistosoma japonicum/imunologia , Esquistossomose Japônica/imunologia , Animais , Antígenos CD1d/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Hepatócitos/metabolismo , Hepatócitos/patologia , Interações Hospedeiro-Parasita , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Células T Matadoras Naturais/parasitologia , Schistosoma japonicum/patogenicidade , Esquistossomose Japônica/metabolismo , Esquistossomose Japônica/parasitologia , Células Th1/imunologia , Células Th1/metabolismo , Células Th1/parasitologia , Células Th2/imunologia , Células Th2/metabolismo , Células Th2/parasitologia
8.
Int Immunopharmacol ; 91: 107291, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33360084

RESUMO

Present treatment regimen on visceral leishmaniasis has multiple limitations including severe side effects, toxicity, and resistance of Leishmania strains. Amphotericin B is a well-established pharmacologically approved drug; however, mainly toxicity is a foremost issue with that drug. Recently, our group identified eugenol oleate as an anti-leishmanial immunomodulatory compound. The important objectives of this present study was to evaluate the possible synergistic effect of eugenol oleate with amphotericin B to reduce the toxicity of this approved drug. Results obtained from this study signified that combination of eugenol oleate and amphotericin B showed indifferent combinatorial effect against promastigotes with xΣFIC 1.015, while, moderate synergistic activity with xΣFIC 0.456 against amastigotes. It was also notable that eugenol oleate (2.5 µM) with low concentrations of amphotericin B (0.3125 µM) showed 96.45% parasite reduction within L. donovani-infected murine macrophages. Furthermore, eugenol oleate and amphotericin B significantly (p < 0.01) enhanced the nitrite generation, and pro-inflammatory cytokines (IL-12, IFN-γ and TNF-α) in infected macrophages in vitro and in BALB/c mice in vivo. Eugenol oleate (10 mg/Kg b. wt.) with amphotericin B (1 mg/Kg b.wt.) significantly (p < 0.01) controlled the parasite burden in liver by 96.2% and in spleen by 93.12%. Hence, this study strongly suggested the synergic potential of eugenol oleate with low concentration of amphotericin B in experimental visceral leishmaniasis through anti-leishmanial immune response.


Assuntos
Anfotericina B/farmacologia , Leishmania donovani/efeitos dos fármacos , Leishmaniose Visceral/tratamento farmacológico , Macrófagos Peritoneais/efeitos dos fármacos , Tripanossomicidas/farmacologia , Animais , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Interações Hospedeiro-Parasita , Mediadores da Inflamação/metabolismo , Leishmania donovani/imunologia , Leishmania donovani/patogenicidade , Leishmaniose Visceral/imunologia , Leishmaniose Visceral/metabolismo , Leishmaniose Visceral/parasitologia , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/metabolismo , Fígado/parasitologia , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Macrófagos Peritoneais/parasitologia , Camundongos Endogâmicos BALB C , Nitritos/metabolismo , Carga Parasitária , Baço/efeitos dos fármacos , Baço/imunologia , Baço/metabolismo , Baço/parasitologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/metabolismo , Células Th1/parasitologia , Equilíbrio Th1-Th2 , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Células Th2/metabolismo , Células Th2/parasitologia
9.
Vet Res ; 51(1): 107, 2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32854770

RESUMO

Trichinella spiralis maintains chronic infections within its host. Muscle larvae excretory-secretory products (MLES) typically induce parasite-specific immune responses such as the Th2 response and regulatory T cells (Tregs) by modulating dendritic cell (DC) phenotype via the recognition of pattern recognition receptors (PRRs), such as Nod-like receptors (NLRs). We aimed to investigate the role of NLRP3 in T. spiralis-triggered immune response. We found that larvae burden was increased in NLRP3-/- mice compared to wild type (WT) mice. Administration of MLES induced higher levels of IL-4, IL-10, TGF-ß and population of Tregs in WT mice than in NLRP3-/- mice. In vitro, we showed that increased expression of CD40 on the surface of MLES-treated DCs was inhibited after NLRP3 knockout. Increased production of IL-1ß, IL-18, IL-10 and TGF-ß, but not IL-12p70, was significantly diminished in the absence of NLRP3. Furthermore, our results demonstrated that MLES-treated DCs induced higher levels of IL-4, IL-10 and TGF-ß and populations of Tregs in vitro. These inductions were abolished by NLRP3 deficiency in DCs, suggesting that NLRP3 in MLES-treated DCs plays a role in promoting the Th2 and Treg response. Taken together, we identified for the first time the involvement of NLRP3 in host defences against T. spiralis.


