Implications of co-infection ofLeptomonasin visceral leishmaniasis in India

Parasitology ◽  
2015 ◽  
Vol 142 (14) ◽  
pp. 1657-1662 ◽  
Author(s):  
ANGAMUTHU SELVAPANDIYAN ◽  
KAVITA AHUJA ◽  
NITI PURI ◽  
ANUJA KRISHNAN
Keyword(s):  
Immune Response ◽  
Visceral Leishmaniasis ◽  
Leishmania Donovani ◽  
Vaccine Development ◽  
Indian Subcontinent ◽  
Clinical Isolates ◽  
Protozoan Parasites ◽  
New Paradigm ◽  
Insect Parasite ◽  
Kala Azar

SUMMARYProtozoan parasitesLeishmania donovani(family: Trypanosomatidae) cause fatal visceral leishmaniasis (VL) and the infection relapses in apparently cured population as post kala-azar dermal leishmaniasis (PKDL) in the Indian subcontinent. In recent years co-infection of another Trypanosomatid parasiteLeptomonaswithL. donovaniduring VL/PKDL in this region has become prominent. The observation of clinically lesser-known insect parasite,Leptomonasin leishmaniasis is intriguing to researchers. The presence of Leishmania look alikeLeptomonasin the cultures of clinical isolates ofLeishmaniahas been worrisome to those, who prefer to work with pureLeishmaniacultures for drug and vaccine development or immune response studies. The exact implications of such a co-habitation, which might lead to a delay in the diagnostics of VL and elevate mortality, need a thorough investigation. Also whetherLeptomonasis involved in leishmaniasis manifestation needs to be ascertained. Thus we are currently witnessing a new paradigm of a parasitic co-infection in VL/PKDL cases in India and this review outlines various opportunities for further research in understanding such emerging co-infection.

scholarly journals Relapse after Treatment with Miltefosine for Visceral Leishmaniasis Is Associated with Increased Infectivity of the Infecting Leishmania donovani Strain

mBio ◽  
2013 ◽  
Vol 4 (5) ◽  
Author(s):  
Keshav Rai ◽  
Bart Cuypers ◽  
Narayan Raj Bhattarai ◽  
Surendra Uranw ◽  
Maya Berg ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Treatment Failure ◽  
Relapse Rate ◽  
Leishmania Donovani ◽  
Indian Subcontinent ◽  
Drug Susceptibility ◽  
Current View ◽  
Content Type ◽  
Control Programs ◽  
Kala Azar

ABSTRACTLeishmania donovaniis an intracellular protozoan parasite that causes leishmaniasis, which can range from a self-healing cutaneous disease to a fatal visceral disease depending on the infecting species. Miltefosine is currently the latest and only oral antileishmanial that came out of drug discovery pipelines in the past few decades, but recent reports indicate a significant decline in its efficacy against visceral leishmaniasis (also known as kala-azar) in the Indian subcontinent. This relapse rate of up to 20% within 12 months after treatment was shown not to be related to reinfection, drug quality, drug exposure, or drug-resistant parasites. We therefore aimed to assess other phenotypes of the parasite that may affect treatment outcome and found a significant association between the number of metacyclic parasites, parasite infectivity, and patient treatment outcome in the Indian subcontinent. Together with previous studies on resistance ofL. donovaniagainst pentavalent antimonials, these data suggest that the infectivity of the parasite, or related phenotypes, might be a more determinant factor for treatment failure in visceral leishmaniasis than drug susceptibility, warranting a reassessment of our current view on treatment failure and drug resistance in leishmaniasis and beyond.IMPORTANCEThe high miltefosine relapse rate poses a major challenge for the current Kala-Azar Elimination Program in the Indian subcontinent and other leishmaniasis control programs worldwide. This relapse rate could not be related to reinfection, drug-resistant parasites, or reduced treatment quality. Here we report that an increased infectivity of the parasite is associated with miltefosine relapse of visceral leishmaniasis (VL) patients. These results supplement those obtained with antimonial-resistantL. donovaniwhere an increased infectivity was also observed. This challenges the current view ofLeishmaniadrug susceptibility being the biggest parasitic factor that contributes to treatment failure in leishmaniasis. These selected more infectious parasites may pose an additional burden to leishmaniasis control programs, highlighting the importance of multifaceted control measures to achieve leishmaniasis elimination in the Indian subcontinent and other regions where leishmaniasis is endemic.

scholarly journals Impact of sequelae of visceral leishmaniasis and their contribution to ongoing transmission of Leishmania donovani

