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1.
Prostate ; 79(11): 1316-1325, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31212384

RESUMO

BACKGROUND: Urogenital infection with Schistosoma haematobium is a risk factor for the development of squamous cell carcinoma of the urinary bladder. The pathophysiology is thought to be mediated in part by inflammation, cellular damage, and bladder regeneration induced by the parasitic infection. Herein, we report an unusual case of schistosomiasis of the prostate that was found concurrent with prostate adenocarcinoma in a radical prostatectomy specimen from a man in the United States. METHODS: The infecting Schistosoma species was characterized via histomorphology and acid-fast stain. The concurrent Gleason score 6 prostate cancer was assessed for ETS transcription factor ERG (ERG), phosphatase and tensin homolog (PTEN), p27, and p53 status using immunohistochemistry (IHC). Cellular proliferation and the presence of intermediate cells in prostatic atrophy were assessed via immunostaining for Ki67 and CK903, respectively. RESULTS: Histomorphology and acid-fast stain of the infecting species were consistent with S. haematobium. We classified the Gleason score 6 prostate adenocarcinoma via IHC as ERG positive, PTEN intact, p27 intact, and without p53 nuclear accumulation. The prostatic epithelium immediately adjacent to the schistosomiasis-related granulomatous inflammation was atrophic and accompanied by increased cellular proliferation and the presence of intermediate cells. Upon literature review, we determined that prostate schistosomiasis is associated with a young age of prostate cancer diagnosis and highly aggressive prostate cancer. CONCLUSIONS: This is a rare case of prostate schistosomiasis in the United States; however, prostate schistosomiasis occurs frequently in endemic areas. The patient had traveled to a Schistosoma-endemic region, which was the likely location of exposure to the parasite. To our knowledge, this is the first report of the association of proliferative inflammatory atrophy and intermediate cells with schistosomiasis of the prostate. We propose that prostate schistosomiasis may be considered as a risk factor for the development of prostate cancer in geographic regions where Schistosoma species are endemic.


Assuntos
Adenocarcinoma/parasitologia , Carcinogênese/patologia , Próstata/parasitologia , Neoplasias da Próstata/parasitologia , Esquistossomose/patologia , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Humanos , Inflamação/parasitologia , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Próstata/patologia , Próstata/cirurgia , Prostatectomia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Esquistossomose/complicações
2.
Prostate ; 79(10): 1133-1146, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31050003

RESUMO

BACKGROUND: Trichomonas vaginalis (Tv) is the most common sexually transmitted parasite. It is detected in prostatic tissue of benign prostatic hyperplasia, prostatitis, and prostate cancer (PCa) and has been suggested to cause chronic prostatitis. Moreover, up to 20% of all cancers worldwide are associated with chronic inflammation. Here, we investigated whether inflammatory mediators produced by normal human prostate epithelial cells (RWPE-1) stimulated with Tv could promote growth and invasiveness of PCa cells. METHODS: Conditioned medium of RWPE-1 cells was prepared by stimulating them with Tv (trichomonad-conditioned medium [TCM]) and without Tv (conditioned medium [CM]). Promotion of PCa cells (PC3, DU145, and LNCaP) was assessed by wound healing, proliferation, and invasion assays. RESULTS: We observed that the production of interleukin (IL)-1ß, IL-6, CCL2, CXCL8, prostaglandin-E2 (PGE2 ), and COX2 by RWPE-1 cells was increased by stimulating them with Tv. When PCa cells were incubated with TCM, their proliferation, invasion, and migration increased. Moreover, they showed increased epithelial-mesenchymal transition (EMT)-related markers by a reduction in epithelial markers and an increase in mesenchymal markers. In vivo, xenograft tumor tissues injected with TCM also showed increased expression of cyclin D1 and proliferating cell nuclear antigen, as well as induction of EMT. Receptors and signal molecules of PCa cells increased in response to exposure to TCM, and blocking receptors (CXCR1, CXCR2, C-C chemokine receptor 2, glycoprotein 130, EP2, and EP4) reduced the proliferation of PCa cells with decreased production of cytokines (CCL2, IL-6, and CXCL8) and PGE2 , and expression of NF-κB and Snail1. CONCLUSIONS: Our results suggest that Tv infection may be one of the factors creating the supportive microenvironment to promote proliferation and invasiveness of PCa cells.


