scholarly journals Transcriptional Blood Signatures for Active and Amphotericin B Treated Visceral Leishmaniasis in India

2019 ◽  
Author(s):  
Michaela Fakiola ◽  
Om-Prakash Singh ◽  
Genevieve Syn ◽  
Toolika Singh ◽  
Bhawana Singh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Single Dose ◽  
Visceral Leishmaniasis ◽  
Amphotericin B ◽  
Leishmania Donovani ◽  
Indian Subcontinent ◽  
Expression Patterns ◽  
Disease Outbreaks ◽  
Asymptomatic Infection ◽  
Healthy Controls

AbstractAmphotericin B provides improved therapy for visceral leishmaniasis (VL) caused by Leishmania donovani, with single dose liposomal-encapsulated Ambisome providing the best cure rates. The VL elimination program aims to reduce the incidence rate in the Indian subcontinent to <1/10,000 population/year. Ability to predict which asymptomatic individuals (e.g. anti-leishmanial IgG and/or Leishmania-specific modified Quantiferon positive) will progress to clinical VL would help in monitoring disease outbreaks. Here we examined whole blood transcriptional profiles associated with asymptomatic infection, active disease, and in treated cases. Two independent microarray experiments were performed, with analysis focussed primarily on differentially expressed genes (DEGs) concordant across both experiments. No DEGs were identified for IgG or Quantiferon positive asymptomatic groups compared to negative healthy endemic controls. We therefore concentrated on comparing concordant DEGs from active cases with all healthy controls, and in examining differences in the transcriptome following different regimens of drug treatment. In these comparisons 6 major themes emerged: (i) expression of genes and enrichment of gene sets associated with erythrocyte function in active cases; (ii) strong evidence for enrichment of gene sets involved in cell cycle in comparing active cases with healthy controls; (iii) identification of IFNG encoding interferon-γ as the major hub gene in concordant gene expression patterns across experiments comparing active cases with healthy controls or with treated cases; (iv) enrichment for interleukin signalling (IL-1/3/4/6/7/8) and a prominent role for CXCL10/9/11 and chemokine signalling pathways in comparing active cases with treated cases; (v) the novel identification of Aryl Hydrocarbon Receptor signalling as a significant canonical pathway when comparing active cases with healthy controls or with treated cases; and (vi) global expression profiling support for more effective cure at day 30 post-treatment with a single dose of liposomal encapsulated amphotericin B compared to multi-dose non-liposomal amphotericin B treatment over 30 days.Author SummaryVisceral leishmaniasis (VL), also known as kala-azar, is a potentially fatal disease caused by intracellular parasites of the Leishmania donovani species complex. VL is a serious public health problem in rural India, causing high morbidity and mortality, as well as major costs to local and national health budgets. Amphotericin B provides improved therapy for VL with single dose liposomal-encapsulated Ambisome, now affordable through WHO-negotiated price reductions, providing the best cure rates. The VL elimination program aims to reduce the incidence rate in the Indian subcontinent to <1/10,000 population/year. By assessing immune responses to parasites in people infected with L. donovani, but with different clinical status, we can determine the requirements for immune cell development and predict which asymptomatic individuals, for example healthy individuals with high anti-leishmanial antibody levels, will progress to clinical VL. This will help in monitoring disease outbreaks. In this study we looked at global gene expression patterns in whole blood to try to understand more about asymptomatic infection, active VL, and the progress to cure in cases treated with single or multi-dose amphotericin B. The signatures of gene expression identified aid in our understanding of disease pathogenesis and provide novel targets for therapeutic intervention in the future.

scholarly journals Pharmacodynamics and Biodistribution of Single-Dose Liposomal Amphotericin B at Different Stages of Experimental Visceral Leishmaniasis

2017 ◽  
Vol 61 (9) ◽  
Author(s):  
Andrew A. Voak ◽  
Andy Harris ◽  
Zeeshan Qaiser ◽  
Simon L. Croft ◽  
Karin Seifert
Keyword(s):  
Single Dose ◽  
Visceral Leishmaniasis ◽  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Leishmania Donovani ◽  
Drug Distribution ◽  
Liposomal Amphotericin B ◽  
Total Drug ◽  
Content Type ◽  
Drug Levels