Assuntos
Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Linfócitos T Reguladores/imunologia , Células Th2/imunologia , Trichinella spiralis/fisiologia , Triquinelose/genética , Animais , Feminino , Larva/crescimento & desenvolvimento , Larva/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/parasitologia , Células Th2/parasitologia , Trichinella spiralis/crescimento & desenvolvimento , Triquinelose/parasitologia
10.
Infect Immun ; 88(8)2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32341115

RESUMO

The parasites and eggs of helminths, including schistosomes, are associated with factors that can modulate the nature and outcomes of host immune responses, particularly enhancing type 2 immunity and impairing the effects of type 1 and type 17 immunity. The main species of schistosomes that cause infection in humans are capable of generating a microenvironment that allows survival of the parasite by evasion of the immune response. Schistosome infections are associated with beneficial effects on chronic immune disorders, including allergies, autoimmune diseases, and alloimmune responses. Recently, there has been increasing research interest in the role of schistosomes in immunoregulation during human infection, and the mechanisms underlying these roles continue to be investigated. Further studies may identify potential opportunities to develop new treatments for immune disease. In this review, we provide an update on the advances in our understanding of schistosome-associated modulation of the cells of the innate and adaptive immune systems as well as the potential role of schistosome-associated factors as therapeutic modulators of immune disorders, including allergies, autoimmune diseases, and transplant immunopathology. We also discuss potential opportunities for targeting schistosome-induced immunoregulation for future translation to the clinical setting.


Assuntos
Doenças Autoimunes/terapia , Hipersensibilidade/terapia , Fatores Imunológicos/uso terapêutico , Schistosoma japonicum/imunologia , Schistosoma mansoni/imunologia , Esquistossomose/terapia , Imunidade Adaptativa/efeitos dos fármacos , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/parasitologia , Doenças Autoimunes/patologia , Hipersensibilidade/imunologia , Hipersensibilidade/parasitologia , Hipersensibilidade/patologia , Evasão da Resposta Imune , Imunidade Inata/efeitos dos fármacos , Imunomodulação , Imunoterapia/métodos , Transplante de Órgãos/reabilitação , Schistosoma japonicum/química , Schistosoma mansoni/química , Esquistossomose/imunologia , Esquistossomose/parasitologia , Esquistossomose/patologia , Células Th1/imunologia , Células Th1/parasitologia , Células Th17/imunologia , Células Th17/parasitologia , Células Th2/imunologia , Células Th2/parasitologia , Zigoto/química , Zigoto/imunologia
11.
J Immunol Res ; 2019: 3562672, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31815153

RESUMO

The immune response against Haemonchus contortus infections is primarily associated with the Th2 profile. However, the exact mechanisms associated with increased sheep resistance against this parasite remains poorly elucidated. The present study is aimed at evaluating mediators from the innate immune response in lambs of the Morada Nova Brazilian breed with contrasting H. contortus resistance phenotypes. Briefly, 287 lambs were characterized through fecal egg counts (FEC) and packed cell volume (PCV) after two independent experimental parasitic challenges with 4,000 H. contortus L3. 20 extreme resistance phenotypes (10 most resistant and 10 most susceptible) were selected, subjected to a third artificial infection with 4,000 L3, and euthanized 7 days later. Tissue samples were collected from abomasal fundic and pyloric mucosa and abomasal lymph nodes. Blood samples were collected at days 0 and 7 of the third parasitic challenge. RNA was extracted from tissue and blood samples for relative quantification of innate immune-related genes by RT-qPCR. For the abomasal fundic mucosa, increased TNFα and IL1ß expression levels (P < 0.05) were found in the susceptible animals, while resistant animals had IL33 superiorly expressed (P < 0.05). Higher levels (P < 0.05) of TLR2 and CFI were found in the abomasal pyloric mucosa of resistant animals. TNFα was at higher levels (P < 0.05) in the blood of susceptible lambs, at day 0 of the third artificial infection. The exacerbated proinflammatory response observed in susceptible animals, at both local and systemic levels, may be a consequence of high H. contortus parasitism. This hypothesis is corroborated by the higher blood levels of TNFα before the onset of infection, which probably remained elevated from the previous parasitic challenges. On the other hand, resistant lambs had an enhanced response mediated by TLR recognition and complement activation. Nevertheless, this is the first study to directly associate sheep parasitic resistance with IL33, an innate trigger of the Th2-polarized response.