Assuntos
Proliferação de Células/fisiologia , Células Epiteliais/patologia , Invasividade Neoplásica/patologia , Neoplasias da Próstata/patologia , Prostatite/patologia , Trichomonas vaginalis , Quimiocina CCL2/metabolismo , Dinoprostona/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/parasitologia , Humanos , Inflamação/metabolismo , Inflamação/parasitologia , Inflamação/patologia , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Masculino , Próstata/metabolismo , Próstata/parasitologia , Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/parasitologia , Prostatite/metabolismo , Prostatite/parasitologia , Tricomoníase/metabolismo , Tricomoníase/patologia
3.
Methods Mol Biol ; 1971: 315-349, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30980313

RESUMO

Experimental cutaneous leishmaniasis of mice is a valuable model to study the immune response to the protozoan pathogen Leishmania and to define mechanisms of parasite control and resolution of inflammation as well as of parasite evasion and chronicity of disease. In addition, over many years Leishmania-infected mice have been successfully used to analyze the function of newly discovered immune cell types, transcription factors, cytokines, and effector mechanisms in vivo. In this chapter we present detailed protocols for the culture, propagation, and inoculation of Leishmania promastigotes, the monitoring of the course of cutaneous infection, the determination of the tissue parasite burden and for the phenotyping of the ensuing immune response. The focus lies on the L. major mouse model, but an overview on other established models of murine cutaneous leishmaniasis is also provided.


Assuntos
Modelos Animais de Doenças , Leishmania/crescimento & desenvolvimento , Leishmaniose Cutânea/parasitologia , Estágios do Ciclo de Vida , Carga Parasitária , Animais , Doença Crônica , Inflamação/metabolismo , Inflamação/parasitologia , Inflamação/patologia , Leishmaniose Cutânea/metabolismo , Leishmaniose Cutânea/patologia , Camundongos , Camundongos Endogâmicos BALB C
4.
Int Immunopharmacol ; 70: 324-337, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30852288

RESUMO

We investigated the effect in vitro and in vivo of doxycycline hyclate (Dx), a broad-spectrum antibiotic inhibitor of matrix metaloproteinases (MMPs), on adult Schistosoma mansoni worms and granulomatous liver inflammation in infected mice. Adult S. mansoni worms in culture treated with different concentrations of Dx (50-180 µg/mL) were studied for eight days to assess its morphology, eggs production, and mortality. Uninfected mice and those infected with S. mansoni, untreated and treated with praziquantel (Pz; 200 mg/kg) or Dx (50 mg/kg), were evaluated for 60 days. Our results indicated that Dx induced dose-dependent integumentary lesions (bubbles, tubercle collapse, spicule disappearance, peeling, and erosion), reduced mating rate and eggs-laying in adult S. mansoni worms. The effective lethal dose required to kill 50% of worms was 112.0 µg/mL Dx (DL50). In mice, S. mansoni infection induced hepatomegaly, intense IL-4, IL-10, TNF-α and TGF-ß production, granulomatous inflammation and hepatic glycogen depletion. The number and size of the granulomas was similar in untreated and Dx-treated animals. Untreated animals showed a predominance of productive granulomas, and intense MMP-2 and MMP-9 activities. Dx-treated mice exhibited a significant increase in IL-4 levels, tissue inflammation, proportion of involutive granulomas, and hepatic collagenogenesis, as well as attenuated MMP-2 and MMP-9 activities. Our findings indicated that Dx is toxic to adult S. mansoni worms in vitro. However, in vitro beneficial effects were not reproduced in vivo, since Dx treatment increased liver granulomatous inflammation and collagenogenesis in S. mansoni-infected mice by a process potentially associated with Dx-mediated hepatic MMP-2 and MMP-9 inhibition.


Assuntos
Antimaláricos/uso terapêutico , Doxiciclina/uso terapêutico , Granuloma/imunologia , Inflamação/imunologia , Fígado/imunologia , Schistosoma mansoni/fisiologia , Esquistossomicidas/imunologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Granuloma/parasitologia , Humanos , Imunomodulação , Infertilidade , Inflamação/parasitologia , Interleucina-4/metabolismo , Fígado/parasitologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Praziquantel/uso terapêutico , Schistosoma mansoni/efeitos dos fármacos
5.
Niger J Clin Pract ; 22(2): 270-275, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30729954

RESUMO

Background: Parasitic infestation of the appendix is uncommon. Parasitic infections can cause inflammation in the appendix and can imitate acute appendicitis clinically. Enterobius vermicularis and Taenia species are among the most common parasitic agents causing acute appendicitis. Objective: We have studied the ratio of parasites causing acute appendicitis in appendectomy specimens and whether there is any relationship between the type of the parasite, histopathological type of acute appendicitis, age of the patient, and gender of the patient in the appendectomy cases. Materials and Methods: We retrospectively analyzed the data of 2400 patients who underwent appendectomy with the prediagnosis of acute appendicitis between 1st January 2004 and 31st March 2018 at Erzincan University. The age of the patient, gender of the patient, histopathologic type of acute appendicitis, and the type of parasite were retrospectively analyzed. Positive appendectomy specimens for histopathological features of acute appendicitis were classified into four groups: catarrhal appendicitis, suppurative appendicitis, gangrenous appendicitis, and perforated appendicitis. Results: In all, 1451 were males and 949 were females. The mean age was 25.51 years. No acute inflammation was found in 36 appendectomy specimens. The distribution of 2364 cases involving acute appendicitis was as follows: catarrhal appendicitis: 438, suppurative appendicitis: 300, gangrenous appendicitis: 1082, and perforated appendicitis: 544. Parasites were identified in 32 cases. The ratio of appendices to parasites was 1.3%. The number of appendectomy cases with Enterobius vermicularis was 22, and the number with Taenia species was 10. Conclusion: Although they are a rare cause of acute appendicitis, parasitic infestations must always be considered. Accurate identification of acute appendicitis and appropriate therapy will improve the quality of life as much as the prevention of acute appendicitis sourced from parasites.


