scholarly journals Central Asian Rodents as Model Animals for Leishmania major and Leishmania donovani Research

2020 ◽  
Vol 8 (9) ◽  
pp. 1440
Author(s):  
Barbora Vojtkova ◽  
Tatiana Spitzova ◽  
Jan Votypka ◽  
Tereza Lestinova ◽  
Iveta Kominkova ◽  
...  
Keyword(s):  
Standard Model ◽  
Leishmania Donovani ◽  
Leishmania Major ◽  
Skin Lesions ◽  
Rodent Species ◽  
Sand Fly ◽  
Phodopus Sungorus ◽  
Self Healing ◽  
Natural Sand ◽  
Disease Spectrum

The clinical manifestation of leishmaniases depends on parasite species, host genetic background, and immune response. Manifestations of human leishmaniases are highly variable, ranging from self-healing skin lesions to fatal visceral disease. The scope of standard model hosts is insufficient to mimic well the wide disease spectrum, which compels the introduction of new model animals for leishmaniasis research. In this article, we study the susceptibility of three Asian rodent species (Cricetulus griseus, Lagurus lagurus, and Phodopus sungorus) to Leishmania major and L. donovani. The external manifestation of the disease, distribution, as well as load of parasites and infectiousness to natural sand fly vectors, were compared with standard models, BALB/c mice and Mesocricetus auratus. No significant differences were found in disease outcomes in animals inoculated with sand fly- or culture-derived parasites. All Asian rodent species were highly susceptible to L. major. Phodopus sungorus showed the non-healing phenotype with the progressive growth of ulcerative lesions and massive parasite loads. Lagurus lagurus and C. griseus represented the healing phenotype, the latter with high infectiousness to vectors, mimicking best the character of natural reservoir hosts. Both, L. lagurus and C. griseus were also highly susceptible to L. donovani, having wider parasite distribution and higher parasite loads and infectiousness than standard model animals.

scholarly journals Expression of Inducible Nitric Oxide Synthase in Skin Lesions of Patients with American Cutaneous Leishmaniasis

2002 ◽  
Vol 70 (8) ◽  
pp. 4638-4642 ◽  
Author(s):  
Muna Qadoumi ◽  
Inge Becker ◽  
Norbert Donhauser ◽  
Martin Röllinghoff ◽  
Christian Bogdan
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Cutaneous Leishmaniasis ◽  
Leishmania Donovani ◽  
Leishmania Major ◽  
Parasite Burden ◽  
Skin Lesions ◽  
And Function ◽  
Oxide Synthase

ABSTRACT Cytokine-inducible (or type 2) nitric oxide synthase (iNOS) is indispensable for the resolution of Leishmania major or Leishmania donovani infections in mice. In contrast, little is known about the expression and function of iNOS in human leishmaniasis. Here, we show by immunohistological analysis of skin biopsies from Mexican patients with local (LCL) or diffuse (DCL) cutaneous leishmaniasis that the expression of iNOS was most prominent in LCL lesions with small numbers of parasites whereas lesions with a high parasite burden (LCL or DCL) contained considerably fewer iNOS-positive cells. This is the first study to suggest an antileishmanial function of iNOS in human Leishmania infections in vivo.

scholarly journals Preclinical validation of a second generation leishmanization vaccine against vector transmitted fatal visceral leishmaniasis

2020 ◽  
Author(s):  
Subir Karmakar ◽  
Nevien Ismail ◽  
Fabiano Oliveira ◽  
James Oristian ◽  
Wen Wei Zhang ◽  
...  
Keyword(s):  
Immune Response ◽  
Visceral Leishmaniasis ◽  
Leishmania Donovani ◽  
Leishmania Major ◽  
Protective Efficacy ◽  
Sand Fly ◽  
Endemic Region ◽  
Cytokines And Chemokines ◽  
Human Leishmaniasis ◽  
Strong Candidate

