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1.
PLoS One ; 15(1): e0228176, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31999729

RESUMO

Visceral leishmaniasis (VL) is a severe, systemic and potentially lethal parasitosis. The lung, like any other organ, can be affected in VL, and interstitial pneumonitis has been described in past decades. This research aimed to bring more recent knowledge about respiratory impairment in VL, characterizing pulmonary involvement through clinical, radiographic and tomographic evaluation. This is an observational, cross-sectional study that underwent clinical evaluation, radiography and high-resolution computed tomography of the chest in patients admitted with the diagnosis of VL in a university service in Northeast Brazil, from January 2015 to July 2018. The sample consisted of 42 patients. Computed tomography was considered abnormal in 59% of patients. Images compatible with pulmonary interstitial involvement were predominant (50%). The most observed respiratory symptom was cough (33.3%), followed by tachypnea (14.1%). Chest radiography was altered in only four patients. VL is a disease characterized by systemic involvement and broad spectrum of clinical manifestations. The respiratory symptoms and tomographic alterations found show that the involvement of respiratory system in VL deserves attention because it is more common than previously thought. Chest X-ray may not reveal this impairment.


Assuntos
Leishmaniose Visceral/complicações , Pneumopatias/parasitologia , Adolescente , Adulto , Criança , Pré-Escolar , Tosse/parasitologia , Estudos Transversais , Feminino , Humanos , Leishmaniose Visceral/diagnóstico por imagem , Leishmaniose Visceral/fisiopatologia , Pneumopatias/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X , Adulto Jovem
2.
Transbound Emerg Dis ; 67(1): 318-327, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31512804

RESUMO

The objective of this study was to identify changes in serum proteome in dogs that may occur after an experimental infection at subclinical and clinical stages of canine leishmaniosis (CanL). For this purpose, canine pre- and post-infection with Leishmania infantum serum proteomes in the same dogs were analysed by a high-throughput label-based quantitative LC-MS/MS proteomic approach. A total of 169 proteins were identified, and 74 of them including complement C8 alpha chain, adiponectin, transferrin, sphingomyelin phosphodiesterase acid-like 3A and immunoglobulins showed different modulation between the different stages of CanL. These proteins could be considered as potential serum biomarkers of early diagnostic or disease progression in CanL. Additionally, biological pathways modulated during CanL such as blood coagulation or gonadotropin-releasing hormone receptor were revealed, which could help to understand the pathological mechanisms of the disease.


Assuntos
Biomarcadores/sangue , Doenças do Cão/sangue , Leishmania infantum/metabolismo , Leishmaniose Visceral/veterinária , Proteoma , Animais , Cromatografia Líquida/veterinária , Doenças do Cão/fisiopatologia , Doenças do Cão/virologia , Cães , Leishmania infantum/isolamento & purificação , Leishmaniose Visceral/sangue , Leishmaniose Visceral/fisiopatologia , Leishmaniose Visceral/virologia , Proteômica , Espectrometria de Massas em Tandem/veterinária
3.
Parasitol Res ; 118(9): 2705-2713, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31359134

RESUMO

Artemisinin, extracted from a medicinal herb Artemisia annua, is widely used to treat malaria and has shown potent anticancer activity. Artemisinin has been found to be effective against experimental visceral and cutaneous leishmaniasis. Despite extensive research to understand the complex mechanism of resistance to artemisinin, several questions remain unanswered. The artesunate (ART)-resistant line of Leishmania donovani was selected and cellular mechanisms associated with resistance to artemisinin were investigated. ART-resistant (AS-R) parasites showed reduced susceptibility towards ART both at promastigote and amastigote stage compared with ART sensitive (WT) parasites. WT and AS-R parasites were both more susceptible to ART at the early log phase of growth compared with late log phase. AS-R parasites were more infective to the host macrophages (p < 0.05). Evaluation of parasites' tolerance towards host microbicidal mechanisms revealed that AS-R parasites were more tolerant to complement-mediated lysis and nitrosative stress. ROS levels were modulated in presence of ART in AS-R parasites infected macrophages. Interestingly, infection of macrophages by AS-R parasites led to modulated levels of host interleukins, IL-2 and IL-10, in addition to nitric oxide. Additionally, AS-R parasites showed upregulated expression of genes of unfolded protein response pathway including methyltransferase domain-containing protein (HSP40) and flagellar attachment zone protein (prefoldin), that are reported to be associated with ART resistance in Plasmodium falciparum malaria. This study presents in vitro model of artemisinin-resistant Leishmania parasite and cellular mechanisms associated with ART resistance in Leishmania.