Assuntos
Apendicectomia , Apendicite/microbiologia , Apendicite/parasitologia , Apêndice/patologia , Enterobíase/parasitologia , Enterobius/isolamento & purificação , Inflamação/parasitologia , Doença Aguda , Adolescente , Adulto , Animais , Apendicite/diagnóstico , Apendicite/patologia , Apendicite/cirurgia , Apêndice/parasitologia , Enterobíase/diagnóstico , Enterobíase/epidemiologia , Feminino , Gangrena/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Estudos Retrospectivos
6.
Behav Brain Res ; 359: 737-748, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30253194

RESUMO

Toxoplasma gondii is a protozoan parasite that can cause a latent infection in the central nervous system, leading to neurobehavioral abnormalities in the host. However, the mechanism underlying these changes remains relatively unexplored. In this study, we detected behavioral changes, pathological injury, secretion of neurotransmitters and related signal pathway in mice infected by T. gondii using behavioral test, histopathology, immunofluorescence staining, western blotting, HPLC and real time PCR. Mice showed neurobehavioral disturbances two months after infection with T. gondii. Histopathology revealed the activation of astrocytes and microglia, apoptosis of neurons and decreases in synapses in the brain of infected mice. Excessive secretion of cytokines and chemokines was detected in the brains of mice infected by T. gondii compared to uninfected mice. Furthermore, T. gondii infection led to abnormalities in neurotransmitters and the activation of NF-κB and dopamine (DA) signaling pathways in the infected mice. In conclusion, excessive activation of the inflammation in the brain could induce neuronal apoptosis in mice chronically infected with T. gondii. Dysregulation of the dopaminergic neurotransmitter could provide an explanation of neurobehavioral disorders in infected hosts.


Assuntos
Inflamação/etiologia , Inflamação/metabolismo , Transtornos Mentais/etiologia , Transtornos do Humor/etiologia , Neurotransmissores/metabolismo , Toxoplasmose/complicações , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Doença Crônica , Modelos Animais de Doenças , Comportamento Exploratório/fisiologia , Feminino , Regulação da Expressão Gênica , Proteína Glial Fibrilar Ácida/metabolismo , Elevação dos Membros Posteriores/fisiologia , Marcação In Situ das Extremidades Cortadas , Inflamação/parasitologia , /parasitologia , Aprendizagem em Labirinto/fisiologia , Transtornos Mentais/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Proteínas dos Microfilamentos/metabolismo , Transtornos do Humor/parasitologia , Fosfopiruvato Hidratase/metabolismo , Sinaptotagmina I/metabolismo
7.
Avian Pathol ; 48(2): 121-134, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30556415

RESUMO

It is well established that the endothelium plays a prominent role in the pathogenesis of various infectious diseases in mammals. However, little is known about the role of endothelial cells (EC) as targets for avian pathogens and their contribution to the pathogenesis of infectious diseases in galliform birds. First, we explored the innate immune response of primary chicken aortic endothelial cells (pchAEC), obtained from 18-day-old embryos, to stimulation with pathogen-associated molecular patterns or recombinant chicken interferons (type I, II and III IFNs). In spite of the abundant expression of a number of innate immune receptors, marked cytokine responses to stimulation with pathogen-associated molecular patterns were only seen in pchAEC treated with the TLR3 agonist polyI:C (pI:C) and the MDA5 agonist liposome-complexed polyI:C (L-pI:C), as was assessed by quantitative PCR and luciferase-based IFN-I/NFκB reporter assays. Treatments of pchAEC with IFN-α, IFN-γ and IFN-λ resulted in STAT1-phosphorylation/activation, as was revealed by immunoblotting. Next, we demonstrated that pchAEC are susceptible to infection with a variety of poultry pathogens, including Marek's disease virus (MDV), infectious bursal disease virus (IBDV), avian pathogenic Escherichia coli (APEC) and Eimeria tenella. Our data highlight that chicken EC are potential targets for viral, bacterial and protozoan pathogens in gallinaceous poultry and may partake in the inflammatory and antimicrobial response. The pchAEC infection model used herein will allow further studies interrogating avian pathogen interactions with vascular EC. RESEARCH HIGHLIGHTS Use of a well-defined primary chicken aortic endothelial cell (pchAEC) culture model for studying avian host-pathogen interactions. pchAEC are responsive to innate immune stimulation with viral pathogen-associated molecular patterns and chicken type I, II and III interferons. pchAEC are susceptible to infections with economically important poultry pathogens, including MDV, IBDV, APEC and Eimeria tenella.