AbstractVisceral Leishmaniasis (VL) is fatal if untreated. There is no licensed vaccine available against human leishmaniasis. We recently demonstrated protection in mice against L. major infection using a CRISPR genome edited attenuated Leishmania major strain (LmCen−/−). Here, as a pre-clinical step, we evaluated the protective efficacy of LmCen−/− against VL induced by sand fly transmitted Leishmania donovani in hamsters. Intradermal immunization of hamsters with LmCen−/− did not develop any lesion; while still priming a pro-inflammatory immune response. When challenged with L. donovani either by intradermal needle injection or by infected sand flies, LmCen−/−-immunized hamsters were protected, not showing spleen or liver pathology averting VL fatality compared to control animals. Spleen cells from LmCen−/− immunized and infected sand fly challenged hamsters produced significantly higher Th1-associated cytokines and chemokines including IFN-γ and TNF-α, and significantly reduced expression of the anti-inflammatory cytokines IL-10 and IL-21, compared to non-immunized challenged animals. We further developed a GLP-grade LmCen−/− which showed equal protection as laboratory-grade LmCen−/− parasites in hamsters. Importantly, GLP-grade LmCen−/− parasites also induced a proinflammatory immune response in the PBMCs isolated from healthy people living in non-endemic and endemic for VL as well as cured VL people living in endemic region. Together, this study demonstrates that the LmCen−/− parasites are safe and efficacious against VL and it is a strong candidate vaccine to be tested in a human clinical trial.

scholarly journals A clinical study to optimise a sand fly biting protocol for use in a controlled human infection model of cutaneous leishmaniasis (the FLYBITE study)

2021 ◽  
Vol 6 ◽  
pp. 168
Author(s):  
Vivak Parkash ◽  
Helen Ashwin ◽  
Jovana Sadlova ◽  
Barbora Vojtkova ◽  
Georgina Jones ◽  
...  
Keyword(s):  
Focus Groups ◽  
Leishmania Major ◽  
Human Infection ◽  
Sand Fly ◽  
Infection Model ◽  
Sand Flies ◽  
Serious Adverse Events ◽  
Natural Sand ◽  
Early Evaluation ◽  
Significant Difference

Background: Leishmaniasis is a globally important yet neglected parasitic disease transmitted by phlebotomine sand flies. With new candidate vaccines in or near the clinic, a controlled human challenge model (CHIM) using natural sand fly challenge would provide a method for early evaluation of prophylactic efficacy. Methods: We evaluated the biting frequency and adverse effects resulting from exposure of human volunteers to bites of either Phlebotomus papatasi or P. duboscqi, two natural vectors of Leishmania major. 12 healthy participants were recruited (mean age 40.2 ± 11.8 years) with no history of significant travel to regions where L. major-transmitting sand flies are prevalent. Participants were assigned to either vector by 1:1 allocation and exposed to five female sand flies for 30 minutes in a custom biting chamber. Bite frequency was recorded to confirm a bloodmeal was taken. Participant responses and safety outcomes were monitored using a visual analogue scale (VAS), clinical examination, and blood biochemistry. Focus groups were subsequently conducted to explore participant acceptability. Results: All participants had at least one successful sand fly bite with none reporting any serious adverse events, with median VAS scores of 0-1/10 out to day 21 post-sand fly bite. Corresponding assessment of sand flies confirmed that for each participant at least 1/5 sand flies had successfully taken a bloodmeal (overall mean 3.67±1.03 bites per participant). There was no significant difference between P. papatasi and P. duboscqi in the number of bites resulting from 5 sand flies applied to human participants (3.3±0.81 vs 3.00±1.27 bites per participant; p=0.56).  In the two focus groups (n=5 per group), themes relating to positive participant-reported experiences of being bitten and the overall study, were identified. Conclusions: These results validate a protocol for achieving successful sand fly bites in humans that is safe, well-tolerated and acceptable for participants. Clinicaltrials.gov registration: NCT03999970 (27/06/2019)

scholarly journals Imported cutaneous leishmaniasis: molecular investigation unveils Leishmania major in Bangladesh

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Md Anik Ashfaq Khan ◽  
Rajashree Chowdhury ◽  
Rupen Nath ◽  
Sören Hansen ◽  
Progga Nath ◽  
...  
Keyword(s):  
Skin Biopsy ◽  
Cutaneous Leishmaniasis ◽  
Leishmania Donovani ◽  
Leishmania Major ◽  
Migrant Worker ◽  
Human Mobility ◽  
Skin Lesions ◽  
Careful Consideration ◽  
Molecular Tests ◽  
Imported Cases

