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Leishmania major centrin knock-out parasites reprogram tryptophan metabolism to induce a pro-inflammatory response

Leishmaniasis is a parasitic disease that is prevalent in 90 countries, and yet no licensed human vaccine exists against it. Toward control of leishmaniasis, we have developed Leishmania major centrin gene deletion mutant strains (LmCen(−/−)) as a live attenuated vaccine, which induces a strong IFN-...

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Autores principales: Oljuskin, Timur, Azodi, Nazli, Volpedo, Greta, Bhattacharya, Parna, Markle, Hannah L., Hamano, Shinjiro, Matlashewski, Greg, Satoskar, Abhay R., Gannavaram, Sreenivas, Nakhasi, Hira L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10517402/
https://www.ncbi.nlm.nih.gov/pubmed/37744403
http://dx.doi.org/10.1016/j.isci.2023.107593
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author Oljuskin, Timur
Azodi, Nazli
Volpedo, Greta
Bhattacharya, Parna
Markle, Hannah L.
Hamano, Shinjiro
Matlashewski, Greg
Satoskar, Abhay R.
Gannavaram, Sreenivas
Nakhasi, Hira L.
author_facet Oljuskin, Timur
Azodi, Nazli
Volpedo, Greta
Bhattacharya, Parna
Markle, Hannah L.
Hamano, Shinjiro
Matlashewski, Greg
Satoskar, Abhay R.
Gannavaram, Sreenivas
Nakhasi, Hira L.
author_sort Oljuskin, Timur
collection PubMed
description Leishmaniasis is a parasitic disease that is prevalent in 90 countries, and yet no licensed human vaccine exists against it. Toward control of leishmaniasis, we have developed Leishmania major centrin gene deletion mutant strains (LmCen(−/−)) as a live attenuated vaccine, which induces a strong IFN-γ-mediated protection to the host. However, the immune mechanisms of such protection remain to be understood. Metabolomic reprogramming of the host cells following Leishmania infection has been shown to play a critical role in pathogenicity and shaping the immune response following infection. Here, we applied untargeted mass spectrometric analysis to study the metabolic changes induced by infection with LmCen(−/−) and compared those with virulent L. major parasite infection to identify the immune mechanism of protection. Our data show that immunization with LmCen(−/−) parasites, in contrast to virulent L. major infection promotes a pro-inflammatory response by utilizing tryptophan to produce melatonin and downregulate anti-inflammatory kynurenine-AhR and FICZ-AhR signaling.
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spelling pubmed-105174022023-09-24 Leishmania major centrin knock-out parasites reprogram tryptophan metabolism to induce a pro-inflammatory response Oljuskin, Timur Azodi, Nazli Volpedo, Greta Bhattacharya, Parna Markle, Hannah L. Hamano, Shinjiro Matlashewski, Greg Satoskar, Abhay R. Gannavaram, Sreenivas Nakhasi, Hira L. iScience Article Leishmaniasis is a parasitic disease that is prevalent in 90 countries, and yet no licensed human vaccine exists against it. Toward control of leishmaniasis, we have developed Leishmania major centrin gene deletion mutant strains (LmCen(−/−)) as a live attenuated vaccine, which induces a strong IFN-γ-mediated protection to the host. However, the immune mechanisms of such protection remain to be understood. Metabolomic reprogramming of the host cells following Leishmania infection has been shown to play a critical role in pathogenicity and shaping the immune response following infection. Here, we applied untargeted mass spectrometric analysis to study the metabolic changes induced by infection with LmCen(−/−) and compared those with virulent L. major parasite infection to identify the immune mechanism of protection. Our data show that immunization with LmCen(−/−) parasites, in contrast to virulent L. major infection promotes a pro-inflammatory response by utilizing tryptophan to produce melatonin and downregulate anti-inflammatory kynurenine-AhR and FICZ-AhR signaling. Elsevier 2023-08-29 /pmc/articles/PMC10517402/ /pubmed/37744403 http://dx.doi.org/10.1016/j.isci.2023.107593 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Oljuskin, Timur
Azodi, Nazli
Volpedo, Greta
Bhattacharya, Parna
Markle, Hannah L.
Hamano, Shinjiro
Matlashewski, Greg
Satoskar, Abhay R.
Gannavaram, Sreenivas
Nakhasi, Hira L.
Leishmania major centrin knock-out parasites reprogram tryptophan metabolism to induce a pro-inflammatory response
title Leishmania major centrin knock-out parasites reprogram tryptophan metabolism to induce a pro-inflammatory response
title_full Leishmania major centrin knock-out parasites reprogram tryptophan metabolism to induce a pro-inflammatory response
title_fullStr Leishmania major centrin knock-out parasites reprogram tryptophan metabolism to induce a pro-inflammatory response
title_full_unstemmed Leishmania major centrin knock-out parasites reprogram tryptophan metabolism to induce a pro-inflammatory response
title_short Leishmania major centrin knock-out parasites reprogram tryptophan metabolism to induce a pro-inflammatory response
title_sort leishmania major centrin knock-out parasites reprogram tryptophan metabolism to induce a pro-inflammatory response
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10517402/
https://www.ncbi.nlm.nih.gov/pubmed/37744403
http://dx.doi.org/10.1016/j.isci.2023.107593
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