Assuntos
Interações Hospedeiro-Patógeno , Imunidade Inata , Interferons/metabolismo , Doenças das Aves Domésticas/imunologia , Animais , Linhagem Celular Tumoral , Células Cultivadas , Embrião de Galinha , Galinhas , Células Endoteliais/imunologia , Endotélio/imunologia , Feminino , Inflamação/microbiologia , Inflamação/parasitologia , Inflamação/veterinária , Interferons/genética , Doenças das Aves Domésticas/microbiologia , Doenças das Aves Domésticas/parasitologia
9.
Immunol Res ; 66(6): 637-641, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30554380

RESUMO

The distinction that in areas where helminthic infections are common, autoimmune diseases are less prevalent, led to the investigation of immune modulatory properties of helminths and their derivatives. Such are phosphorylcholine (PC) moieties which are a component of secreted products of helminths. PC has been broadly studied for its attenuating effects on the human immune system. In an attempt to develop a novel therapeutic small molecule for the treatment of autoimmune conditions, we have conjugated PC with tuftsin, a natural immunomodulatory tetrapeptide, to create TPC. Herein, we review our findings regarding the effects of TPC in murine models of three autoimmune diseases-systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), and rheumatic arthritis (RA), as well as ex-vivo samples from giant cell arteritis (GCA) patients. In all four disease models examined, TPC was shown to attenuate the inflammatory response by reducing expression of pro-inflammatory cytokines and altering the phenotype of T cell expression. In murine models, TPC has further produced a significant improvement in clinical disease scores with no significant side effects noted. Our findings suggest TPC presents promising potential as a novel therapeutic agent for the effective treatment of various autoimmune conditions.


Assuntos
Autoimunidade/efeitos dos fármacos , Helmintos/efeitos dos fármacos , Fosforilcolina/farmacologia , Fosforilcolina/uso terapêutico , Tuftsina/farmacologia , Tuftsina/uso terapêutico , Animais , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/parasitologia , Helmintíase/tratamento farmacológico , Helmintíase/parasitologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/parasitologia
10.
Front Immunol ; 9: 2492, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30459767

RESUMO

Schistosomiasis is a major cause of morbidity in humans invoked by chronic infection with parasitic trematodes of the genus Schistosoma. Schistosomes have a complex life-cycle involving infections of an aquatic snail intermediate host and a definitive mammalian host. In humans, adult male and female worms lie within the vasculature. Here, they propagate and eggs are laid. These eggs must then be released from the host to continue the life cycle. Schistosoma mansoni and Schistosoma japonicum reside in the mesenteric circulation of the intestines with egg excreted in the feces. In contrast, S. haematobium are present in the venus plexus of the bladder, expelling eggs in the urine. In an impressive case of exploitation of the host immune system, this process of Schistosome "eggs-iting" the host is immune dependent. In this article, we review the formation of the egg granuloma and explore how S. mansoni eggs laid in vasculature must usurp immunity to induce regulated inflammation, to facilitate extravasation through the intestinal wall and to be expelled in the feces. We highlight the roles of immune cell populations, stromal factors, and egg secretions in the process of egg excretion to provide a comprehensive overview of the current state of knowledge regarding a vastly unexplored mechanism.


Assuntos
Ovos , Granuloma/imunologia , Inflamação/parasitologia , Intestinos/parasitologia , Schistosoma/fisiologia , Esquistossomose/imunologia , Bexiga Urinária/parasitologia , Animais , Fezes/parasitologia , Granuloma/parasitologia , Interações Hospedeiro-Patógeno , Humanos , Estágios do Ciclo de Vida , Esquistossomose/parasitologia , Urina/parasitologia
11.
Front Immunol ; 9: 2557, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30473696

RESUMO

Diet composition may play a crucial role in shaping host immune responses and commensal gut microbiota populations. Bioactive dietary components, such as inulin, have been extensively studied for their bioactive properties, particularly in modulating gut immune function and reducing inflammation. It has been shown that colonization with gastrointestinal parasitic worms (helminths) may alleviate chronic inflammation through promotion of T-helper cell type (Th) 2 and T-regulatory immune responses and alterations in the gut microbiome. In this study, we investigated if dietary inulin could modulate mucosal immune function in pigs during colonization with the porcine whipworm Trichuris suis. T. suis infection induced a typical Th2-biased immune response characterized by transcriptional changes in Th2- and barrier function-related genes, accompanied by intestinal remodeling through increased epithelial goblet and tuft cell proliferation. We observed that inulin also up-regulated Th2-related immune genes (IL13, IL5), and suppressed Th1-related pro-inflammatory genes (IFNG, IL1A, IL8) in the colon. Notably, inulin augmented the T. suis-induced responses with increased transcription of key Th2 and mucosal barrier genes (e.g., IL13, TFF3), and synergistically suppressed pro-inflammatory genes, such as IFNG and CXCL9. 16S rRNA sequencing of proximal colon digesta samples revealed that inulin supplementation reduced the abundance of bacterial phyla linked to inflammation, such as Proteobacteria and Firmicutes, and simultaneously increased Actinobacteria and Bacteroidetes. Interestingly, pigs treated with both inulin and T. suis displayed the highest Bacteroidetes: Firmicutes ratio and the lowest gut pH, suggesting an interaction of diet and helminth infection that stimulates the growth of beneficial bacterial species. Overall, our data demonstrate that T. suis infection and inulin co-operatively enhance anti-inflammatory immune responses, which is potentially mediated by changes in microbiota composition. Our results highlight the intricate interactions between diet, immune function and microbiota composition in a porcine helminth infection model. This porcine model should facilitate further investigations into the use of bioactive diets as immunomodulatory mediators against inflammatory conditions, and how diet and parasites may influence gut health.