Abstract Background The main clinical forms of leishmaniasis in Bangladesh are visceral leishmaniasis and post-kala-azar dermal leishmaniasis, which are caused by Leishmania donovani. Imported cutaneous leishmaniasis (CL) is emerging globally due mainly to increased human mobility. In recent years, several imported CL cases have also been reported in Bangladesh. Sporadic atypical cases of CL can be challenging for diagnosis and clinical management, while occurrence of infection on a frequent basis can be alarming. We report of a case of a Bangladeshi temporary-migrant worker who, upon return, presented development of skin lesions that are characteristic of CL. Methods A serum sample was collected and tested with an rK39 immunochromatographic test. Nucleic acid from skin biopsy derived culture sample was extracted and screened with a real-time PCR assay which targets the conserved REPL repeat region of L. donovani complex. The internal transcribed spacer 2 region of the ribosomal RNA gene cluster was amplified and sequenced. Results The suspect had a history of travel in both CL and VL endemic areas and had a positive rK39 test result. Based on clinical presentation, travel history and demonstration of the parasite in the skin biopsy, CL was diagnosed and the patient underwent a combination therapy with Miltefosine and liposomal amphotericin B. While typical endemic species were not detected, we identified Leishmania major, a species that, to our knowledge, has never been reported in Bangladesh. Conclusions Proper monitoring and reporting of imported cases should be given careful consideration for both clinical and epidemiological reasons. Molecular tests should be performed in diagnosis to avoid dilemma, and identification of causative species should be prioritized.

scholarly journals A Second Generation Leishmanization Vaccine with a Markerless Attenuated Leishmania major Strain using CRISPR gene editing

2020 ◽  
Author(s):  
Wen Wei Zhang ◽  
Subir Karmakar ◽  
Sreenivas Gannavaram ◽  
Ranadhir Dey ◽  
Patrick Lypaczewski ◽  
...  
Keyword(s):  
Second Generation ◽  
Leishmania Major ◽  
Parasite Burden ◽  
Skin Lesions ◽  
Genetically Engineered ◽  
Sand Fly ◽  
Sand Flies ◽  
Host Protection ◽  
Marker Free ◽  
Immunocompromised Mice

AbstractLeishmaniasis is a debilitating and often fatal neglected tropical disease caused by Leishmania protozoa transmitted by infected sand flies. Vaccination through leishmanization with live Leishmania major has been used successfully but is no longer practiced because it resulted in unacceptable skin lesions. A second generation leishmanization is described here using a CRISPR genome edited L. major strain (LmCen-/-). Notably, LmCen-/- is the first genetically engineered gene deleted Leishmania strain that is antibiotic resistant marker free and does not have any off-target mutations. Mice immunized with LmCen-/- had virtually no visible lesions following challenge with L. major-infected sand flies while non-immunized animals developed large and progressive lesions with a 2-log fold higher parasite burden. LmCen-/- immunization showed protection and an immune response comparable to leishmanization. LmCen-/- is safe since it was unable to cause disease even in immunocompromised mice, induces robust host protection against vector sand fly challenge and because it is marker free, can be advanced to human vaccine trials.

scholarly journals The Phlebotomus Papatasi Transcriptomic Response to Trypanosomatid-contaminated Blood is Robust but non-specific

2020 ◽  
Author(s):  
Megan A. Sloan ◽  
Jovana Sadlova ◽  
Tereza Lestinova ◽  
Mandy J. Sanders ◽  
James A. Cotton ◽  
...  
Keyword(s):  
Blood Meal ◽  
Leishmania Donovani ◽  
Leishmania Major ◽  
Sand Fly ◽  
Phlebotomus Papatasi ◽  
Transcriptomic Response ◽  
Infected Blood ◽  
New Thinking ◽  
Contaminated Blood ◽  
Generation Sequencing

