A second generation leishmanization vaccine with a markerless attenuated Leishmania major strain using CRISPR gene editing

Leishmaniasis is a 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 occasional skin lesions. A second generation lei...

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Published inNature communications Vol. 11; no. 1; pp. 3461 - 14
Main Authors Zhang, Wen-Wei, Karmakar, Subir, Gannavaram, Sreenivas, Dey, Ranadhir, Lypaczewski, Patrick, Ismail, Nevien, Siddiqui, Abid, Simonyan, Vahan, Oliveira, Fabiano, Coutinho-Abreu, Iliano V., DeSouza-Vieira, Thiago, Meneses, Claudio, Oristian, James, Serafim, Tiago D., Musa, Abu, Nakamura, Risa, Saljoughian, Noushin, Volpedo, Greta, Satoskar, Monika, Satoskar, Sanika, Dagur, Pradeep K., McCoy, J. Philip, Kamhawi, Shaden, Valenzuela, Jesus G., Hamano, Shinjiro, Satoskar, Abhay R., Matlashewski, Greg, Nakhasi, Hira L.
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 10.07.2020
Nature Publishing Group
Nature Portfolio
Subjects
42/41
45/23
45/77
631/1647/1511
631/250/590/1867
631/326/417/2546
64/60
692/308/575
96/31
Antibiotic resistance
Antibiotics
Clinical trials
CRISPR
Disease transmission
Drug resistance
Genetic engineering
Genetic modification
Genome editing
Genomes
Humanities and Social Sciences
Immune response
Immune system
Immunization
Leishmania
Leishmania major
Leishmaniasis
Lesions
Markers
multidisciplinary
Mutation
Parasites
Protozoa
Science
Science (multidisciplinary)
Skin diseases
Skin lesions
Tropical diseases
Vaccination
Vaccines
Vector-borne diseases
Online AccessGet full text
ISSN2041-1723
2041-1723
DOI10.1038/s41467-020-17154-z