Assuntos
Antiprotozoários/administração & dosagem , Artemisininas/administração & dosagem , Leishmania donovani/efeitos dos fármacos , Leishmaniose Visceral/genética , Leishmaniose Visceral/imunologia , Extratos Vegetais/administração & dosagem , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Animais , Artemisia annua/química , Artesunato/administração & dosagem , Feminino , Proteínas de Choque Térmico HSP40/genética , Proteínas de Choque Térmico HSP40/imunologia , Interações Hospedeiro-Parasita , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Leishmania donovani/crescimento & desenvolvimento , Leishmaniose Visceral/parasitologia , Leishmaniose Visceral/fisiopatologia , Macrófagos/imunologia , Camundongos Endogâmicos BALB C
4.
Trop Doct ; 49(1): 59-61, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30453836

RESUMO

Visceral leishmaniasis (VL) is a neglected disease. Our retrospective study describes 38 clinical and epidemiological characteristics of VL in patients admitted to a paediatric hospital in Tehran, Iran, who came from different geographical regions, indicating that the disease has spread to most parts of the country. Some 76.3% of the children documented suffered with symptoms of the disease for two months before admission.


Assuntos
Leishmaniose Visceral/diagnóstico , Leishmaniose Visceral/epidemiologia , Criança , Pré-Escolar , Feminino , Hospitalização/estatística & dados numéricos , Hospitais Pediátricos , Humanos , Lactente , Irã (Geográfico)/epidemiologia , Leishmaniose Visceral/fisiopatologia , Masculino , Doenças Negligenciadas/diagnóstico , Doenças Negligenciadas/epidemiologia , Doenças Negligenciadas/fisiopatologia , Estudos Retrospectivos
6.
Am J Trop Med Hyg ; 99(6): 1541-1546, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30328408

RESUMO

Common in four continents, visceral leishmaniasis (VL) is an important but neglected disease. Human immunodeficiency virus (HIV) infection increases the risk of developing VL in people from leishmaniasis-endemic areas, with worse prognosis when there is coinfection. We conducted a cross-sectional study to determine the prevalence of HIV/VL coinfection in patients admitted in three referral hospitals for HIV/acquired immunodeficiency syndrome (AIDS) in Pernambuco, Brazil, and to compare epidemiological, clinical, and laboratory characteristics among HIV/VL coinfected and HIV mono-infected individuals. The sample consisted of HIV patients aged 18 years or more, in a period of data collection of 6 months. We performed four Leishmania tests-polymerase chain reaction (PCR), direct agglutination test, rK39, and latex agglutination test-and individuals with at least one positive test were considered coinfected. The HIV/VL coinfection prevalence we found was 16.9%. We observed large variation in prevalence according to the Leishmania test used, with low coincidence of positive tests. The most frequent symptoms found were weight loss (75.6%), fever (67.6%), and cough (55.3%). When we compared HIV/VL coinfected and HIV mono-infected groups we did not observe statistically significant differences. Low educational level (P = 0.004) and pallor (P = 0.009) were more frequent in the coinfected group. Serum albumin level was higher in coinfected individuals (P = 0.009). It is important to follow-up these individuals to understand the dynamics of VL in people living with HIV. New tests are necessary, ideally differentiating active from latent infection. Testing for VL in people with HIV is important and should be considered as part of the initial investigation in these individuals.


