Deficiency of p110δ isoform of the phosphoinositide 3 kinase leads to enhanced resistance to Leishmania donovani.
Visceral leishmaniasis is the most clinically relevant and dangerous form of human leishmaniasis. Most traditional drugs for treatment of leishmaniasis are toxic, possess many adverse reactions and drug resistance is emerging. Therefore, there is urgent need for identification of new therapeutic tar...
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ftdoajarticles:oai:doaj.org/article:42a56213bf0f4b3287df081c0ce2d35a 2023-05-15T15:14:21+02:00 Deficiency of p110δ isoform of the phosphoinositide 3 kinase leads to enhanced resistance to Leishmania donovani. Forough Khadem Zhirong Mou Dong Liu Sanjay Varikuti Abhay Satoskar Jude E Uzonna 2014-06-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0002951 https://doaj.org/article/42a56213bf0f4b3287df081c0ce2d35a EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC4063731?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0002951 https://doaj.org/article/42a56213bf0f4b3287df081c0ce2d35a PLoS Neglected Tropical Diseases, Vol 8, Iss 6, p e2951 (2014) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2014 ftdoajarticles https://doi.org/10.1371/journal.pntd.0002951 2022-12-31T01:33:07Z Visceral leishmaniasis is the most clinically relevant and dangerous form of human leishmaniasis. Most traditional drugs for treatment of leishmaniasis are toxic, possess many adverse reactions and drug resistance is emerging. Therefore, there is urgent need for identification of new therapeutic targets. Recently, we found that mice with an inactivating knock-in mutation in the p110δ isoform of pi3k, (p110δ(d910a)) are hyper resistant to L. major, develop minimal cutaneous lesion and rapidly clear their parasite. Here, we investigated whether pi3k signaling also regulates resistance to L. donovani, one of the causative agents of visceral leishmaniasis.WT and p110δ(D910A) mice (on a BALB/c background) were infected with L. donovani. At different time points, parasite burden and granuloma formation were assessed. T and B cell responses in the liver and spleen were determined. In addition, Tregs were expanded in vivo and its impact on resistance was assessed. We found that p110δ(D910A) mice had significantly reduced splenomegaly and hepatomegaly and these organs harbored significantly fewer parasites than those of WT mice. Interestingly, infected p110δ(D910A) mice liver contains fewer and less organized granulomas than their infected WT counterparts. Cells from p110δ(D910A) mice were significantly impaired in their ability to produce cytokines compared to WT mice. The percentage and absolute numbers of Tregs in infected p110δ(D910A) mice were lower than those in WT mice throughout the course of infection. In vivo expansion of Tregs in infected p110δ(D910A) mice abolished their enhanced resistance to L. donovani infection.Our results indicate that the enhanced resistance of p110δ(D910A) mice to L. donovani infection is due to impaired activities of Tregs. They further show that resistance to Leishmania in the absence of p110δ signaling is independent of parasite species, suggesting that targeting the PI3K signaling pathway may be useful for treatment of both visceral and cutaneous leishmaniasis. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLoS Neglected Tropical Diseases 8 6 e2951 |
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Directory of Open Access Journals: DOAJ Articles |
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English |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Forough Khadem Zhirong Mou Dong Liu Sanjay Varikuti Abhay Satoskar Jude E Uzonna Deficiency of p110δ isoform of the phosphoinositide 3 kinase leads to enhanced resistance to Leishmania donovani. |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Visceral leishmaniasis is the most clinically relevant and dangerous form of human leishmaniasis. Most traditional drugs for treatment of leishmaniasis are toxic, possess many adverse reactions and drug resistance is emerging. Therefore, there is urgent need for identification of new therapeutic targets. Recently, we found that mice with an inactivating knock-in mutation in the p110δ isoform of pi3k, (p110δ(d910a)) are hyper resistant to L. major, develop minimal cutaneous lesion and rapidly clear their parasite. Here, we investigated whether pi3k signaling also regulates resistance to L. donovani, one of the causative agents of visceral leishmaniasis.WT and p110δ(D910A) mice (on a BALB/c background) were infected with L. donovani. At different time points, parasite burden and granuloma formation were assessed. T and B cell responses in the liver and spleen were determined. In addition, Tregs were expanded in vivo and its impact on resistance was assessed. We found that p110δ(D910A) mice had significantly reduced splenomegaly and hepatomegaly and these organs harbored significantly fewer parasites than those of WT mice. Interestingly, infected p110δ(D910A) mice liver contains fewer and less organized granulomas than their infected WT counterparts. Cells from p110δ(D910A) mice were significantly impaired in their ability to produce cytokines compared to WT mice. The percentage and absolute numbers of Tregs in infected p110δ(D910A) mice were lower than those in WT mice throughout the course of infection. In vivo expansion of Tregs in infected p110δ(D910A) mice abolished their enhanced resistance to L. donovani infection.Our results indicate that the enhanced resistance of p110δ(D910A) mice to L. donovani infection is due to impaired activities of Tregs. They further show that resistance to Leishmania in the absence of p110δ signaling is independent of parasite species, suggesting that targeting the PI3K signaling pathway may be useful for treatment of both visceral and cutaneous leishmaniasis. |
format |
Article in Journal/Newspaper |
author |
Forough Khadem Zhirong Mou Dong Liu Sanjay Varikuti Abhay Satoskar Jude E Uzonna |
author_facet |
Forough Khadem Zhirong Mou Dong Liu Sanjay Varikuti Abhay Satoskar Jude E Uzonna |
author_sort |
Forough Khadem |
title |
Deficiency of p110δ isoform of the phosphoinositide 3 kinase leads to enhanced resistance to Leishmania donovani. |
title_short |
Deficiency of p110δ isoform of the phosphoinositide 3 kinase leads to enhanced resistance to Leishmania donovani. |
title_full |
Deficiency of p110δ isoform of the phosphoinositide 3 kinase leads to enhanced resistance to Leishmania donovani. |
title_fullStr |
Deficiency of p110δ isoform of the phosphoinositide 3 kinase leads to enhanced resistance to Leishmania donovani. |
title_full_unstemmed |
Deficiency of p110δ isoform of the phosphoinositide 3 kinase leads to enhanced resistance to Leishmania donovani. |
title_sort |
deficiency of p110δ isoform of the phosphoinositide 3 kinase leads to enhanced resistance to leishmania donovani. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2014 |
url |
https://doi.org/10.1371/journal.pntd.0002951 https://doaj.org/article/42a56213bf0f4b3287df081c0ce2d35a |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 8, Iss 6, p e2951 (2014) |
op_relation |
http://europepmc.org/articles/PMC4063731?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0002951 https://doaj.org/article/42a56213bf0f4b3287df081c0ce2d35a |
op_doi |
https://doi.org/10.1371/journal.pntd.0002951 |
container_title |
PLoS Neglected Tropical Diseases |
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8 |
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6 |
container_start_page |
e2951 |
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1766344813711458304 |