Assuntos
Aminopeptidases/genética , Resistência à Doença/genética , Hemoncose/imunologia , Imunidade Inata , Doenças dos Ovinos/imunologia , Receptor 2 Toll-Like/genética , Aminopeptidases/imunologia , Animais , Fezes/parasitologia , Feminino , Mucosa Gástrica/imunologia , Mucosa Gástrica/patologia , Expressão Gênica , Hemoncose/genética , Hemoncose/parasitologia , Hemoncose/patologia , Haemonchus/imunologia , Haemonchus/patogenicidade , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-33/genética , Interleucina-33/imunologia , Linfonodos/imunologia , Linfonodos/patologia , Contagem de Ovos de Parasitas , Fenótipo , Ovinos , Doenças dos Ovinos/genética , Doenças dos Ovinos/parasitologia , Doenças dos Ovinos/patologia , Células Th2/imunologia , Células Th2/parasitologia , Células Th2/patologia , Receptor 2 Toll-Like/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
12.
PLoS Pathog ; 15(11): e1007926, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31730667

RESUMO

The majority of experiments investigating the immune response to gastrointestinal helminth infection use a single bolus infection. However, in situ individuals are repeatedly infected with low doses. Therefore, to model natural infection, mice were repeatedly infected (trickle infection) with low doses of Trichuris muris. Trickle infection resulted in the slow acquisition of immunity reflected by a gradual increase in worm burden followed by partial expulsion. Flow cytometry revealed that the CD4+ T cell response shifted from Th1 dominated to Th2 dominated, which coincided with an increase in Type 2 cytokines. The development of resistance following trickle infection was associated with increased worm expulsion effector mechanisms including goblet cell hyperplasia, Muc5ac production and increased epithelial cell turn over. Depletion of CD4+ T cells reversed resistance confirming their importance in protective immunity following trickle infection. In contrast, depletion of group 2 innate lymphoid cells did not alter protective immunity. T. muris trickle infection resulted in a dysbiotic mircrobiota which began to recover alpha diversity following the development of resistance. These data establish trickle infection as a robust and informative model for analysis of immunity to chronic intestinal helminth infection more akin to that observed under natural infection conditions and confirms the importance of CD4+ T cell adaptive immunity in host protection.


Assuntos
Anticorpos Anti-Helmínticos/imunologia , Hipersensibilidade/imunologia , Imunidade Inata/imunologia , Intestinos/imunologia , Pulmão/imunologia , Tricuríase/imunologia , Trichuris/imunologia , Imunidade Adaptativa , Animais , Anticorpos Anti-Helmínticos/sangue , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/parasitologia , Hipersensibilidade/parasitologia , Intestinos/parasitologia , Intestinos/patologia , Pulmão/parasitologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células Th2/imunologia , Células Th2/parasitologia , Tricuríase/sangue , Tricuríase/parasitologia
13.
Infect Immun ; 87(10)2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31285249