2019 ◽  
Vol 77 (6) ◽  
Author(s):  
Malcolm S Duthie ◽  
Yasuyuki Goto ◽  
Prakash Ghosh ◽  
Dinesh Mondal
Keyword(s):  
Visceral Leishmaniasis ◽  
Leishmania Donovani ◽  
Positive Impact ◽  
Indian Subcontinent ◽  
Intervention Strategies ◽  
Diagnostic Methods ◽  
Control Programs ◽  
Kala Azar ◽  
New Treatments

ABSTRACT Visceral leishmaniasis (VL) in the Old World is caused by infection with Leishmania donovani. Although the numbers of new reported cases of VL in Africa have been relatively stable for several years, the low numbers currently reported on the Indian subcontinent suggest a positive impact of new treatments and intervention strategies. In both regions, however, VL relapse and post-kala-azar dermal leishmaniasis (PKDL) maintain infectious reservoirs and therefore present a threat to control programs. In this review, we outline the evolving appreciation of PKDL as an impactful disease in its own right and discuss the various diagnostic methods that can be applied for the detection and characterization of PKDL cases. We also highlight the data that indicate the potential, and likely contribution, of PKDL cases to ongoing transmission of L. donovani.

scholarly journals A Novel Bioimpedance-Based Detection of Miltefosine Susceptibility Among Clinical Leishmania donovani Isolates of the Indian Subcontinent Exhibiting Resistance to Multiple Drugs

2021 ◽  
Vol 11 ◽  
Author(s):  
Souradeepa Ghosh ◽  
Souvik Biswas ◽  
Sandip Mukherjee ◽  
Arijit Pal ◽  
Aaditya Saxena ◽  
...  
Keyword(s):  
Leishmania Donovani ◽  
Indian Subcontinent ◽  
Accurate Determination ◽  
Clinical Isolates ◽  
Protein Thiol ◽  
Hamster Model ◽  
Spectra Analysis ◽  
Thiol Content ◽  
Multiple Drugs

The extent of susceptibility towards miltefosine (Mil), amphotericin B (AmpB), and paromomycin (Paro) was measured among 19 clinical isolates of Leishmania donovani (LD). Thirteen of these clinical isolates were reported to exhibit low susceptibility towards sodium stibogluconate (SSG-R), while six of them were highly susceptible (SSG-S). The degree of clearance of amastigotes (EC50) for these predefined SSG-R- and SSG-S-infected macrophages was determined against Mil, AmpB, and Paro. Two out of the 13 SSG-R isolates (BHU575 and BHU814) showed low susceptibility towards all three drugs studied, while the rest of the 11 SSG-R isolates showed varying degrees of susceptibility either towards none or only towards individual drugs. Interestingly, all the SSG-S isolates showed high susceptibility towards Mil/AmpB/Paro. The total intracellular non-protein thiol content of the LD promastigotes, which have been previously reported to be positively co-related with EC50 towards SSG, was found to be independent from the degree of susceptibility towards Mil/AmpB/Paro. Impedance spectra analysis, which quantifies membrane resistance, revealed lower impedimetric values for all those isolates exhibiting low efficacy to Mil (Mil-R). Our analysis points out that while non-protein thiol content can be an attribute of SSG-R, lower impedimetric values can be linked with lower Mil susceptibility, although neither of these parameters seems to get influenced by the degree of susceptibility towards AmpB/Paro. Finally, a correlation analysis with established biological methods suggests that impedance spectral analysis can be used for the accurate determination of lower Mil susceptibility among LD isolates, which is further validated in the LD-infected in vivo hamster model.

scholarly journals Use of Antimony in the Treatment of Leishmaniasis: Current Status and Future Directions

2011 ◽  
Vol 2011 ◽  
pp. 1-23 ◽  
Author(s):  
Arun Kumar Haldar ◽  
Pradip Sen ◽  
Syamal Roy
Keyword(s):  
Leishmania Donovani ◽  
Indian Subcontinent ◽  
Current Status ◽  
Vanadium Compounds ◽  
Future Directions ◽  
Kala Azar ◽  
Efflux Mechanism ◽  
Transplantation Antigens ◽  
Antigen Presenting