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Abstract Leishmaniasis is a 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 occasional skin lesions. A second generation leishmanization is described here using a CRISPR genome edited L. major strain ( LmCen −/− ). Notably, LmCen −/− is a genetically engineered centrin gene knock-out mutant strain that is antibiotic resistant marker free and does not have detectable off-target mutations. Mice immunized with LmCen −/− have no visible lesions following challenge with L. major -infected sand flies, while non-immunized animals develop large and progressive lesions with a 2-log fold higher parasite burden. LmCen −/− immunization results in protection and an immune response comparable to leishmanization. LmCen −/− is safe since it is unable to cause disease 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. Here, the authors engineer an attenuated knock-out Leishmania ( LmCen −/− ) vaccine that is safe in immunocompromised mice and induces an immune response and protection similar to leishmanization with wild-type Leishmania . Since LmCen −/− is antibiotic resistant marker free, it is a candidate for clinical development.
AbstractList Leishmaniasis is a 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 occasional skin lesions. A second generation leishmanization is described here using a CRISPR genome edited L. major strain ( LmCen −/− ). Notably, LmCen −/− is a genetically engineered centrin gene knock-out mutant strain that is antibiotic resistant marker free and does not have detectable off-target mutations. Mice immunized with LmCen −/− have no visible lesions following challenge with L. major -infected sand flies, while non-immunized animals develop large and progressive lesions with a 2-log fold higher parasite burden. LmCen −/− immunization results in protection and an immune response comparable to leishmanization. LmCen −/− is safe since it is unable to cause disease 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.
Leishmaniasis is a 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 occasional skin lesions. A second generation leishmanization is described here using a CRISPR genome edited L. major strain (LmCen-/-). Notably, LmCen-/- is a genetically engineered centrin gene knock-out mutant strain that is antibiotic resistant marker free and does not have detectable off-target mutations. Mice immunized with LmCen-/- have no visible lesions following challenge with L. major-infected sand flies, while non-immunized animals develop large and progressive lesions with a 2-log fold higher parasite burden. LmCen-/- immunization results in protection and an immune response comparable to leishmanization. LmCen-/- is safe since it is unable to cause disease 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.Leishmaniasis is a 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 occasional skin lesions. A second generation leishmanization is described here using a CRISPR genome edited L. major strain (LmCen-/-). Notably, LmCen-/- is a genetically engineered centrin gene knock-out mutant strain that is antibiotic resistant marker free and does not have detectable off-target mutations. Mice immunized with LmCen-/- have no visible lesions following challenge with L. major-infected sand flies, while non-immunized animals develop large and progressive lesions with a 2-log fold higher parasite burden. LmCen-/- immunization results in protection and an immune response comparable to leishmanization. LmCen-/- is safe since it is unable to cause disease 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.
Leishmaniasis is a 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 occasional skin lesions. A second generation leishmanization is described here using a CRISPR genome edited L. major strain (LmCen−/−). Notably, LmCen−/− is a genetically engineered centrin gene knock-out mutant strain that is antibiotic resistant marker free and does not have detectable off-target mutations. Mice immunized with LmCen−/− have no visible lesions following challenge with L. major-infected sand flies, while non-immunized animals develop large and progressive lesions with a 2-log fold higher parasite burden. LmCen−/− immunization results in protection and an immune response comparable to leishmanization. LmCen−/− is safe since it is unable to cause disease 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.Here, the authors engineer an attenuated knock-out Leishmania (LmCen−/−) vaccine that is safe in immunocompromised mice and induces an immune response and protection similar to leishmanization with wild-type Leishmania. Since LmCen−/− is antibiotic resistant marker free, it is a candidate for clinical development.
Here, the authors engineer an attenuated knock-out Leishmania (LmCen −/−) vaccine that is safe in immunocompromised mice and induces an immune response and protection similar to leishmanization with wild-type Leishmania. Since LmCen −/− is antibiotic resistant marker free, it is a candidate for clinical development.
Leishmaniasis is a 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 occasional skin lesions. A second generation leishmanization is described here using a CRISPR genome edited L. major strain ( LmCen −/− ). Notably, LmCen −/− is a genetically engineered centrin gene knock-out mutant strain that is antibiotic resistant marker free and does not have detectable off-target mutations. Mice immunized with LmCen −/− have no visible lesions following challenge with L. major -infected sand flies, while non-immunized animals develop large and progressive lesions with a 2-log fold higher parasite burden. LmCen −/− immunization results in protection and an immune response comparable to leishmanization. LmCen −/− is safe since it is unable to cause disease 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. Here, the authors engineer an attenuated knock-out Leishmania ( LmCen −/− ) vaccine that is safe in immunocompromised mice and induces an immune response and protection similar to leishmanization with wild-type Leishmania . Since LmCen −/− is antibiotic resistant marker free, it is a candidate for clinical development.
ArticleNumber 3461
Author Gannavaram, Sreenivas
Siddiqui, Abid
Serafim, Tiago D.
Valenzuela, Jesus G.
Simonyan, Vahan
Oliveira, Fabiano
Saljoughian, Noushin
Meneses, Claudio
Kamhawi, Shaden
Volpedo, Greta
Zhang, Wen-Wei
Ismail, Nevien
Karmakar, Subir
Hamano, Shinjiro
Dagur, Pradeep K.
Dey, Ranadhir
Nakhasi, Hira L.
Oristian, James
Lypaczewski, Patrick
Musa, Abu
Satoskar, Monika
DeSouza-Vieira, Thiago
Matlashewski, Greg
Coutinho-Abreu, Iliano V.
McCoy, J. Philip
Satoskar, Sanika
Nakamura, Risa
Satoskar, Abhay R.
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Snippet Leishmaniasis is a neglected tropical disease caused by Leishmania protozoa transmitted by infected sand flies. Vaccination through leishmanization with live...
Leishmaniasis is a neglected tropical disease caused by Leishmania protozoa transmitted by infected sand flies. Vaccination through leishmanization with live...
Here, the authors engineer an attenuated knock-out Leishmania (LmCen −/−) vaccine that is safe in immunocompromised mice and induces an immune response and...
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Antibiotic resistance
Antibiotics
Clinical trials
CRISPR
Disease transmission
Drug resistance
Genetic engineering
Genetic modification
Genome editing
Genomes
Humanities and Social Sciences
Immune response
Immune system
Immunization
Leishmania
Leishmania major
Leishmaniasis
Lesions
Markers
multidisciplinary
Mutation
Parasites
Protozoa
Science
Science (multidisciplinary)
Skin diseases
Skin lesions
Tropical diseases
Vaccination
Vaccines
Vector-borne diseases
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Title A second generation leishmanization vaccine with a markerless attenuated Leishmania major strain using CRISPR gene editing
URI https://link.springer.com/article/10.1038/s41467-020-17154-z
https://www.proquest.com/docview/2422035221
https://www.proquest.com/docview/2423068539
https://pubmed.ncbi.nlm.nih.gov/PMC7351751
https://doaj.org/article/a50605a064c049859dfcd1fb76a10dad
Volume 11
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