RESUMO

Granuloma formation is a key host immune response generated to confine invading pathogens and limit extensive host damage. It consists of an accumulation of host immune cells around a pathogen. This host response has been extensively studied in the context of inflammatory diseases. However, there is much less known about Th2-type granulomas generated in response to parasitic worms. Based on in vitro data, innate immune cells within the granuloma are thought to immobilize and kill parasites but also act to repair damaged tissue. Understanding this dual function is key. The two billion people and many livestock/wild animals infected with helminths demonstrate that granulomas are not effective at clearing infection. However, the lack of high mortality highlights their importance in ensuring that parasite migration/tissue damage is restricted and wound healing is effective. In this review, we define two key cellular players (macrophages and eosinophils) and their associated molecular players involved in Th2 granuloma function. To date, the underlying mechanisms remain poorly understood, which is in part due to a lack of conclusive studies. Most have been performed in vitro rather than in vivo, using cells that have not been obtained from granulomas. Experiments using genetically modified mouse strains and/or antibody/chemical-mediated cell depletion have also generated conflicting results depending on the model. We discuss the caveats of previous studies and the new tools available that will help fill the gaps in our knowledge and allow a better understanding of the balance between immune killing and healing.


Assuntos
Eosinófilos/imunologia , Granuloma/imunologia , Helmintíase/imunologia , Helmintos/imunologia , Mucosa Intestinal/imunologia , Macrófagos/imunologia , Células Th2/imunologia , Animais , Comunicação Celular , Citocinas/biossíntese , Citocinas/imunologia , Modelos Animais de Doenças , Eosinófilos/parasitologia , Eosinófilos/patologia , Granuloma/parasitologia , Granuloma/patologia , Helmintíase/parasitologia , Helmintíase/patologia , Helmintos/crescimento & desenvolvimento , Helmintos/patogenicidade , Interações Hospedeiro-Parasita/imunologia , Humanos , Imunidade Inata , Mucosa Intestinal/patologia , Macrófagos/parasitologia , Macrófagos/patologia , Camundongos , Células Th2/parasitologia , Células Th2/patologia , Cicatrização/imunologia
14.
Commun Biol ; 2: 169, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31098402

RESUMO

Interaction between innate immune cells and parasite plays a key role in the immunopathogenesis of lymphatic filariasis. Despite being professional antigen presenting cells critical for the pathogen recognition, processing and presenting the antigens for mounting T cell responses, the dendritic cell response and its role in initiating CD4+ T cell response to filaria, in particular Wuchereria bancrofti, the most prevalent microfilaria is still not clear. Herein, we demonstrate that a 70 kDa phosphorylcholine-binding W. bancrofti sheath antigen induces human dendritic cell maturation and secretion of several pro-inflammatory cytokines. Further, microfilarial sheath antigen-stimulated dendritic cells drive predominantly Th1 and regulatory T cell responses while Th17 and Th2 responses are marginal. Mechanistically, sheath antigen-induced dendritic cell maturation, and Th1 and regulatory T cell responses are mediated via toll-like receptor 4 signaling. Our data suggest that W. bancrofti sheath antigen exploits dendritic cells to mediate distinct CD4+ T cell responses and immunopathogenesis of lymphatic filariasis.


Assuntos
Células Dendríticas/imunologia , Interações Hospedeiro-Parasita/imunologia , Microfilárias/imunologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Receptor 4 Toll-Like/genética , Wuchereria bancrofti/imunologia , Animais , Apresentação de Antígeno , Antígenos de Helmintos/genética , Antígenos de Helmintos/imunologia , Antígenos de Helmintos/farmacologia , Diferenciação Celular , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/parasitologia , Filariose Linfática/genética , Filariose Linfática/imunologia , Filariose Linfática/parasitologia , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Regulação da Expressão Gênica , Humanos , Imunidade Inata , Interferon gama/genética , Interferon gama/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Ativação Linfocitária , Microfilárias/genética , Microfilárias/patogenicidade , Transdução de Sinais , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/parasitologia , Células Th1/efeitos dos fármacos , Células Th1/parasitologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th17/parasitologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Células Th2/parasitologia , Receptor 4 Toll-Like/imunologia , Wuchereria bancrofti/genética , Wuchereria bancrofti/patogenicidade
15.
Exp Dermatol ; 28(3): 321-323, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30703249