Assuntos
Mucosa Intestinal/imunologia , Inulina/imunologia , Suínos/imunologia , Suínos/parasitologia , Células Th2/imunologia , Tricuríase/imunologia , Trichuris/imunologia , Animais , Colo/imunologia , Colo/parasitologia , Dieta/métodos , Feminino , Microbioma Gastrointestinal/imunologia , Inflamação/imunologia , Inflamação/parasitologia , Mucosa Intestinal/parasitologia , Masculino , Membrana Mucosa/imunologia , Membrana Mucosa/parasitologia , RNA Ribossômico 16S/imunologia , Doenças dos Suínos/imunologia , Doenças dos Suínos/parasitologia , Tricuríase/parasitologia , Tricuríase/veterinária
12.
Malar J ; 17(1): 426, 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30442134

RESUMO

BACKGROUND: The intimate interaction between the pathophysiology of the human host and the biology of the Plasmodium falciparum parasite results in a wide spectrum of disease outcomes in malaria. Development of severe disease is associated with a progressively augmented imbalance in pro- and anti-inflammatory responses to high parasite loads and sequestration of parasitized erythrocytes. Although these phenomena collectively constitute common denominators for the wide variety of discrete severe malaria manifestations, the mechanistic rationales behind discrepancies in outcome are poorly understood. Exploration of the human pathophysiological response by variations in protein profiles in plasma presents an excellent opportunity to increase the understanding. This is ultimately required for better prediction, prevention and treatment of malaria, which is essential for ongoing elimination and eradication efforts. RESULTS: An affinity proteomics approach was used to analyse 541 paediatric plasma samples collected from community controls and patients with mild or severe malaria in Rwanda. Protein profiles were generated with an antibody-based suspension bead array containing 255 antibodies targetting 115 human proteins. Here, 57 proteins were identified with significantly altered levels (adjusted p-values < 0.001) in patients with malaria compared to controls. From these, the 27 most significant proteins (adjusted p-values < 10-14) were selected for a stringent analysis approach. Here, 24 proteins showed elevated levels in malaria patients and included proteins involved in acute inflammatory response as well as cell adhesion. The remaining three proteins, also implicated in immune regulation and cellular adhesivity, displayed lower abundance in malaria patients. In addition, 37 proteins (adjusted p-values < 0.05) were identified with increased levels in patients with severe compared to mild malaria. This set includes, proteins involved in tissue remodelling and erythrocyte membrane proteins. Collectively, this approach has been successfully used to identify proteins both with known and unknown association with different stages of malaria. CONCLUSION: In this study, a high-throughput affinity proteomics approach was used to find protein profiles in plasma linked to P. falciparum infection and malaria disease progression. The proteins presented herein are mainly involved in inflammatory response, cellular adhesion and as constituents of erythrocyte membrane. These findings have a great potential to provide increased conceptual understanding of host-parasite interaction and malaria pathogenesis.


Assuntos
Proteínas Sanguíneas/metabolismo , Interações Hospedeiro-Parasita , Malária Falciparum/fisiopatologia , Malária/fisiopatologia , Plasmodium falciparum/fisiologia , Adesão Celular , Criança , Pré-Escolar , Eritrócitos/parasitologia , Feminino , Humanos , Lactente , Inflamação/parasitologia , Inflamação/fisiopatologia , Malária/parasitologia , Malária Falciparum/parasitologia , Masculino , Ruanda
13.
Proc Natl Acad Sci U S A ; 115(43): 11042-11047, 2018 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-30291189

RESUMO

Sickness behaviors are a conserved set of stereotypic responses to inflammatory diseases. We recently demonstrated that interfering with inflammation-induced anorexia led to metabolic changes that had profound effects on survival of acute inflammatory conditions. We found that different inflammatory states needed to be coordinated with corresponding metabolic programs to actuate tissue-protective mechanisms. Survival of viral inflammation required intact glucose utilization pathways, whereas survival of bacterial inflammation required alternative fuel substrates and ketogenic programs. We thus hypothesized that organismal metabolism would be important in other classes of infectious inflammation and sought to understand its role in the prototypic parasitic disease malaria. Utilizing the cerebral malaria model, Plasmodium berghei ANKA (PbA) infection in C57BL/6J male mice, we unexpectedly found that inhibition of glycolysis using 2-deoxy glucose (2DG) conferred protection from cerebral malaria. Unlike vehicle-treated animals, 2DG-treated animals did not develop cerebral malaria and survived until ultimately succumbing to fatal anemia. We did not find any differences in parasitemia or pathogen load in affected tissues. There were no differences in the kinetics of anemia. We also did not detect differences in immune infiltration in the brain or in blood-brain barrier permeability. Rather, on pathological analyses performed on the entire brain, we found that 2DG prevented the formation of thrombi and thrombotic complications. Using thromboelastography (TEG), we found that 2DG-treated animals formed clots that were significantly less strong and stable. Together, these data suggest that glucose metabolism is involved in inflammation-induced hemostasis and provide a potential therapeutic target in treatment of cerebral malaria.