Assuntos
Infecções por HIV/epidemiologia , HIV/genética , Hospitalização , Leishmania/genética , Leishmaniose Visceral/epidemiologia , Adolescente , Adulto , Testes de Aglutinação , Brasil/epidemiologia , Coinfecção , Estudos Transversais , Feminino , HIV/imunologia , HIV/isolamento & purificação , Infecções por HIV/parasitologia , Infecções por HIV/fisiopatologia , Infecções por HIV/virologia , Humanos , Leishmania/imunologia , Leishmania/isolamento & purificação , Leishmaniose Visceral/parasitologia , Leishmaniose Visceral/fisiopatologia , Leishmaniose Visceral/virologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Prevalência
7.
Artigo em Inglês | MEDLINE | ID: mdl-30175073

RESUMO

In Latin America, zoonotic visceral leishmaniasis (ZVL) arising from infection by L. infantum is primarily transmitted by Lutzomyia longipalpis sand flies. Dogs, which are chronic reservoirs of L. infantum, are considered a significant risk factor for acquisition of ZVL due to their close proximity to humans. In addition, as a vector-borne disease the intensity of exposure to vector sand flies can also enhance the risk of developing ZVL. Traditionally, IFN-γ and IL-10 are considered as the two main cytokines which determine the outcome of visceral leishmaniasis. However, more recently, the literature has demonstrated that different mediators, such as lipid mediators (PGE-2, PGF-2 alfa, LTB-4, resolvins) and other important inflammatory and anti-inflammatory cytokines are also involved in the pathogenicity of ZVL. Analysis of a greater number of mediators allows for a more complete view of disease immunopathogenesis. Additionally, our knowledge has expanded to encompass different biomarkers associated to disease severity and healing after specific treatments. These parameters can also be used to better define new potential targets for vaccines and chemotherapy for ZVL. Here, we will provide an overview of ZVL biomarkers identified for both humans and dogs and discuss their merits and shortcomings. We will also discuss biomarkers of vector exposure as an additional tool in our arsenal to combat ZVL.


Assuntos
Biomarcadores/sangue , Citocinas/sangue , Doenças do Cão/patologia , Mediadores da Inflamação/sangue , Leishmaniose Visceral/patologia , Leishmaniose Visceral/veterinária , Zoonoses/patologia , Animais , Doenças do Cão/diagnóstico , Doenças do Cão/fisiopatologia , Cães , Humanos , América Latina , Leishmaniose Visceral/diagnóstico , Leishmaniose Visceral/fisiopatologia , Zoonoses/diagnóstico , Zoonoses/fisiopatologia
8.
Lancet ; 392(10151): 951-970, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-30126638

RESUMO

Leishmaniasis is a poverty-related disease with two main clinical forms: visceral leishmaniasis and cutaneous leishmaniasis. An estimated 0·7-1 million new cases of leishmaniasis per year are reported from nearly 100 endemic countries. The number of reported visceral leishmaniasis cases has decreased substantially in the past decade as a result of better access to diagnosis and treatment and more intense vector control within an elimination initiative in Asia, although natural cycles in transmission intensity might play a role. In east Africa however, the case numbers of this fatal disease continue to be sustained. Increased conflict in endemic areas of cutaneous leishmaniasis and forced displacement has resulted in a surge in these endemic areas as well as clinics across the world. WHO lists leishmaniasis as one of the neglected tropical diseases for which the development of new treatments is a priority. Major evidence gaps remain, and new tools are needed before leishmaniasis can be definitively controlled.


Assuntos
Antiprotozoários/uso terapêutico , Leishmaniose Cutânea , Leishmaniose Visceral , Animais , Coinfecção/complicações , Vetores de Doenças , Saúde Global , Infecções por HIV/complicações , Humanos , Leishmania , Leishmaniose Cutânea/diagnóstico , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/epidemiologia , Leishmaniose Cutânea/fisiopatologia , Leishmaniose Visceral/diagnóstico , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/epidemiologia , Leishmaniose Visceral/fisiopatologia
10.
PLoS Negl Trop Dis ; 12(7): e0006646, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30036391

