Live Attenuated <i>Leishmania donovani</i> Centrin Gene–Deleted Parasites Induce IL-23–Dependent IL-17–Protective Immune Response against Visceral Leishmaniasis in a Murine Model

Banerjee, Saumyabrata; Bhattacharya, Pinaki; Dagur, Pradeep K.; Karmakar, Shilpi; Ismail, Nevien; Joshi, Amritanshu B.; Akue, Adovi; KuKuruga, Mark; McCoy, J. Philip; Dey, Ranadhir; Nakhasi, Hira L.

doi:10.4049/jimmunol.1700674

Cited by 54 publications

(32 citation statements)

References 81 publications

(120 reference statements)

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“…Importantly LmCen -/- parasites elicited protection against sand fly challenge that was deemed necessary but was neither performed or was not demonstrated in previous vaccination studies 20,38,41,42 . These observations using a cutaneous model of infection are consistent with our previous findings that immunization with LdCen-/- parasites were protective against visceral leishmaniasis in different animal models 26–28,30,46 .…”

Section: Discussionsupporting

confidence: 92%

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

Zhang

Karmakar²,

Gannavaram³

et al. 2020

Preprint

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Leishmaniasis is a debilitating and often fatal neglected tropical disease caused by 29 Leishmania protozoa transmitted by infected sand flies. Vaccination through leishmanization with 30live Leishmania major has been used successfully but is no longer practiced because it resulted in 31 unacceptable skin lesions. A second generation leishmanization is described here using a CRISPR 32 genome edited L. major strain (LmCen -/-). Notably, LmCen -/is the first genetically engineered 33 gene deleted Leishmania strain that is antibiotic resistant marker free and does not have any off-34 target mutations. Mice immunized with LmCen -/had virtually no visible lesions following 35 challenge with L. major-infected sand flies while non-immunized animals developed large and 36 progressive lesions with a 2-log fold higher parasite burden. LmCen -/immunization showed 37 protection and an immune response comparable to leishmanization. LmCen -/is safe since it was 38 unable to cause disease even in immunocompromised mice, induces robust host protection against 39 vector sand fly challenge and because it is marker free, can be advanced to human vaccine trials. 40 41 42 Leishmaniasis is a neglected disease caused by infection with protozoans of the genus Leishmania 43 that is transmitted by infected sand flies 1 . Worldwide, an estimated 1 billion people are at risk of 44 infection in tropical and subtropical countries where up to 1.7 million new cases in 98 countries 45 occur each year 2,3 . The disease pathology ranges from localized skin ulcers (cutaneous 46 leishmaniasis, CL) to fatal systemic disease (visceral leishmaniasis, VL), depending on the species 47 of the infecting Leishmania parasite 1,4 . Treatment options for both VL and CL are limited and there 48 is poor surveillance in the most highly endemic countries 1,5 . A prophylactic vaccine would be an 49 effective intervention for protection against this disease, reducing transmission and supporting the 50 elimination of leishmaniasis globally. Currently there are no available vaccines against any form 51 of human leishmaniasis. 52Unlike most parasitic infections, patients who recover from leishmaniasis naturally or following 53 drug treatment develop immunity against reinfection indicating that the development of an 54 effective vaccine should be feasible 6-8 . Furthermore, leishmanization, a process in which 55 deliberate infections with a low dose of virulent Leishmania major provides greater than 90% 56 protection against reinfection and has been used in several countries of the Middle East and the 57 former Soviet Union 9-11 . Leishmanization is however no longer practiced because it is ethically 58 unacceptable due to the resulting skin lesions that last for months at the site of inoculation. The 59 overall strategy of this study is to develop the next generation leishmanization that is safer by 60 providing a protective immune response against cutaneous leishmaniasis without causing skin 61 lesions. 4In case of leishmaniasis cell mediated immunity is critical, and...

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Section: Discussionsupporting

confidence: 92%

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

Zhang

Karmakar²,

Gannavaram³

et al. 2020

Preprint

Self Cite

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“…In order to measure protection in populations already exposed, it is possible to infect with knock-out parasites and give a live challenge, as has been done in mice [28]. We need better markers to identify who has been exposed.…”

Section: Discussionmentioning

confidence: 99%

Report of the Fifth Post-Kala-Azar Dermal Leishmaniasis Consortium Meeting, Colombo, Sri Lanka, 14–16 May 2018

et al. 2020

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“…Central and effector memory cells are fundamental to parasite elimination and disease control [47,48]. Central memory T-cells have an important role in the immune response, being responsible for the renewal of memory cells of the immune system while effector memory cells migrate to the infection site and eliminate the pathogen [49].…”

Section: Discussionmentioning

confidence: 99%

Synthetic Peptides Elicit Strong Cellular Immunity in Visceral Leishmaniasis Natural Reservoir and Contribute to Long-Lasting Polyfunctional T-Cells in BALB/c Mice

et al. 2019

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Reverse vaccinology or immunoinformatics is a computational methodology which integrates data from in silico epitope prediction, associated to other important information as, for example, the predicted subcellular location of the proteins used in the design of the context of vaccine development. This approach has the potential to search for new targets for vaccine development in the predicted proteome of pathogenic organisms. To date, there is no effective vaccine employed in vaccination campaigns against visceral leishmaniasis (VL). For the first time, herein, an in silico, in vitro, and in vivo peptide screening was performed, and immunogenic peptides were selected to constitute VL peptide-based vaccines. Firstly, the screening of in silico potential peptides using dogs naturally infected by L. infantum was conducted and the peptides with the best performance were selected. The mentioned peptides were used to compose Cockt-1 (cocktail 1) and Cockt-2 (cocktail 2) in combination with saponin as the adjuvant. Therefore, tests for immunogenicity, polyfunctional T-cells, and the ability to induce central and effector memory in T-lymphocytes capacity in reducing the parasite load on the spleen for Cockt-1 and Cockt-2 were performed. Among the vaccines under study, Cockt-1 showed the best results, eliciting CD4+ and CD8+ polyfunctional T-cells, with a reduction in spleen parasitism that correlates to the generation of T CD4+ central memory and T CD8+ effector memory cells. In this way, our findings corroborate the use of immunoinformatics as a tool for the development of future vaccines against VL.

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Live Attenuated Leishmania donovani Centrin Gene–Deleted Parasites Induce IL-23–Dependent IL-17–Protective Immune Response against Visceral Leishmaniasis in a Murine Model

Cited by 54 publications

References 81 publications

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

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

Report of the Fifth Post-Kala-Azar Dermal Leishmaniasis Consortium Meeting, Colombo, Sri Lanka, 14–16 May 2018

Synthetic Peptides Elicit Strong Cellular Immunity in Visceral Leishmaniasis Natural Reservoir and Contribute to Long-Lasting Polyfunctional T-Cells in BALB/c Mice

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