Assuntos
Encéfalo/imunologia , Encéfalo/parasitologia , Glucose/imunologia , Glucose/metabolismo , Tolerância Imunológica/imunologia , Malária Cerebral/imunologia , Malária Cerebral/metabolismo , Animais , Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/parasitologia , Modelos Animais de Doenças , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/parasitologia , Malária Cerebral/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Parasitemia/imunologia , Plasmodium berghei/imunologia
14.
Artigo em Inglês | MEDLINE | ID: mdl-30297367

RESUMO

The oral drug miltefosine (MIL) was introduced in the Indian subcontinent in the year 2002 for the treatment of visceral leishmaniasis (VL). However, recent reports on its declining efficacy and increasing relapse rates pose a serious concern. An understanding of the factors contributing to MIL tolerance in Leishmania parasites is critical. In the present study, we assessed the role of the lipase precursor-like protein (Lip) in conferring tolerance to miltefosine by episomally overexpressing Lip in Leishmania donovani (LdLip++). We observed a significant increase (∼3-fold) in the MIL 50% inhibitory concentration (IC50) at both the promastigote (3.90 ± 0.68 µM; P < 0.05) and intracellular amastigote (9.10 ± 0.60 µM; P < 0.05) stages compared to the wild-type counterpart (LdNeo) (MIL IC50s of 1.49 ± 0.20 µM at the promastigote stage and 3.95 ± 0.45 µM at the amastigote stage). LdLip++ parasites exhibited significantly (P < 0.05) increased infectivity to host macrophages and increased metacyclogenesis and tolerance to MIL-induced oxidative stress. The susceptibility of LdLip++ to other antileishmanial drugs (sodium antimony gluconate and amphotericin B) remained unchanged. In comparison to LdNeo, the LdLip++ parasites elicited high host interleukin-10 (IL-10) cytokine expression levels (1.6-fold; P < 0.05) with reduced expression of the cytokine tumor necrosis factor alpha (TNF-α) (1.5-fold; P < 0.05), leading to a significantly (P < 0.01) increased ratio of IL-10/TNF-α. The above-described findings suggest a role of lipase precursor-like protein in conferring tolerance to the oral antileishmanial drug MIL in L. donovani parasites.


Assuntos
Interações Hospedeiro-Patógeno/efeitos dos fármacos , Leishmania donovani/efeitos dos fármacos , Leishmania donovani/patogenicidade , Fosforilcolina/análogos & derivados , Proteínas de Protozoários/metabolismo , Animais , Antiprotozoários/farmacologia , Citocinas/metabolismo , Resistência a Medicamentos/efeitos dos fármacos , Resistência a Medicamentos/genética , Feminino , Interações Hospedeiro-Patógeno/fisiologia , Inflamação/metabolismo , Inflamação/parasitologia , Leishmania donovani/genética , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/parasitologia , Lipase/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Camundongos Endogâmicos BALB C , Estresse Oxidativo , Fosforilcolina/farmacologia
15.
Int J Exp Pathol ; 99(5): 236-248, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30320480

RESUMO

Hydroxymethylnitrofurazone (NFOH) is a nitrofurazone prodrug effective in vivo during acute infections, and it has less hepatotoxicity effect than the standard drug benznidazole (BZN) which has been used during short- and long-term treatment. In the present study, we induced the indeterminate form of Chagas disease in mice with a Y strain of Trypanosoma cruzi and analysed the histopathological data about the effects of NFOH and BZN on different tissues, including the heart, skeletal muscle, liver, kidney, colon, spleen and brain. After infection, BALB/c mice were treated with NFOH (150 mg/kg) and BZN (60 mg/kg) for 60 days and then submitted to immunosuppression using dexamethasone (5 mg/kg) for 14 days. Two trained analysts, as part of a blind evaluation, examined the results using serial sections of 3 mm diameter in two different moments. The results showed reactivation of the disease only in the infected nontreated group (POS). After treatment, amastigote nests were found in the heart, colon, liver and skeletal muscle in the POS group and in the heart and liver of the BZN group. Interestingly, amastigote nests were not found in the NFOH and NEG groups. The histopathological analysis showed fewer tissue lesions and parasite infiltrates in the NFOH group when compared with the BZN and POS groups. We have not observed any increase in the levels of hepatocellular injury biomarkers (AST/ALT) in the NFOH group. These in vivo studies show the potential for NFOH as an effective and safe compound useful as an anti-T. cruzi agent.