RESUMO

BACKGROUND: Endoplasmic reticulum (ER) stress generated unfolded stress response (UPR) is a basic survival mechanism which protects cell under unfavourable conditions. Leishmania parasite modulates host macrophages in various ways to ensure its survival. Modulation of PI3K-Akt pathway in delayed apoptotic induction of host; enables parasite to stabilize the infection for further propagation. METHODOLOGY: Infected RAW macrophages were exposed to campothecin or thagsigargin and phosphorylation status of PERK, Akt, BAD and Cyt-C was determined through western blotting using phospho specific antibody. Expression at transcriptional level for cIAP1 &2, ATF4, CHOP, ATF3, HO-1 and sXBP1 was determined using real time PCR. For inhibition studies, RAW macrophages were pre-treated with PERK inhibitor GSK2606414 before infection. FINDINGS: Our studies in RAW macrophages showed that induction of host UPR against L.donovani infection activates Akt mediated pathway which delays apoptotic induction of the host. Moreover, Leishmania infection results in phosphorylation and activation of host PERK enzyme and increased transcription of genes of inhibitor of apoptosis gene family (cIAP) mRNA. In our inhibition studies, we found that inhibition of infection induced PERK phosphorylation under apoptotic inducers reduces the Akt phosphorylation and fails to activate further downstream molecules involved in protection against apoptosis. Also, inhibition of PERK phosphorylation under oxidative exposure leads to increased Nitric Oxide production. Simultaneously, decreased transcription of cIAP mRNA upon PERK phosphorylation fates the host cell towards apoptosis hence decreased infection rate. CONCLUSION: Overall the findings from the study suggests that Leishmania modulated host UPR and PERK phosphorylation delays apoptotic induction in host macrophage, hence supports parasite invasion at early stages of infection.


Assuntos
Apoptose , Leishmania donovani/fisiologia , Leishmaniose Visceral/enzimologia , Leishmaniose Visceral/fisiopatologia , Macrófagos/parasitologia , Resposta a Proteínas não Dobradas , eIF-2 Quinase/metabolismo , Animais , Estresse do Retículo Endoplasmático , Interações Hospedeiro-Parasita , Humanos , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Leishmania donovani/genética , Leishmaniose Visceral/parasitologia , Macrófagos/enzimologia , Camundongos , Fosforilação , Células RAW 264.7 , eIF-2 Quinase/genética
11.
J Biol Chem ; 293(7): 2617-2630, 2018 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-29269416

RESUMO

Autophagy is essential for cell survival under stress and has also been implicated in host defense. Here, we investigated the interactions between Leishmania donovani, the main etiological agent of visceral leishmaniasis, and the autophagic machinery of human macrophages. Our results revealed that during early infection-and via activation of the Akt pathway-Leishmania actively inhibits the induction of autophagy. However, by 24 h, Leishmania switched from being an inhibitor to an overall inducer of autophagy. These findings of a dynamic, biphasic response were based on the accumulation of lipidated light chain 3 (LC3), an autophagosome marker, by Western blotting and confocal fluorescence microscopy. We also present evidence that Leishmania induces delayed host cell autophagy via a mechanism independent of reduced activity of the mechanistic target of rapamycin (mTOR). Notably, Leishmania actively inhibited mTOR-regulated autophagy even at later stages of infection, whereas there was a clear induction of autophagy via some other mechanism. In this context, we examined host inositol monophosphatase (IMPase), reduced levels of which have been implicated in mTOR-independent autophagy, and we found that IMPase activity is significantly decreased in infected cells. These findings indicate that Leishmania uses an alternative pathway to mTOR to induce autophagy in host macrophages. Finally, RNAi-mediated down-regulation of host autophagy protein 5 (ATG5) or autophagy protein 9A (ATG9A) decreased parasite loads, demonstrating that autophagy is essential for Leishmania survival. We conclude that Leishmania uses an alternative pathway to induce host autophagy while simultaneously inhibiting mTOR-regulated autophagy to fine-tune the timing and magnitude of this process and to optimize parasite survival.


Assuntos
Autofagia , Interações Hospedeiro-Parasita , Leishmania donovani/crescimento & desenvolvimento , Leishmaniose Visceral/fisiopatologia , Proteína 5 Relacionada à Autofagia/genética , Proteína 5 Relacionada à Autofagia/metabolismo , Humanos , Leishmania donovani/genética , Leishmania donovani/fisiologia , Leishmaniose Visceral/genética , Leishmaniose Visceral/metabolismo , Leishmaniose Visceral/parasitologia , Macrófagos/citologia , Macrófagos/metabolismo , Macrófagos/parasitologia , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Monoéster Fosfórico Hidrolases/genética , Monoéster Fosfórico Hidrolases/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
12.
Rev Soc Bras Med Trop ; 50(5): 613-620, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29160507