In the recent past the standard treatment of kala-azar involved the use of pentavalent antimonials Sb(V). Because of progressive rise in treatment failure to Sb(V) was limited its use in the treatment program in the Indian subcontinent. Until now the mechanism of action of Sb(V) is not very clear. Recent studies indicated that both parasite and hosts contribute to the antimony efflux mechanism. Interestingly, antimonials show strong immunostimulatory abilities as evident from the upregulation of transplantation antigens and enhanced T cell stimulating ability of normal antigen presenting cells when treated with Sb(V) in vitro. Recently, it has been shown that some of the peroxovanadium compounds have Sb(V)-resistance modifying ability in experimental infection with Sb(V) resistant Leishmania donovani isolates in murine model. Thus, vanadium compounds may be used in combination with Sb(V) in the treatment of Sb(V) resistance cases of kala-azar.

scholarly journals Leishmania donovani Secretory Mevalonate Kinase Regulates Host Immune Response and Facilitates Phagocytosis

2021 ◽  
Vol 11 ◽  
Author(s):  
Tanvir Bamra ◽  
Taj Shafi ◽  
Sushmita Das ◽  
Manjay Kumar ◽  
Manas Ranjan Dikhit ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Leishmania Donovani ◽  
Indian Subcontinent ◽  
Parasite Burden ◽  
Host Immune Response ◽  
Host Cells ◽  
Interleukin 4 ◽  
Host Immune System ◽  
Mevalonate Kinase

Summary StatementLeishmania secretes over 151 proteins during in vitro cultivation. Cellular functions of one such novel protein: mevalonate kinase is discussed here; signifying its importance in Leishmania infection.Visceral Leishmaniasis is a persistent infection, caused by Leishmania donovani in Indian subcontinent. This persistence is partly due to phagocytosis and evasion of host immune response. The underlying mechanism involves secretory proteins of Leishmania parasite; however, related studies are meagre. We have identified a novel secretory Leishmania donovani glycoprotein, Mevalonate kinase (MVK), and shown its importance in parasite internalization and immuno-modulation. In our studies, MVK was found to be secreted maximum after 1 h temperature stress at 37°C. Its secretion was increased by 6.5-fold in phagolysosome-like condition (pH ~5.5, 37°C) than at pH ~7.4 and 25°C. Treatment with MVK modulated host immune system by inducing interleukin-10 and interleukin-4 secretion, suppressing host’s ability to kill the parasite. Peripheral blood mononuclear cell (PBMC)-derived macrophages infected with mevalonate kinase-overexpressing parasites showed an increase in intracellular parasite burden in comparison to infection with vector control parasites. Mechanism behind the increase in phagocytosis and immunosuppression was found to be phosphorylation of mitogen-activated protein (MAP) kinase pathway protein, Extracellular signal-regulated kinases-1/2, and actin scaffold protein, cortactin. Thus, we conclude that Leishmania donovani Mevalonate kinase aids in parasite engulfment and subvert the immune system by interfering with signal transduction pathways in host cells, which causes suppression of the protective response and facilitates their persistence in the host. Our work elucidates the involvement of Leishmania in the process of phagocytosis which is thought to be dependent largely on macrophages and contributes towards better understanding of host pathogen interactions.

scholarly journals Application of kDNA Minicircle PCR-RFLP to Characterize Leishmania donovani Clinical Isolates Obtained from Post-Kala-Azar Dermal Leishmaniasis in Eastern Nepal

2019 ◽  
Vol 2019 ◽  
pp. 1-8
Author(s):  
Ojesh Pokhrel ◽  
Keshav Rai ◽  
Narayan Raj Bhattarai ◽  
Suman Rijal ◽  
Arpana Rijal ◽  
...  
Keyword(s):  
Leishmania Donovani ◽  
Clinical Isolates ◽  
Rdna Genes ◽  
Kala Azar ◽  
Pcr Rflp ◽  
Potential Reservoir ◽  
Rflp Assay ◽  
Epidemiological Characterization

Post-kala-azar dermal leishmaniasis (PKDL) is a skin manifestation of visceral leishmaniasis (VL) which develops after apparent cure in some patients. PKDL is considered as the potential reservoir for the VL infection. Molecular epidemiological characterization of L. donovani isolates obtained from VL and PKDL isolates is essentially required in order to understand the transmission dynamics of the VL infection. To date, genetic variation among the VL and PKDL L. donovani isolates was not fully elucidated. Therefore, 14 clinical isolates from VL and 4 clinical isolates from PKDL were speciated by hsp70 and rDNA genes. Further characterization of L. donovani by haspB PCR demonstrates two different genotypes. All PKDL isolates have the same genetic structure. kDNA PCR-RFLP assay revealed 18 different genotypes; however, structural analysis showed the two distinct kDNA genotype population (k = 2). The kDNA fingerprint patterns of parasites from hilly districts were clustered separately from low-land districts. Therefore, further study with a large number of samples is urgently required for systematic characterization of the clinical isolates to track the molecular epidemiology of the Leishmania donovani causing VL and the role of PKDL as a reservoir.