RESUMO

Proinflammatory IL-17 plays an important role in various diseases and defence against extracellular microorganisms. Healing of leishmaniasis is promoted by Th1/Tc1 cells, whereas Th2/Treg are associated with worsened disease outcome. In addition, high expression of IL-17A in Leishmania-susceptible BALB/c and artificial overexpression of IL-17A in T cells in resistant C57BL/6 mice worsened disease outcome. Since C57BL/6 mice lacking only IL-17A exhibited no phenotype, and IL-17A and IL-17F share similar receptors, but differentially regulate chemokine secretion, we studied mice lacking both IL-17A and IL-17F (IL-17A/F-/- ) in infections with Leishmania major. Interestingly, lesion volumes and parasite burdens were comparable to controls, IL-17A/F-/- mice developed a Th1/Tc1 phenotype, and exhibited normal lesion resolution. Thus, in C57BL/6 mice, secretion of IL-17A and IL-17F does not influence disease progression. It appears that-depending on the genetic background-cytokines of the IL-17 family might be responsible for disease progression primarily in susceptible mice.


Assuntos
Interleucina-17/imunologia , Leishmaniose/imunologia , Células Th1/parasitologia , Células Th2/parasitologia , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/parasitologia , Cruzamentos Genéticos , Citocinas/metabolismo , Progressão da Doença , Feminino , Linfócitos Intraepiteliais/citologia , Linfócitos Intraepiteliais/parasitologia , Leishmania/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Fenótipo , Células Th1/citologia , Células Th2/citologia
16.
Front Immunol ; 9: 2232, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30356668

RESUMO

Group-2 innate lymphoid cells (ILC2) play critical roles in the initiation and maintenance of type-2 immune responses, predominantly through their production of the type-2 cytokines IL-5, IL-9, and IL-13. ILC2 are essential for the efficient elimination of helminth parasites, but also contribute to the detrimental type-2 immune responses that underlie diseases such as asthma and allergy. While several transcription factors have been identified that regulate the development and function of ILC2, less is known about the post-transcriptional mechanisms that regulate these processes. We identified micro-RNAs (miRNAs) that are co-ordinately regulated in ILC2 from mice exposed to two different stimuli, namely IL-33 "alarmin" administration or Nippostrongylus brasiliensis parasitic worm infection. miR-155 is upregulated in ILC2 in response to both stimuli and miR-155-/- mice had impaired IL-33-driven ILC2 responses. Using mixed bone marrow chimeras, we demonstrate that this deficit is intrinsic to ILC2 and that miR-155 protects ILC2 from apoptosis, while having little impact on ILC2 proliferation or cytokine production. These data reveal a subset of miRNAs that are regulated upon ILC2 activation and establish a specific role for miR-155 in regulating ILC2 survival following activation.


Assuntos
Apoptose/imunologia , Imunidade Inata/imunologia , Linfócitos/imunologia , MicroRNAs/imunologia , Animais , Apoptose/genética , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Células Cultivadas , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Interleucina-33/imunologia , Linfócitos/metabolismo , Linfócitos/parasitologia , Camundongos Knockout , Camundongos Transgênicos , MicroRNAs/genética , MicroRNAs/metabolismo , Nippostrongylus/imunologia , Nippostrongylus/fisiologia , Células Th2/imunologia , Células Th2/metabolismo , Células Th2/parasitologia
17.
Biosci Rep ; 38(6)2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30341242

RESUMO

Infection with helminth parasites evokes a complex cellular response in the host, where granulocytes (i.e. eosinophils, basophils and mast cells (MCs)) feature prominently. In addition to being used as markers of helminthic infections, MCs have been implicated in worm expulsion since animals defective in c-kit signaling, which results in diminished MC numbers, can have delayed worm expulsion. The role of MCs in the rejection of the rat tapeworm, Hymenolepsis diminuta, from the non-permissive mouse host is not known. MC-deficient mice display a delay in the expulsion of H. diminuta that is accompanied by a less intense splenic Th2 response, as determined by in vitro release of interleukin (IL)-4, IL-5 and IL-13 cytokines. Moreover, worms retrieved from MC-deficient mice were larger than those from wild-type (WT) mice. Assessment of gut-derived IL-25, IL-33, thymic stromal lymphopoietin revealed lower levels in uninfected MC-deficient mice compared with WT, suggesting a role for MCs in homeostatic control of these cytokines: differences in these gut cytokines between the mouse strains were not observed after infection with H. diminuta Finally, mice infected with H. diminuta display less severe dinitrobenzene sulphonic acid (DNBS)-induced colitis, and this beneficial effect of the worm was unaltered in MC-deficient mice challenged with DNBS, as assessed by a macroscopic disease score. Thus, while MCs are not essential for rejection of H. diminuta from mice, their absence slows the kinetics of expulsion allowing the development of greater worm biomass prior to successful rejection of the parasitic burden.