RESUMO

INTRODUCTION: Visceral leishmaniasis (VL) and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) co-infection has been a research topic of interest worldwide. In Brazil, it has been observed that there is a relative underreporting and failure in the understanding and management of this important association. The aim of this study was to analyze epidemiological and clinical aspects of patients with VL with and without HIV/AIDS. METHODS: We conducted an observational and analytical study of patients with VL followed in a Reference Service in the State of Maranhão, Brazil from 2007-2013. RESULTS: In total 126 patients were enrolled, of which 61 (48.4%) were co-infected with HIV/AIDS. There were more males among those with HIV/AIDS (85.2%, P>0.05) or with VL only (81.5%, P>0.05). These findings significantly differed based on age group (P<0.003); the majority of patients were aged 31-40 years (41.0%) and 21-30 years (32.3%) among those with and without HIV/AIDS co-infection, respectively. The incidence of diarrhea and splenomegaly significantly differed between the two groups (P=0.0014 and P=0.019, respectively). The myelogram parasitic examination was used most frequently among those with HIV/AIDS (91.8%), followed by those with VL only (69.2%). VL recurrences and mortality were significantly higher in the HIV/AIDS co-infected patients (P<0.0001 and P=0.012, respectively). CONCLUSIONS: Patients with VL with or without HIV/AIDS co-infection were mostly adult men. Diarrhea was more frequent in HIV/AIDS co-infected patients, whereas splenomegaly was more common in patients with VL only. In the group of HIV/AIDS co-infected patients, there was a higher rate of VL recurrence and mortality.


Assuntos
Síndrome de Imunodeficiência Adquirida/epidemiologia , Coinfecção/epidemiologia , Leishmaniose Visceral/epidemiologia , Síndrome de Imunodeficiência Adquirida/complicações , Síndrome de Imunodeficiência Adquirida/fisiopatologia , Adolescente , Adulto , Distribuição por Idade , Idoso , Contagem de Células Sanguíneas , Brasil/epidemiologia , Criança , Pré-Escolar , Coinfecção/fisiopatologia , Diarreia/epidemiologia , Diarreia/etiologia , Feminino , Humanos , Leishmaniose Visceral/complicações , Leishmaniose Visceral/fisiopatologia , Masculino , Pessoa de Meia-Idade , Distribuição por Sexo , Fatores Socioeconômicos , Esplenomegalia/epidemiologia , Esplenomegalia/etiologia , Carga Viral , Adulto Jovem
13.
Rev Soc Bras Med Trop ; 50(5): 670-674, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29160515

RESUMO

INTRODUCTION: This study aimed to draw clinical and epidemiological comparisons between visceral leishmaniasis (VL) and VL associated with human immunodeficiency virus (HIV) infection. METHOD: Retrospective study. RESULTS: Of 473 cases of VL, 5.5% were coinfected with HIV. The highest proportion of cases of both VL and VL/HIV were found among men. A higher proportion of VL cases was seen in children aged 0-10 years, whereas coinfection was more common in those aged 18-50 years. CONCLUSIONS: VL/HIV coinfected patients presented slightly differently to and had a higher mortality rate than those with VL only.


Assuntos
Coinfecção/epidemiologia , Infecções por HIV/epidemiologia , Leishmaniose Visceral/epidemiologia , Adolescente , Adulto , Distribuição por Idade , Fatores Etários , Brasil/epidemiologia , Criança , Pré-Escolar , Coinfecção/tratamento farmacológico , Coinfecção/fisiopatologia , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/fisiopatologia , Humanos , Incidência , Lactente , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/fisiopatologia , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Distribuição por Sexo , Fatores Socioeconômicos , Resultado do Tratamento , Adulto Jovem
14.
PLoS Negl Trop Dis ; 11(10): e0005921, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28968400