Assuntos
Doença de Chagas/tratamento farmacológico , Nitrofurazona/análogos & derivados , Trypanosoma cruzi/efeitos dos fármacos , Animais , Doença de Chagas/parasitologia , Doença de Chagas/patologia , Modelos Animais de Doenças , Inflamação/tratamento farmacológico , Inflamação/parasitologia , Inflamação/patologia , Rim/efeitos dos fármacos , Rim/patologia , Fígado/parasitologia , Fígado/patologia , Masculino , Camundongos , Músculo Esquelético/patologia , Nitrofurazona/química , Nitrofurazona/farmacologia , Nitroimidazóis/uso terapêutico
16.
Immunity ; 49(4): 654-665.e5, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30266340

RESUMO

Recruitment of immune cells with antimicrobial activities is essential to fight local infections but has the potential to trigger immunopathology. Whether the immune system has the ability to sense inflammation intensity and self-adjust accordingly to limit tissue damage remains to be fully established. During local infection with an intracellular pathogen, we have shown that nitric oxide (NO) produced by recruited monocyte-derived cells was essential to limit inflammation and cell recruitment. Mechanistically, we have provided evidence that NO dampened monocyte-derived cell cytokine and chemokine production by inhibiting cellular respiration and reducing cellular ATP:ADP ratio. Such metabolic control operated at the tissue level but only when a sufficient number of NO-producing cells reached the site of infection. Thus, NO production and activity act as a quorum sensing mechanism to help terminate the inflammatory response.


Assuntos
Citocinas/imunologia , Inflamação/imunologia , Monócitos/imunologia , Óxido Nítrico/imunologia , Animais , Células Cultivadas , Citocinas/metabolismo , Células HEK293 , Interações Hospedeiro-Parasita/imunologia , Humanos , Inflamação/metabolismo , Inflamação/parasitologia , Leishmania major/imunologia , Leishmania major/fisiologia , Leishmaniose Cutânea/imunologia , Leishmaniose Cutânea/metabolismo , Leishmaniose Cutânea/parasitologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/parasitologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Monócitos/metabolismo , Monócitos/parasitologia , Óxido Nítrico/metabolismo , Percepção de Quorum/imunologia
17.
Am J Pathol ; 188(11): 2674-2687, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30121257

RESUMO

Toxoplasmosis is one of the leading parasitic diseases worldwide. Some data suggest that chronic acquired toxoplasmosis could be linked to behavioral alterations in humans. The parasite infects neurons, forming immunologically silent cysts. Cerebral microcirculation homeostasis is determinant to brain functions, and pathologic states can alter capillarity or blood perfusion, leading to neurodegeneration and cognitive deficits. Albino mice were infected with Toxoplasma gondii (ME49 strain) and analyzed after 10, 40, and 180 days. Infected mice presented decreased cerebral blood flow at 10 and 40 days post infection (dpi), which were restored at 180 dpi, as shown by laser speckle contrast imaging. Intravital microscopy demonstrated that infection led to significant capillary rarefaction, accompanied by neuroinflammation, with microglial activation and increased numbers of rolling and adherent leukocytes to the wall of cerebral capillaries. Acetylcholine-induced vasodilation was altered at all time points, and blood brain barrier permeability was evident in infected animals at 40 dpi. Infection reduced angiogenesis, with a decreased number of isolectin B4-stained blood vessels and a decrease in length and branching of laminin-stained capillaries. Sulfadiazine reduced parasite load and partially repaired microvascular damages. We conclude that T. gondii latent infection causes a harmful insult in the brain, promoting neuroinflammation and microcirculatory dysfunction in the brain, with decreased angiogenesis and can contribute to a neurodegenerative process.


Assuntos
Barreira Hematoencefálica/patologia , Endotélio Vascular/patologia , Inflamação/patologia , Microcirculação , Neurônios/patologia , Toxoplasma/patogenicidade , Toxoplasmose Cerebral/patologia , Animais , Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/parasitologia , Endotélio Vascular/imunologia , Endotélio Vascular/parasitologia , Feminino , Inflamação/imunologia , Inflamação/parasitologia , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/imunologia , Neurônios/parasitologia , Toxoplasmose Cerebral/imunologia , Toxoplasmose Cerebral/parasitologia
18.
Cytokine ; 112: 27-31, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30145061

RESUMO

Leishmania is an obligate intracellular parasite uses low pH phagolysosomal compartments of host macrophages as their final abode. IL-1ß is a pro inflammatory cytokine, which is secreted by immune cells to trigger inflammation and this has been found profoundly in the lesions caused by Leishmania pathogens. But the specific role of this cytokine on host cell macrophages during infection has not been fully explored. Here in, we have showed that prolonged exposure of IL-1ß on macrophages increases the parasite burden. Pre-treatment of bone marrow derived macrophages (BMDM) with IL-1ß also generates significantly higher amount of anti-inflammatory cytokine IL-10. As IL-10 plays crucial role in the establishment of infection, enhanced production of IL-10 observed upon IL-1ß treatment could contribute to the progression of the disease. By quantifying the production of Nitric oxide (NO), we further report that the pretreatment of IL-1ß fails to produce the nitric oxide. By measuring the footpad thickness in two different mice strains of differential susceptibility we showed IL-1ß treatment increases parasitic burden. As our results shows that the exposure of IL-1ß helps in disease progression, IL-1ß signalling may be an attractive target for future therapeutic intervention.