ABSTRACT Visceral leishmaniasis is a neglected tropical disease that causes significant morbidity and mortality worldwide. Characterization of the pharmacokinetics and pharmacodynamics of antileishmanial drugs in preclinical models is important for drug development and use. Here we investigated the pharmacodynamics and drug distribution of liposomal amphotericin B (AmBisome) in Leishmania donovani-infected BALB/c mice at three different dose levels and two different time points after infection. We additionally compared drug levels in plasma, liver, and spleen in infected and uninfected BALB/c mice over time. At the highest administered dose of 10 mg/kg AmBisome, >90% parasite inhibition was observed within 2 days after drug administration, consistent with drug distribution from blood to tissue within 24 h and a fast rate of kill. Decreased drug potency was observed in the spleen when AmBisome was administered on day 35 after infection, compared to day 14 after infection. Amphotericin B concentrations and total drug amounts per organ were lower in liver and spleen when AmBisome was administered at the advanced stage of infection and compared to those in uninfected BALB/c mice. However, the magnitude of difference was lower when total drug amounts per organ were estimated. Differences were also noted in drug distribution to L. donovani-infected livers and spleens. Taken together, our data suggest that organ enlargement and other pathophysiological factors cause infection- and organ-specific drug distribution and elimination after administration of single-dose AmBisome to L. donovani-infected mice. Plasma drug levels were not reflective of changes in drug levels in tissues.

scholarly journals Early Response of CD8+ T Cells in COVID-19 Patients

2021 ◽  
Vol 11 (12) ◽  
pp. 1291
Author(s):  
Deni Ramljak ◽  
Martina Vukoja ◽  
Marina Curlin ◽  
Katarina Vukojevic ◽  
Maja Barbaric ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
T Cells ◽  
Mrna Expression ◽  
Cd8 T Cells ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Effector Memory ◽  
Healthy Controls ◽  
Ifn Γ

Healthy and controlled immune response in COVID-19 is crucial for mild forms of the disease. Although CD8+ T cells play important role in this response, there is still a lack of studies showing the gene expression profiles in those cells at the beginning of the disease as potential predictors of more severe forms after the first week. We investigated a proportion of different subpopulations of CD8+ T cells and their gene expression patterns for cytotoxic proteins (perforin-1 (PRF1), granulysin (GNLY), granzyme B (GZMB), granzyme A (GZMA), granzyme K (GZMK)), cytokine interferon-γ (IFN-γ), and apoptotic protein Fas ligand (FASL) in CD8+ T cells from peripheral blood in first weeks of SARS-CoV-2 infection. Sixteen COVID-19 patients and nine healthy controls were included. The absolute counts of total lymphocytes (p = 0.007), CD3+ (p = 0.05), and CD8+ T cells (p = 0.01) in COVID-19 patients were significantly decreased compared to healthy controls. In COVID-19 patients in CD8+ T cell compartment, we observed lower frequency effector memory 1 (EM1) (p = 0.06) and effector memory 4 (EM4) (p < 0.001) CD8+ T cells. Higher mRNA expression of PRF1 (p = 0.05) and lower mRNA expression of FASL (p = 0.05) at the fifth day of the disease were found in COVID-19 patients compared to healthy controls. mRNA expression of PRF1 (p < 0.001) and IFN-γ (p < 0.001) was significantly downregulated in the first week of disease in COVID-19 patients who progressed to moderate and severe forms after the first week, compared to patients with mild symptoms during the entire disease course. GZMK (p < 0.01) and FASL (p < 0.01) mRNA expression was downregulated in all COVID-19 patients compared to healthy controls. Our results can lead to a better understanding of the inappropriate immune response of CD8+ T cells in SARS-CoV2 with the faster progression of the disease.

scholarly journals Diagnosis of Visceral Leishmaniasis by Enzyme-Linked Immunosorbent Assay Using Urine Samples

2002 ◽  
Vol 9 (4) ◽  
pp. 789-794 ◽  
Author(s):  
Mohammad Zahidul Islam ◽  
Makoto Itoh ◽  
S. M. Shamsuzzaman ◽  
Rusella Mirza ◽  
Farzana Matin ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Sensitivity And Specificity ◽  
Immunosorbent Assay ◽  
Leishmania Donovani ◽  
Laboratory Diagnosis ◽  
Urine Samples ◽  
Enzyme Linked Immunosorbent Assay ◽  
Healthy Controls ◽  
Serum Samples ◽  
Crude Antigen

ABSTRACT A diagnostic method has been developed to detect anti-Leishmania donovani immunoglobulin G (IgG) in urine by enzyme-linked immunosorbent assay (ELISA). In measuring anti-L. donovani IgG, IgA, and IgM in urine, the method performed best in the detection of IgG. The sensitivity and specificity of the assay were determined with panels of urine samples from 62 visceral leishmaniasis (VL) patients, 59 healthy controls from areas of endemicity, 53 healthy controls from areas of nonendemicity, 59 malaria patients, 13 tuberculosis patients, 23 cutaneous leishmaniasis patients, and 7 patients with other diseases. Using L. donovani promastigote crude antigen, the test had 93.5% sensitivity (58 positives of 62 VL patient samples) and 89.3% specificity (191 negatives of 214 non-VL patient samples). The ELISA with acetone-treated L. donovani promastigote antigen raised the sensitivity and specificity to 95.0 and 95.3%, respectively. Western blot analysis revealed that most of the samples that cross-reacted with crude antigen in ELISA did not recognize any antigenic component of L. donovani crude antigen. We also checked 40 serum samples from the same group of VL patients for anti-L. donovani IgG and got 90.0% sensitivity with both crude and acetone-treated antigens. As collection of urine is much easier than collection of serum, the detection of anti-L. donovani IgG in urine with acetone-treated antigen will be useful in epidemiological studies. It could be an adjunct of laboratory diagnosis.