RESUMO

BACKGROUND: South Sudan is one of the most endemic countries for visceral leishmaniasis (VL), and is frequently affected by large epidemics. In resource-limited settings, clinicians require a simple clinical tool to identify VL patients who are at increased risk of dying, and who need specialised treatment with liposomal amphotericin B and other supportive care. The aim of this study was to develop and validate a clinical severity scoring system based on risk factors for death in VL patients in South Sudan. METHODS: A retrospective analysis was conducted of data from a cohort of 6,633 VL patients who were treated in the Médecins Sans Frontières (MSF) hospital in Lankien between July 2013 and June 2015. Risk factors for death during treatment were identified using multivariable logistic regression models, and the regression coefficients were used to develop a severity scoring system. Sensitivity and specificity of score cut-offs were assessed by receiver operating characteristic (ROC) analysis. RESULTS: In multivariable models, risk factors for death in adult VL patients were: anaemia (odds ratio (OR) 4.46 (95% CI 1.58-12.6) for Hb <6g/dL compared with ≥9g/dL), nutritional status (OR 4.84 (2.09-11.2) for BMI <13 kg/m2 compared with ≥16 kg/m2), weakness (OR 4.20 (1.82-9.73) for collapsed compared with normal weakness), jaundice (OR 3.41 (1.17-9.95)), and oedema/ascites (OR 4.86 (1.67-14.1)). For children and adolescents the risk factors were: age (OR 10.7 (6.3-18.3) for age <2 years compared with 6-18 years), anaemia (OR 7.76 (4.15-14.5) for Hb <6g/dL compared with ≥9g/dL), weakness (OR 3.13 (22.8-105.2) for collapsed compared with normal weakness), and jaundice (OR 12.8 (4.06-40.2)). Severity scoring predictive ability was 74.4% in adults and 83.4% in children and adolescents. CONCLUSION: Our evidenced-based severity scoring system demonstrated sufficient predictive ability to be operationalised as a clinical tool for rational allocation of treatment to VL patients at MSF centres in South Sudan.


Assuntos
Doenças Endêmicas , Leishmaniose Visceral/epidemiologia , Índice de Gravidade de Doença , Adolescente , Adulto , Criança , Técnicas de Apoio para a Decisão , Feminino , Hospitalização , Humanos , Imunocompetência , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/mortalidade , Leishmaniose Visceral/fisiopatologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Curva ROC , Recidiva , Estudos Retrospectivos , Fatores de Risco , Sudão do Sul/epidemiologia , Adulto Jovem
15.
PLoS Pathog ; 13(7): e1006465, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28671989

RESUMO

Visceral leishmaniasis is associated with significant changes in hematological function but the mechanisms underlying these changes are largely unknown. In contrast to naïve mice, where most long-term hematopoietic stem cells (LT-HSCs; LSK CD150+ CD34- CD48- cells) in bone marrow (BM) are quiescent, we found that during Leishmania donovani infection most LT-HSCs had entered cell cycle. Loss of quiescence correlated with a reduced self-renewal capacity and functional exhaustion, as measured by serial transfer. Quiescent LT-HSCs were maintained in infected RAG2 KO mice, but lost following adoptive transfer of IFNγ-sufficient but not IFNγ-deficient CD4+ T cells. Using mixed BM chimeras, we established that IFNγ and TNF signalling pathways converge at the level of CD4+ T cells. Critically, intrinsic TNF signalling is required for the expansion and/or differentiation of pathogenic IFNγ+CD4+ T cells that promote the irreversible loss of BM function. These findings provide new insights into the pathogenic potential of CD4+ T cells that target hematopoietic function in leishmaniasis and perhaps other infectious diseases where TNF expression and BM dysfunction also occur simultaneously.


Assuntos
Células da Medula Óssea/citologia , Linfócitos T CD4-Positivos/citologia , Células-Tronco Hematopoéticas/citologia , Leishmania donovani/fisiologia , Leishmaniose Visceral/fisiopatologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Células da Medula Óssea/metabolismo , Ciclo Celular , Proliferação de Células , Hematopoese , Células-Tronco Hematopoéticas/metabolismo , Humanos , Interferon gama/genética , Interferon gama/metabolismo , Leishmaniose Visceral/metabolismo , Leishmaniose Visceral/parasitologia , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Fator de Necrose Tumoral alfa/genética
16.
Trans R Soc Trop Med Hyg ; 111(4): 163-171, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28673017