Assuntos
Infecções por Cestoides/imunologia , Colite/imunologia , Interações Hospedeiro-Parasita/imunologia , Mastócitos/imunologia , Animais , Biomassa , Infecções por Cestoides/parasitologia , Colite/induzido quimicamente , Colite/parasitologia , Dinitrofluorbenzeno/análogos & derivados , Dinitrofluorbenzeno/toxicidade , Humanos , Hymenolepis diminuta/imunologia , Hymenolepis diminuta/patogenicidade , Mastócitos/parasitologia , Camundongos , Ratos , Baço/parasitologia , Células Th2/imunologia , Células Th2/parasitologia
18.
J Biol Chem ; 293(27): 10425-10434, 2018 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-29666186

RESUMO

Dendritic cells (DC) and cytokines produced by DC play crucial roles in inducing and regulating pro-/anti-inflammatory and Th1/Th2 responses. DC are known to produce a Th1-promoting cytokine, interleukin (IL)-12, in response to malaria and other pathogenic infections, but it is thought that DC do not produce Th2-promoting cytokine, IL-4. Here, we show that a protein factor of malaria parasites induces IL-4 responses by CD11chiMHCIIhiCD3ϵ-CD49b-CD19-FcϵRI- DC via PI3K-Akt-NF-κB signaling independent of TLR-MyD88/TRIF. Malaria parasite-activated DC induced IL-4 responses by T cells both in vitro and in vivo, favoring Th2, and il-4-deficient DC were unable to induce IL-4 expression by T cells. Interestingly, lethal parasites, Plasmodium falciparum and Plasmodium berghei ANKA, induced IL-4 response primarily by CD8α- DC, whereas nonlethal Plasmodium yoelii induced IL-4 by both CD8α+ and CD8α- DC. In both P. berghei ANKA- and P. yoelii-infected mice, IL-4-expressing CD8α- DC did not express IL-12, but a distinct CD8α- DC subset expressed IL-12. In P. berghei ANKA infection, CD8α+ DC expressed IL-12 but not IL-4, whereas in P. yoelii infection, CD8α+ DC expressed IL-4 but not IL-12. These differential IL-4 and IL-12 responses by DC subsets may contribute to different Th1/Th2 development and clinical outcomes in lethal and nonlethal malaria. Our results for the first time demonstrate that a malaria protein factor induces IL-4 production by DC via PI3K-Akt-NF-κB signaling, revealing signaling and molecular mechanisms that initiate and promote Th2 development.


Assuntos
Células Dendríticas/imunologia , Interleucina-4/metabolismo , Malária/imunologia , Plasmodium yoelii/imunologia , Proteínas de Protozoários/metabolismo , Células Th2/imunologia , Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , Citocinas/metabolismo , Células Dendríticas/metabolismo , Células Dendríticas/parasitologia , Interleucina-4/fisiologia , Malária/metabolismo , Malária/parasitologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas de Protozoários/genética , Transdução de Sinais , Células Th1/imunologia , Células Th1/metabolismo , Células Th1/parasitologia , Células Th2/metabolismo , Células Th2/parasitologia , Receptor 2 Toll-Like/fisiologia , Receptor 4 Toll-Like/fisiologia , Receptor Toll-Like 9/fisiologia
19.
PLoS Biol ; 16(4): e2005504, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29668708