Abstract Background Leishmaniasis, caused by parasites of the genus Leishmania, is a disease that effects up to 8 million people worldwide. Parasites are transmitted to human and animal hosts through the bite of an infected sand fly. Novel strategies for disease control, require a better understanding of the key step for transmission namely, the establishment of infection inside the fly.Methods In this work we wanted to identify fly transcriptomic signatures associated with infected blood meal with non-infected blood meal as our baseline. We used next generation sequencing to describe the transcriptome of the sand fly Phlebotomus papatasi when fed with blood alone or with blood containing one of three trypanosomatids: Leishmania major, Leishmania donovani and Herpetomonas muscarum: a parasite not transmitted to humans.Results Of these, only L. major was able to successfully establish an infection in P. papatasi. However, the transcriptional signatures observed were not specific to success or failure of infection but a generalised response to the blood meal.Conclusions This implies that sand flies perceive Leishmania as just one feature of their microbiome landscape and that any strategy to tackle transmission should focus on the response towards the blood meal rather than parasite establishment. This result will generate new thinking around the concept of stopping transmission by controlling the parasite inside the insect.

scholarly journals The Phlebotomus papatasi systemic transcriptional response to trypanosomatid-contaminated blood does not differ from the non-infected blood meal

2020 ◽  
Author(s):  
Megan A. Sloan ◽  
Jovana Sadlova ◽  
Tereza Lestinova ◽  
Mandy J. Sanders ◽  
James A. Cotton ◽  
...  
Keyword(s):  
Blood Meal ◽  
Leishmania Donovani ◽  
Leishmania Major ◽  
Transcriptional Response ◽  
Sand Fly ◽  
Host Responses ◽  
Sand Flies ◽  
Phlebotomus Papatasi ◽  
New Thinking ◽  
Contaminated Blood

Abstract Background Leishmaniasis, caused by parasites of the genus Leishmania, is a disease that effects up to 8 million people worldwide. Parasites are transmitted to human and animal hosts through the bite of an infected sand fly. Novel strategies for disease control, require a better understanding of the key step for transmission namely, the establishment of infection inside the fly. Methods In this work we wanted to identify fly systemic transcriptomic signatures associated with Leishmania infection. We used next generation sequencing to describe the transcriptome of whole Phlebotomus papatasi sand flies when fed with blood alone (control) or with blood containing one of three trypanosomatids: Leishmania major, Leishmania donovani and Herpetomonas muscarum: a parasite not transmitted to humans. Results Of these, only L. major is able to successfully establish an infection in P. papatasi. However, the transcriptional signatures observed after each parasite-contaminated blood meal were not specific to success or failure of a specific infection and were not different from each other. They were also indistinguishable from non-contaminated blood. Conclusions This implies that sand flies perceive Leishmania as just one feature of their microbiome landscape and that any strategy to tackle transmission should focus on the response towards the blood meal rather than parasite establishment. Alternatively, Leishmania could suppress host responses. These results will generate new thinking around the concept of stopping transmission by controlling the parasite inside the insect.

scholarly journals Evasion of Host Defence by Leishmania donovani: Subversion of Signaling Pathways

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Md. Shadab ◽  
Nahid Ali
Keyword(s):  
Signaling Pathways ◽  
Leishmania Donovani ◽  
Severe Infection ◽  
Skin Lesions ◽  
Host Cells ◽  
Self Healing ◽  
Protozoan Parasites ◽  
Kinase C ◽  
Map Kinase Pathway ◽  
Kinase Pathway

Protozoan parasites of the genus Leishmania are responsible for causing a variety of human diseases known as leishmaniasis, which range from self-healing skin lesions to severe infection of visceral organs that are often fatal if left untreated. Leishmania donovani (L. donovani), the causative agent of visceral leishmaniasis, exemplifys a devious organism that has developed the ability to invade and replicate within host macrophage. In fact, the parasite has evolved strategies to interfere with a broad range of signaling processes in macrophage that includes Protein Kinase C, the JAK2/STAT1 cascade, and the MAP Kinase pathway. This paper focuses on how L. donovani modulates these signaling pathways that favour its survival and persistence in host cells.

scholarly journals The Phlebotomus papatasi systemic transcriptional response to trypanosomatid-contaminated blood does not differ from the non-infected blood meal

2020 ◽  
Author(s):  
Megan A. Sloan ◽  
Jovana Sadlova ◽  
Tereza Lestinova ◽  
Mandy J. Sanders ◽  
James A. Cotton ◽  
...  
Keyword(s):  
Blood Meal ◽  
Leishmania Donovani ◽  
Leishmania Major ◽  
Transcriptional Response ◽  
Sand Fly ◽  
Host Responses ◽  
Sand Flies ◽  
Phlebotomus Papatasi ◽  
New Thinking ◽  
Contaminated Blood