RESUMO

Objective: To characterize the clinical and epidemiological profiles of patients with visceral leishmaniasis (VL) treated with liposomal amphotericin B (LAmB) and to identify prognostic factors for death from VL in 2008-2012 in the state of Minas Gerais, Brazil. Methods: A historical cohort study was conducted using data obtained from treatment requests forms, Brazilian Notifiable Disease Information System and the Mortality Information System. Case-fatality rates of patients with VL treated with LAmB were compared with patients treated with other therapies. Logistic regression analysis was used to identify prognostic factors for death. Results: The overall case-fatality rate of the 577 patients treated with LAmB was 19.4%. Prognostic factors for death from VL were age between 35 and 49 years (OR 2.7; 95% CI 1.3-5.4) and above 50 years (OR 2.6; 95% CI 1.3-4.9), jaundice (OR 2.2; 95% CI 1.2-3.7), kidney disease (OR 2.8; 95% CI 1.6-4.9), presence of other infections (OR 2.4; 95% CI 1.5-4.1), edema (OR 2.0; 95% CI 1.1-3.4), platelet count below 50.000/mm3 (OR 3.6; 95% CI 2.1-6.0), AST higher than 100 U/L (OR 2.2; 95% CI 1.3-3.8), and assistance in non-specialized institutions (OR 1.9; 95% CI 1.0-3.5). Conclusions: Case-fatality rates were higher than that observed among patients with VL treated with other therapies. Identification of prognostic factors of death from VL may allow early diagnosis of patients prone to such outcome and prompt an expeditious and appropriate management of VL to reduce fatality rates.


Assuntos
Anfotericina B/uso terapêutico , Antiprotozoários/uso terapêutico , Leishmaniose Visceral/diagnóstico , Leishmaniose Visceral/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil/epidemiologia , Criança , Pré-Escolar , Estudos de Coortes , Comorbidade , Edema/mortalidade , Feminino , Infecções por HIV/mortalidade , Cardiopatias/mortalidade , Humanos , Lactente , Icterícia/mortalidade , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/fisiopatologia , Falência Hepática/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Insuficiência Renal/mortalidade , Fatores de Risco , Adulto Jovem
17.
PLoS Negl Trop Dis ; 11(7): e0005727, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28732017

RESUMO

Visceral leishmaniasis (VL) is a neglected tropical disease that affects the poorest communities and can cause substantial morbidity and mortality. Visceral leishmaniasis is characterized by the presence of Leishmania parasites in the spleen, liver and bone marrow, hepatosplenomegaly, pancytopenia, prolonged fever, systemic inflammation and low body mass index (BMI). The factors impacting on the severity of VL are poorly characterized. Here we performed a cross-sectional study to assess whether co-infection of VL patients with intestinal parasites influences disease severity, assessed with clinical and haematological data, inflammation, cytokine profiles and BMI. Data from VL patients was similar to VL patients co-infected with intestinal parasites, suggesting that co-infection of VL patients with intestinal parasites does not alter disease severity.


Assuntos
Coinfecção/fisiopatologia , Enteropatias Parasitárias/fisiopatologia , Leishmaniose Visceral/fisiopatologia , Adolescente , Adulto , Animais , Índice de Massa Corporal , Medula Óssea/parasitologia , Estudos de Casos e Controles , Estudos Transversais , Citocinas/análise , Etiópia , Hepatomegalia/parasitologia , Humanos , Modelos Logísticos , Masculino , Parasitos/classificação , Parasitos/isolamento & purificação , Índice de Gravidade de Doença , Esplenomegalia/parasitologia , Adulto Jovem
18.
J Small Anim Pract ; 58(3): 125-138, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28267216

RESUMO

In order to evaluate possible nervous system involvement in canine leishmaniasis, retrospective evaluation of all medical records of leishmaniotic dogs exhibiting neurological signs referred to our hospital over a 5-year period was performed. The records of 10 dogs were reviewed. Depending on the neuroanatomical localisation, the dogs underwent advanced diagnostic imaging, cerebrospinal fluid analysis, electrodiagnostic testing and histopathologic evaluations. The final neurological diagnosis was: meningoencephalitis (n=2), brain haemorrhagic stroke (n=1), haemorrhagic choroiditis (n=1), meningomyelitis (n=2), ischaemic myelopathy (n=1), polymyositis (n=2) and peripheral neuropathy (n=1). This study confirms that both central and peripheral nervous systems can be affected by leishmaniasis and provides an overview on the possible etiopathogenetic mechanisms. In addition, clinical and diagnostic findings, therapy and follow-up of affected dogs are described.