RESUMO

The molecular mechanisms through which dendritic cells (DCs) prime T helper 2 (Th2) responses, including those elicited by parasitic helminths, remain incompletely understood. Here, we report that soluble egg antigen (SEA) from Schistosoma mansoni, which is well known to drive potent Th2 responses, triggers DCs to produce prostaglandin E2 (PGE2), which subsequently-in an autocrine manner-induces OX40 ligand (OX40L) expression to license these DCs to drive Th2 responses. Mechanistically, SEA was found to promote PGE2 synthesis through Dectin-1 and Dectin-2, and via a downstream signaling cascade involving spleen tyrosine kinase (Syk), extracellular signal-regulated kinase (ERK), cytosolic phospholipase A2 (cPLA2), and cyclooxygenase 1 and 2 (COX-1 and COX-2). In addition, this pathway was activated independently of the actions of omega-1 (ω-1), a previously described Th2-priming glycoprotein present in SEA. These findings were supported by in vivo murine data showing that ω-1-independent Th2 priming by SEA was mediated by Dectin-2 and Syk signaling in DCs. Finally, we found that Dectin-2-/-, and to a lesser extent Dectin-1-/- mice, displayed impaired Th2 responses and reduced egg-driven granuloma formation following S. mansoni infection, highlighting the physiological importance of this pathway in Th2 polarization during a helminth infection. In summary, we identified a novel pathway in DCs involving Dectin-1/2-Syk-PGE2-OX40L through which Th2 immune responses are induced.


Assuntos
Células Dendríticas/imunologia , Dinoprostona/imunologia , Lectinas Tipo C/imunologia , Schistosoma mansoni/imunologia , Esquistossomose mansoni/imunologia , Células Th2/imunologia , Animais , Antígenos de Helmintos/imunologia , Antígenos de Helmintos/farmacologia , Comunicação Autócrina , Diferenciação Celular , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 1/imunologia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/imunologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/parasitologia , Dinoprostona/metabolismo , Enterotoxinas/farmacologia , Regulação da Expressão Gênica , Humanos , Lectinas Tipo C/deficiência , Lectinas Tipo C/genética , Sistema de Sinalização das MAP Quinases , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ligante OX40 , Fosfolipases A2/genética , Fosfolipases A2/imunologia , Cultura Primária de Células , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Esquistossomose mansoni/genética , Esquistossomose mansoni/parasitologia , Esquistossomose mansoni/patologia , Quinase Syk/genética , Quinase Syk/imunologia , Células Th2/efeitos dos fármacos , Células Th2/parasitologia , Fatores de Necrose Tumoral/genética , Fatores de Necrose Tumoral/imunologia
20.
Sci Rep ; 8(1): 3782, 2018 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-29491349

RESUMO

Resistance to the intestinal parasitic helminth Trichuris muris requires T-helper 2 (TH2) cellular and associated IgG1 responses, with expulsion typically taking up to 4 weeks in mice. Here, we show that the time-of-day of the initial infection affects efficiency of worm expulsion, with strong TH2 bias and early expulsion in morning-infected mice. Conversely, mice infected at the start of the night show delayed resistance to infection, and this is associated with feeding-driven metabolic cues, such that feeding restriction to the day-time in normally nocturnal-feeding mice disrupts parasitic expulsion kinetics. We deleted the circadian regulator BMAL1 in antigen-presenting dendritic cells (DCs) in vivo and found a loss of time-of-day dependency of helminth expulsion. RNAseq analyses revealed that IL-12 responses to worm antigen by circadian-synchronised DCs were dependent on BMAL1. Therefore, we find that circadian machinery in DCs contributes to the TH1/TH2 balance, and that environmental, or genetic perturbation of the DC clock results in altered parasite expulsion kinetics.


Assuntos
Fatores de Transcrição ARNTL/fisiologia , Ritmo Circadiano , Células Dendríticas/imunologia , Linfonodos/imunologia , Células Th2/imunologia , Tricuríase/imunologia , Trichuris/patogenicidade , Animais , Células Cultivadas , Células Dendríticas/parasitologia , Linfonodos/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T/imunologia , Linfócitos T/parasitologia , Células Th2/parasitologia , Tricuríase/parasitologia
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