scholarly journals Immunoenhancement Combined with Amphotericin B as Treatment for Experimental Visceral Leishmaniasis

2003 ◽  
Vol 47 (8) ◽  
pp. 2513-2517 ◽  
Author(s):  
Henry W. Murray ◽  
Elaine B. Brooks ◽  
Jennifer L. DeVecchio ◽  
Frederick P. Heinzel
Keyword(s):  
Visceral Leishmaniasis ◽  
Total Dose ◽  
Amphotericin B ◽  
Leishmania Donovani ◽  
Low Dose ◽  
Interleukin 12 ◽  
Th1 Cell ◽  
Killing Effect ◽  
Ifn Γ ◽  
Visceral Infection

ABSTRACT To determine if stimulation of Th1-cell-associated immune responses, mediated by interleukin 12 (IL-12) and gamma interferon (IFN-γ), enhance the antileishmanial effect of amphotericin B (AMB), Leishmania donovani-infected BALB/c mice were first treated with (i) exogenous IL-12 to induce IFN-γ, (ii) agonist anti-CD40 monoclonal antibody (MAb) to maintain IL-12 and induce IFN-γ, or (iii) anti-IL-10 receptor (IL-10R) MAb to blockade suppression of IL-12 and IFN-γ. In animals with established visceral infection, low-dose AMB alone (two injections of 1 mg/kg of body weight; total dose, 2 mg/kg) killed 15 to 29% of liver parasites; by themselves, the immunointerventions induced 16 to 33% killing. When the interventions were combined, the leishmanicidal activities increased 3.4-fold (anti-CD40), 6.3-fold (anti-IL-10R), and 9-fold (IL-12) compared with the activities of AMB plus the control preparations; and overall killing (76 to 84%) approximated the 84 to 92% killing effect of 7.5-fold more AMB alone (three injections of 5 mg/kg; total dose, 15 mg/kg). These results suggest that strengthening the host Th1-cell response may be a strategy for the development of AMB-sparing regimens in visceral leishmaniasis.

Single-Dose Liposomal Amphotericin B for Visceral Leishmaniasis in India

2010 ◽  
Vol 362 (6) ◽  
pp. 504-512 ◽  
Author(s):  
Shyam Sundar ◽  
Jaya Chakravarty ◽  
Dipti Agarwal ◽  
Madhukar Rai ◽  
Henry W. Murray
Keyword(s):  
Single Dose ◽  
Visceral Leishmaniasis ◽  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Liposomal Amphotericin B

scholarly journals Socio-economic and behavioural risk factors of visceral leishmaniasis in the East Champaran district of Bihar

2017 ◽  
Vol 4 (5) ◽  
pp. 1577 ◽  
Author(s):  
Navin Kumar ◽  
T. B. Singh ◽  
L. P. Meena
Keyword(s):  
Risk Factors ◽  
Visceral Leishmaniasis ◽  
Leishmania Donovani ◽  
Indian Subcontinent ◽  
Drainage System ◽  
Domestic Animal ◽  
Living Room ◽  
Control Programs ◽  
Behavioural Risk Factors ◽  
Study Results

Background: Visceral leishmaniasis is a chronic and potentially fatal parasitic disease of the viscera which affect the organs due to infection by Leishmania donovani. Visceral Leismaniasis, also known as Kala-Azar (KA) in the Indian subcontinent. The worldwide incidence is estimated to be between 146,700 and 282,800 cases per year. In India, it is endemic in the states Bihar and it contains more than 90 % of the cases of VL.In this region, Leishmania donovani is the only species causing VL. Objective: To find out the socio-economic and behavioural risk factors of VL in East Champaran district of Bihar. Methods: A case-control study was conducted to understand the socio-economic and behavioural risk factors associated with VL in areas of East Champaran district of Bihar, India. A total of 100 VL cases and 100 healthy controls selected randomly from the neighbourhoods of cases were included in the study. Results: The risk factors identified were showed that presence of a granary inside houses (P=0.000), sunlight inside the living room (P=0.000), banana trees near the houses (P=0.003), presence of domestic animal in the house (P=0.044), people sleep near the animal (P=0.000) and drainage system (P=0.000) were risk factors of VL.Conclusions: These results will be useful for further improvement in the VL control programs for intervention strategies in respect of separate granary house other than the living house, presence of sunlight inside the living rooms, banana trees far from the houses, separate domestic shelter for reducing transmission and incidence of this disease.