Assuntos
Doenças do Cão/parasitologia , Leishmania infantum/isolamento & purificação , Leishmaniose Visceral/veterinária , Animais , Doenças do Cão/diagnóstico , Doenças do Cão/patologia , Doenças do Cão/fisiopatologia , Cães , Itália , Leishmaniose Visceral/diagnóstico , Leishmaniose Visceral/patologia , Leishmaniose Visceral/fisiopatologia , Estudos Retrospectivos
19.
Am J Trop Med Hyg ; 96(2): 280-284, 2017 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-27895274

RESUMO

Visceral leishmaniasis (VL) is associated with interstitial pneumonitis according to histology and radiology reports. However, studies to address the functional impact on respiratory function in patients are lacking. We assessed pulmonary function using noninvasive spirometry in a cross-sectional study of hospitalized adult VL patients from Minas Gerais, Brazil, without unrelated lung conditions or acute infections. Lung conditions were graded as normal, restrictive, obstructive, or mixed patterns, according to Brazilian consensus standards for spirometry. To control for regional patterns of lung function, we compared spirometry of patients with regional paired controls. Spirometry detected abnormal lung function in most VL patients (70%, 14/20), usually showing a restrictive pattern, in contrast to regional controls and the standards for normal tests. Alterations in spirometry measurements correlated with hypoalbuminemia, the only laboratory value indicative of severity of parasitic disease. Abnormalities did not correlate with unrelated factors such as smoking or occupation. Clinical data including pulmonary symptoms and duration of therapy were also unrelated to abnormal spirometry findings. We conclude that the severity of VL is correlated with a restrictive pattern of lung function according to spirometry, suggesting that there may be interstitial lung involvement in VL. Further studies should address whether spirometry could serve as an index of disease severity in the management of VL.


Assuntos
Leishmaniose Visceral/diagnóstico , Espirometria , Adolescente , Adulto , Idoso , Brasil , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Leishmaniose Visceral/fisiopatologia , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Testes de Função Respiratória , Espirometria/métodos , Adulto Jovem
20.
Ethiop Med J ; 54(1): 33-6, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27191028

RESUMO

Visceral leishmaniasis (VL) is a ftial and growing public health problem in Ethiopia. VL is recently reported outside the major endemic foci, the lowlands in the northwest and the Omo and Abaroba-plain, Segen and Woito valleys in the southwest. Here, we report a visceral leishmaniasis case from Benishangul-Gumuz Regional state near the Guba area. The patient had no history of travel to known VL endemic areas. The patient is a temporary farm laborer from West Go'jam Zone, Wanbermna District in Amhara Regional State. While in Benishangul-Gumuz, the patient was diagnosed with prolonged and intermittentfever, epistaxis, splenomegaly, skin pallor, diarrhea, cough and oedema. Laboratory diagnosis results showed that he had marked leucopenia, thrombocytopenia and anemia. The patient was suspected of having VL and checked with rK39 immunochromnatography and direct agglutination tests which were positive for anti leishmanial antibodies. After getting full dose of sodium stibogluconate as per the national visceral leishmaniasis treatment guideline, was clinically cured. As the area in Benshangul-Gumuz where this patient contracted visceral leishmaniasis is under social and ecological transformation with large scale projects attracting huge influx of temporary laborers and settlers, due attention is needed with respect to introduction or emergence of VL transmission.


Assuntos
Gluconato de Antimônio e Sódio/administração & dosagem , Leishmania donovani/imunologia , Leishmaniose Visceral , Antiprotozoários/administração & dosagem , Etiópia/epidemiologia , Humanos , Leishmaniose Visceral/diagnóstico , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/epidemiologia , Leishmaniose Visceral/etiologia , Leishmaniose Visceral/fisiopatologia , Masculino , Testes Sorológicos , Resultado do Tratamento , Adulto Jovem
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