scholarly journals Comparison of KAtex, Bone Marrow Aspiration and DAT for the Diagnosis of Visceral Leishmaniasis

2019 ◽  
Vol 6 (1) ◽  
pp. 12-15
Author(s):  
Ishrat Sharmin ◽  
AKM Quamruzzaman ◽  
Rezina Parveen ◽  
M Abdulah Yusuf ◽  
Rashida Akter Khanam
Keyword(s):  
Bone Marrow ◽  
Visceral Leishmaniasis ◽  
Leishmania Donovani ◽  
Bone Marrow Aspiration ◽  
Cross Sectional Study ◽  
Cross Sectional ◽  
Medical College ◽  
Kala Azar ◽  
History Of ◽  
One Year

Background: Newly developed KAtex test can be used as a non invasive tool for diagnosis of Kala-azar. Objectives: The aim of the present study was to compare KAtex, Bone marrow aspiration and DAT to diagnose VL. Methodology: This cross-sectional study was carried out in the Department of Microbiology at Dhaka Medical College, Dhaka, Bangladesh in collaboration with the Department of Parasitology, Institute of Epidemiology, Disease Control and Research (IEDCR), Dhaka, Bangladesh for a period of one year. Clinically suspected Kala-azar (VL) cases of different age and sex attending IEDCR, Dhaka from different Kala-azar endemic areas of Bangladesh were selected for this study. Patients having fever for more than 2 weeks, with or without splenomegaly, having history of loss of body weight following onset of fever were clinically suspected as Kala-azar cases. Microscopy and culture was performed in bone marrow (BM). KAtex was performed with urine sample. Agglutination of sensitized latex indicated presence of Leishmania donovani antigen in urine and thereby visceral leishmaniasis. No agglutination indicates absence of antigen in urine. DAT was done with serums of all cases. Result: Among 130 clinically suspected VL cases, 70 (53.85%) cases were BM positive and 60(46.15%) cases were BM negative. All the 70 BM positive cases were positive by KAtex and DAT. Among 60 BM negative cases, 15 were positive by KAtex and 23 were positive by DAT. The sensitivity of KAtex was 100.0% and specificity was 75.0%. The sensitivity of DAT was 100.0% and specificity is 61.6%. Conclusion: In conclusion, KAtex test is a good diagnostic tool for the detection of VL in comparison with DAT. Bangladesh Journal of Infectious Diseases, June 2019;6(1):12-15

scholarly journals Increased levels of thiols protect antimony unresponsive Leishmania donovani field isolates against reactive oxygen species generated by trivalent antimony

Parasitology ◽  
2007 ◽  
Vol 134 (12) ◽  
pp. 1679-1687 ◽  
Author(s):  
G. MANDAL ◽  
S. WYLLIE ◽  
N. SINGH ◽  
S. SUNDAR ◽  
A. H. FAIRLAMB ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Leishmania Donovani ◽  
Indian Subcontinent ◽  
Current Trend ◽  
Reactive Oxygen ◽  
Clinical Isolates ◽  
Ros Generation ◽  
Scavenging Activity ◽  
Oxygen Species ◽  
Field Isolates

SUMMARYThe current trend of antimony (Sb) unresponsiveness in the Indian subcontinent is a major impediment to effective chemotherapy of visceral leishmaniasis (VL). Although contributory mechanisms studied in laboratory-raised Sb-R parasites include an up-regulation of drug efflux pumps and increased thiols, their role in clinical isolates is not yet substantiated. Accordingly, our objectives were to study the contributory role of thiols in the generation of Sb unresponsiveness in clinical isolates. Promastigotes were isolated from VL patients who were either Sb responsive (n=2) or unresponsive (n=3). Levels of thiols as measured by HPLC and flow cytometry showed higher basal levels of thiols and a faster rate of thiol regeneration in Sb unresponsive strains as compared with sensitive strains. The effects of antimony on generation of reactive oxygen species (ROS) in normal and thiol-depleted conditions as also their H2O2 scavenging activity indicated that in unresponsive parasites, Sb-mediated ROS generation was curtailed, which could be reversed by depletion of thiols and was accompanied by a higher H2O2 scavenging activity. Higher levels of thiols in Sb-unresponsive field isolates from patients with VL protect parasites from Sb-mediated oxidative stress, thereby contributing to the antimony resistance phenotype.

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