The Effect of Iodium 30c on Experimental Visceral Leishmaniasis

Homeopathy ◽  
2020 ◽  
Vol 109 (04) ◽  
pp. 213-223
Author(s):  
Jyoti Joshi ◽  
Chetna Bandral ◽  
Raj Kumar Manchanda ◽  
Anil Khurana ◽  
Debadatta Nayak ◽  
...  
Keyword(s):  
T Cells ◽  
Visceral Leishmaniasis ◽  
Amphotericin B ◽  
Cd8 T Cells ◽  
Therapeutic Efficacy ◽  
Leishmania Donovani ◽  
Neglected Tropical Diseases ◽  
Parasite Load ◽  
Poor People

Abstract Background Leishmaniasis is one of several neglected tropical diseases that warrant serious attention. A disease of socio-economically poor people, it demands safer and cheaper drugs that help to overcome the limitations faced by the existing anti-leishmanials. Complementary or traditional medicines might be a good option, with an added advantage that resistance may not develop against these drugs. Thus, the present investigation was performed to evaluate the anti-leishmanial efficacy of an ultra-diluted homeopathic medicine (Iodium 30c) in experimental visceral leishmaniasis (VL). Methods Compliant with strict ethical standards in animal experimentation, the study was performed in-vivo in inbred BALB/c mice which were injected intravenously with 1 × 107 promastigotes of Leishmania donovani before (therapeutic) or after (prophylactic) treatment with Iodium 30c for 30 days. In other groups of mice (n = 6 per group), amphotericin B served as positive control, infected animals as the disease control, while the naïve controls included normal animals; animals receiving only Iodium 30c or Alcohol 30c served as sham controls. The anti-leishmanial efficacy was assessed by determining the hepatic parasite load and analysing percentages of CD4+ and CD8+ T cells. Biochemical analysis and histological studies were performed to check any toxicities. Results Iodium-treated animals showed a significantly reduced parasite load (to 1503 ± 39 Leishman Donovan Units, LDU) as compared with the infected controls (4489 ± 256 LDU) (p < 0.05): thus, the mean therapeutic efficacy of Iodium 30c was 66.5%. In addition, the population of CD4+ and CD8+ T cells was significantly increased (p < 0.05) after treatment. No toxicity was observed, as evidenced from biochemical and histopathological studies of the liver and kidneys. Efficacy of Iodium 30c prophylaxis was 58.3%, while the therapeutic efficacy of amphotericin B was 85.9%. Conclusion This original study has shown that Iodium 30c had significant impact in controlling parasite replication in experimental VL, though the effect was less than that using standard pharmaceutical treatment.

scholarly journals Inferring transmission trees to guide targeting of interventions against visceral leishmaniasis and post–kala-azar dermal leishmaniasis

2020 ◽  
Vol 117 (41) ◽  
pp. 25742-25750
Author(s):  
Lloyd A. C. Chapman ◽  
Simon E. F. Spencer ◽  
Timothy M. Pollington ◽  
Chris P. Jewell ◽  
Dinesh Mondal ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Indian Subcontinent ◽  
Epidemiological Data ◽  
Asymptomatic Infection ◽  
Disease Spread ◽  
Estimation Methods ◽  
Secondary Case ◽  
Duration Of Symptoms ◽  
Targeted Interventions ◽  
Kala Azar

Understanding of spatiotemporal transmission of infectious diseases has improved significantly in recent years. Advances in Bayesian inference methods for individual-level geo-located epidemiological data have enabled reconstruction of transmission trees and quantification of disease spread in space and time, while accounting for uncertainty in missing data. However, these methods have rarely been applied to endemic diseases or ones in which asymptomatic infection plays a role, for which additional estimation methods are required. Here, we develop such methods to analyze longitudinal incidence data on visceral leishmaniasis (VL) and its sequela, post–kala-azar dermal leishmaniasis (PKDL), in a highly endemic community in Bangladesh. Incorporating recent data on VL and PKDL infectiousness, we show that while VL cases drive transmission when incidence is high, the contribution of PKDL increases significantly as VL incidence declines (reaching 55% in this setting). Transmission is highly focal: 85% of mean distances from inferred infectors to their secondary VL cases were <300 m, and estimated average times from infector onset to secondary case infection were <4 mo for 88% of VL infectors, but up to 2.9 y for PKDL infectors. Estimated numbers of secondary cases per VL and PKDL case varied from 0 to 6 and were strongly correlated with the infector’s duration of symptoms. Counterfactual simulations suggest that prevention of PKDL could have reduced overall VL incidence by up to 25%. These results highlight the need for prompt detection and treatment of PKDL to achieve VL elimination in the Indian subcontinent and provide quantitative estimates to guide spatiotemporally targeted interventions against VL.

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