Abstract Background Leishmaniasis, caused by parasites of the genus Leishmania, is a disease that effects up to 8 million people worldwide. Parasites are transmitted to human and animal hosts through the bite of an infected sand fly. Novel strategies for disease control, require a better understanding of the key step for transmission namely, the establishment of infection inside the fly. Methods In this work we wanted to identify fly systemic transcriptomic signatures associated with Leishmania infection. We used next generation sequencing to describe the transcriptome of whole Phlebotomus papatasi sand flies when fed with blood alone (control) or with blood containing one of three trypanosomatids: Leishmania major, Leishmania donovani and Herpetomonas muscarum: a parasite not transmitted to humans. Results Of these, only L. major is able to successfully establish an infection in P. papatasi. However, the transcriptional signatures observed after each parasite-contaminated blood meal were not specific to success or failure of a specific infection and were not different from each other. They were also indistinguishable from non-contaminated blood. Conclusions This implies that sand flies perceive Leishmania as just one feature of their microbiome landscape and that any strategy to tackle transmission should focus on the response towards the blood meal rather than parasite establishment. Alternatively, Leishmania could suppress host responses. These results will generate new thinking around the concept of stopping transmission by controlling the parasite inside the insect.

scholarly journals Molecular detection of Leishmania donovani, Leishmania major, and Trypanosoma species in Sergentomyia squamipleuris sand flies from a visceral leishmaniasis focus in Merti sub-County, eastern Kenya

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Barrack O. Owino ◽  
Jackline Milkah Mwangi ◽  
Steve Kiplagat ◽  
Hannah Njiriku Mwangi ◽  
Johnstone M. Ingonga ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Mus Musculus ◽  
Blood Meal ◽  
Leishmania Donovani ◽  
Leishmania Major ◽  
Sand Fly ◽  
Health Concern ◽  
Sand Flies ◽  
Reservoir Hosts ◽  
Blood Meals

Abstract Background Visceral leishmaniasis (VL) and zoonotic cutaneous leishmaniasis (ZCL) are of public health concern in Merti sub-County, Kenya, but epidemiological data on transmission, vector abundance, distribution, and reservoir hosts remain limited. To better understand the disease and inform control measures to reduce transmission, we investigated the abundance and distribution of sand fly species responsible for Leishmania transmission in the sub-County and their blood-meal hosts. Methods We conducted an entomological survey in five villages with reported cases of VL in Merti sub-County, Kenya, using CDC miniature light traps and castor oil sticky papers. Sand flies were dissected and identified to the species level using standard taxonomic keys and PCR analysis of the cytochrome c oxidase subunit 1 (cox1) gene. Leishmania parasites were detected and identified by PCR and sequencing of internal transcribed spacer 1 (ITS1) genes. Blood-meal sources of engorged females were identified by high-resolution melting analysis of vertebrate cytochrome b (cyt-b) gene PCR products. Results We sampled 526 sand flies consisting of 8 species, Phlebotomus orientalis (1.52%; n = 8), and 7 Sergentomyia spp. Sergentomyia squamipleuris was the most abundant sand fly species (78.71%; n = 414) followed by Sergentomyia clydei (10.46%; n = 55). Leishmania major, Leishmania donovani, and Trypanosoma DNA were detected in S. squamipleuris specimens. Humans were the main sources of sand fly blood meals. However, we also detected mixed blood meals; one S. squamipleuris specimen had fed on both human and mouse (Mus musculus) blood, while two Ph. orientalis specimens fed on human, hyrax (Procavia capensis), and mouse (Mus musculus) blood. Conclusions Our findings implicate the potential involvement of S. squamipleuris in the transmission of Leishmania and question the dogma that human leishmaniases in the Old World are exclusively transmitted by sand flies of the Phlebotomus genus. The presence of Trypanosoma spp. may indicate mechanical transmission, whose efficiency should be investigated. Host preference analysis revealed the possibility of zoonotic transmission of leishmaniasis and other pathogens in the sub-County. Leishmania major and L. donovani are known to cause ZCL and VL, respectively. However, the reservoir status of the parasites is not uniform. Further studies are needed to determine the reservoir hosts of Leishmania spp. in the area.

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