Characterization of Cross-Protection by Genetically Modified Live-Attenuated <i>Leishmania donovani</i> Parasites against <i>Leishmania mexicana</i>

Dey, Ranadhir; Natarajan, Gayathri; Bhattacharya, Pinaki; Cummings, Hannah; Dagur, Pradeep K.; Terrazas, César; Selvapandiyan, Angamuthu; McCoy, J. Philip; Duncan, Robert C.; Satoskar, Abhay R.; Nakhasi, Hira L.

doi:10.4049/jimmunol.1303145

Cited by 54 publications

(51 citation 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 AttenuatedLeishmania majorStrain 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 AttenuatedLeishmania majorStrain using CRISPR gene editing

Zhang

Karmakar²,

Gannavaram³

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

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“…Recently F1 epitopes derived of nucleoside hydrolase, a component of Leishmune , from L. donovani protected BALB/c mice from the challenge with L. amazonensis , however, immunized mice treated with anti‐CD8 monoclonal antibody abrogated the protective efficacy of this vaccine candidate. The study conducted by Dey and collaborators showed that BALB/c mice immunized with genetically modified live‐attenuated L. donovani and challenge with L. (L.) mexicana presented, mainly, high frequencies of CD8 + IFN‐γ + . Taken together, these studies suggest an essential function of CD8 T lymphocytes for resistance against leishmaniasis during vaccination, as previously related .…”

Section: Discussionmentioning

confidence: 99%

Analysis of iron superoxide dismutase‐encoding DNA vaccine on the evolution of the Leishmania amazonensis experimental infection

Campos

Silva

Ribeiro

et al. 2015

Parasite Immunology

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The present work aimed to evaluate the immunogenicity of Leishmania amazonensis iron superoxide dismutase (SOD)-encoding DNA experimental vaccine and the protective properties of this DNA vaccine during infection. The SOD gene was subcloned into the pVAX1 plasmid, and it was used to immunize BALB/c mice. Twenty-one days after the last immunization, mice were sacrificed (immunogenicity studies) or subcutaneously challenged with L. amazonensis (studies of protection), and alterations in cellular and humoral immune responses were evaluated, as well as the course of infection. Mice only immunized with pVAX1-SOD presented increased frequencies of CD4(+) IFN-γ(+), CD8(+)IFN-γ(+) and CD8(+)IL-4(+) lymphocytes; moreover, high levels of IgG2a were detected. After challenge, mice that were immunized with pVAX1-SOD had increased frequencies of the CD4(+)IL-4(+), CD8(+)IFN-γ(+) and CD8(+)IL-4(+) T lymphocytes. In addition, the lymph node cells produced high amounts of IFN-γ and IL-4 cytokines. Increased IgG2a was also detected. The pattern of immunity induced by pVAX1-SOD partially protected the BALB/c mice from a challenge with L. amazonensis, as the animals presented reduced parasitism and lesion size when compared to controls. Taken together, these results indicate that leishmanial SOD modulates the lymphocyte response, and that the elevation in IFN-γ possibly accounted for the decreased skin parasitism observed in immunized animals.

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“…32,33 Briefly, bone marrow cells were isolated from femurs and tibias of mice, treated with ACK lysis buffer and plated @ 5 million cells/ plate in sterile 100 £ 15 mm vented petri dishes along with complete RPMI medium supplemented with 10% fetal bovine serum (Atlanta Biologicals), 1% penicillin (20 Units/mL)/streptomycin (20 mg/mL) (Life Technologies) and 20ng/mL GMCSF (Peprotech) for 6 d At Day 6, cells from DC culture were collected by gently harvesting the floating fraction of cells to obtain >75% purity of CD11c C DCs in the floating fraction. The remaining cells in the floating fraction did not display lineage specific markers for T cells, B cells, NK cells and macrophages upon flow cytometric analysis.…”

Section: Cultivation and Stimulation Of Bone Marrow Derived Dendriticmentioning

confidence: 99%

Ibrutinib enhances IL-17 response by modulating the function of bone marrow derived dendritic cells

et al. 2015

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Ibrutinib (PCI-32765) is an irreversible dual Btk/Itk inhibitor shown to be effective in treating several B cell malignancies. However, limited studies have been conducted to study the effect of this drug on myeloid cell function. Hence, we studied the effect of ibrutinib treatment on TLR-4 mediated activation of bone marrow derived dendritic cell culture (DCs). Upon ibrutinib treatment, LPS-treated DCs displayed lower synthesis of TNF-a and nitric oxide (NO) and higher induction of IL-6, TGF-b, IL-10 and IL-18. While ibrutinib dampened MHC-II and CD86 expression on DCs, CD80 expression was upregulated. Further, ibrutinib-treated DCs promoted T cell proliferation and enhanced IL-17 production upon co-culture with nylon wool enriched T cells. Taken together, our results indicate that ibrutinib modulates TLR-4 mediated DC activation to promote an IL-17 response. We describe a novel mode of action for ibrutinib on DCs which should be explored to treat other forms of cancer besides B cell malignancies.

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Characterization of Cross-Protection by Genetically Modified Live-Attenuated Leishmania donovani Parasites against Leishmania mexicana

Cited by 54 publications

References 73 publications

A Second Generation Leishmanization Vaccine with a Markerless AttenuatedLeishmania majorStrain using CRISPR gene editing

A Second Generation Leishmanization Vaccine with a Markerless AttenuatedLeishmania majorStrain using CRISPR gene editing

Analysis of iron superoxide dismutase‐encoding DNA vaccine on the evolution of the Leishmania amazonensis experimental infection

Ibrutinib enhances IL-17 response by modulating the function of bone marrow derived dendritic cells

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