Assuntos
Inflamação/imunologia , Interleucina-1beta/metabolismo , Leishmaniose/imunologia , Animais , Medula Óssea/imunologia , Medula Óssea/parasitologia , Feminino , Humanos , Inflamação/parasitologia , Interleucina-10/imunologia , Leishmania/imunologia , Leishmaniose/parasitologia , Macrófagos/imunologia , Macrófagos/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Monócitos/imunologia , Monócitos/parasitologia , Óxido Nítrico/imunologia
19.
Artigo em Inglês | MEDLINE | ID: mdl-29987143

RESUMO

The acute phase of Chagas disease (CD) is characterized by high parasitic proliferation and intense inflammation, exacerbating the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). These reactive molecules are also increased by the metabolism of the nitroheterocyclic compounds benznidazole (BZ) and nifurtimox, the only drugs available for the treatment of CD. This oxidative environment, associated with the intracellular multiplication of Trypanosoma cruzi, leads to tissue destruction, triggering the pathogenic process. Both drugs have limited efficacy and serious side effects, which demonstrates the need to seek alternative therapies. Due to the difficulty in developing new drugs, reviewing therapeutic regimens appears advantageous, and the use of BZ in low doses associated with antioxidants, such as ascorbic acid (AA), would be a valid alternative to attenuate oxidative stress. In our in vivo studies, mice receiving the combination of 7.14 mg/kg of body weight/day AA and 10 mg/kg/day BZ10 (AA+BZ10) showed a reduction in parasitemia that was more effective than that with those receiving BZ or AA alone. The combined treatment was effective in decreasing intracellular ROS and lipid peroxidation in cardiac tissue. Histological and PCR analyzes showed that AA also reduced the cardiac parasitism. However, the greatest benefit was seen in AA+BZ10 group, since cardiac inflammation was significantly reduced. In addition, the combined therapy prevented the hepatic damage induced by the infection. Our findings suggest that AA combined with a low dose of BZ may improve the trypanocidal activity and attenuate the toxic effects of BZ. The decrease in oxidative damage and inflammation observed in mice treated with AA+BZ10 could result in increased cardioprotection.


Assuntos
Ácido Ascórbico/farmacologia , Doença de Chagas/tratamento farmacológico , Nitroimidazóis/farmacologia , Animais , Antioxidantes/metabolismo , Doença de Chagas/parasitologia , Quimioterapia Combinada/métodos , Inflamação/tratamento farmacológico , Inflamação/parasitologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Oxirredução/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos
20.
Sci Rep ; 8(1): 10241, 2018 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-29980718

RESUMO

Multiple protozoans produce homologs of the cytokine MIF which play a role in immune evasion, invasion and pathogenesis. However, how parasite-encoded MIF activity is controlled remains poorly understood. Cytokine activity can be inhibited by intracellular binding partners that are released in the extracellular space during cell death. We investigated the presence of an endogenous parasite protein that was capable of interacting and interfering with MIF activity. A screen for protein-protein interaction was performed using immunoaffinity purification of amebic cell lysate with specific anti-Entamoeba histolytica MIF (EhMIF) antibody followed by mass spectrometry analysis, which revealed an E. histolytica-produced JAB1 protein (EhJAB1) as a potential binding partner. JAB1 was found to be highly conserved in protozoans. Direct interaction between the EhMIF and EhJAB1 was confirmed by several independent approaches with GST pull-down, co-immunoprecipitation, and Biolayer interferometry (BLI) assays. Furthermore, the C-terminal region outside the functional JAMM deneddylase motif was required for EhMIF binding, which was consistent with the top in silico predictions. In addition, EhJAB1 binding blocked EhMIF-induced IL-8 production by human epithelial cells. We report the initial characterization of a parasite-encoded JAB1 and uncover a new binding partner for a protozoan-produced MIF protein, acting as a possible negative regulator of EhMIF.


Assuntos
Anticorpos/imunologia , Entamoeba histolytica/fisiologia , Entamebíase/metabolismo , Inflamação/prevenção & controle , Fatores Inibidores da Migração de Macrófagos/metabolismo , Proteínas de Protozoários/metabolismo , Sequência de Aminoácidos , Citocinas/metabolismo , Entamebíase/imunologia , Entamebíase/parasitologia , Células HCT116 , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/parasitologia , Fatores Inibidores da Migração de Macrófagos/imunologia , Domínios e Motivos de Interação entre Proteínas , Proteínas de Protozoários/imunologia
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