Leishmania major infection in humanized mice induces systemic infection and provokes a nonprotective human immune response.
BACKGROUND: Leishmania (L.) species are the causative agent of leishmaniasis. Due to the lack of efficient vaccine candidates, drug therapies are the only option to deal with cutaneous leishmaniasis. Unfortunately, chemotherapeutic interventions show high toxicity in addition to an increased risk of...
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ftdoajarticles:oai:doaj.org/article:69d6847b385e497a9113653c81b31bac 2023-05-15T15:14:34+02:00 Leishmania major infection in humanized mice induces systemic infection and provokes a nonprotective human immune response. Anja Kathrin Wege Christian Florian Wolfgang Ernst Nicole Zimara Ulrike Schleicher Frank Hanses Maximilian Schmid Uwe Ritter 2012-01-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0001741 https://doaj.org/article/69d6847b385e497a9113653c81b31bac EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC3404120?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0001741 https://doaj.org/article/69d6847b385e497a9113653c81b31bac PLoS Neglected Tropical Diseases, Vol 6, Iss 7, p e1741 (2012) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2012 ftdoajarticles https://doi.org/10.1371/journal.pntd.0001741 2023-01-08T01:37:56Z BACKGROUND: Leishmania (L.) species are the causative agent of leishmaniasis. Due to the lack of efficient vaccine candidates, drug therapies are the only option to deal with cutaneous leishmaniasis. Unfortunately, chemotherapeutic interventions show high toxicity in addition to an increased risk of dissemination of drug-resistant parasites. An appropriate laboratory animal based model is still missing which allows testing of new drug strategies in the context of human immune cells in vivo. METHODOLOGY/PRINCIPAL FINDINGS: Humanized mice were infected subcutaneously with stationary phase promastigote L. major into the footpad. The human immune response against the pathogen and the parasite host interactions were analyzed. In addition we proved the versatility of this new model to conduct drug research studies by the inclusion of orally given Miltefosine. We show that inflammatory human macrophages get infected with Leishmania parasites at the site of infection. Furthermore, a Leishmania-specific human-derived T cell response is initiated. However, the human immune system is not able to prevent systemic infection. Thus, we treated the mice with Miltefosine to reduce the parasitic load. Notably, this chemotherapy resulted in a reduction of the parasite load in distinct organs. Comparable to some Miltefosine treated patients, humanized mice developed severe side effects, which are not detectable in the classical murine model of experimental leishmaniasis. CONCLUSIONS/SIGNIFICANCE: This study describes for the first time L. major infection in humanized mice, characterizes the disease development, the induction of human adaptive and innate immune response including cytokine production and the efficiency of Miltefosine treatment in these animals. In summary, humanized mice might be beneficial for future preclinical chemotherapeutic studies in systemic (visceral) leishmaniasis allowing the investigation of human immune response, side effects of the drug due to cytokine production of activated humane immune cells and the ... Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLoS Neglected Tropical Diseases 6 7 e1741 |
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Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
language |
English |
topic |
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 Anja Kathrin Wege Christian Florian Wolfgang Ernst Nicole Zimara Ulrike Schleicher Frank Hanses Maximilian Schmid Uwe Ritter Leishmania major infection in humanized mice induces systemic infection and provokes a nonprotective human immune response. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
BACKGROUND: Leishmania (L.) species are the causative agent of leishmaniasis. Due to the lack of efficient vaccine candidates, drug therapies are the only option to deal with cutaneous leishmaniasis. Unfortunately, chemotherapeutic interventions show high toxicity in addition to an increased risk of dissemination of drug-resistant parasites. An appropriate laboratory animal based model is still missing which allows testing of new drug strategies in the context of human immune cells in vivo. METHODOLOGY/PRINCIPAL FINDINGS: Humanized mice were infected subcutaneously with stationary phase promastigote L. major into the footpad. The human immune response against the pathogen and the parasite host interactions were analyzed. In addition we proved the versatility of this new model to conduct drug research studies by the inclusion of orally given Miltefosine. We show that inflammatory human macrophages get infected with Leishmania parasites at the site of infection. Furthermore, a Leishmania-specific human-derived T cell response is initiated. However, the human immune system is not able to prevent systemic infection. Thus, we treated the mice with Miltefosine to reduce the parasitic load. Notably, this chemotherapy resulted in a reduction of the parasite load in distinct organs. Comparable to some Miltefosine treated patients, humanized mice developed severe side effects, which are not detectable in the classical murine model of experimental leishmaniasis. CONCLUSIONS/SIGNIFICANCE: This study describes for the first time L. major infection in humanized mice, characterizes the disease development, the induction of human adaptive and innate immune response including cytokine production and the efficiency of Miltefosine treatment in these animals. In summary, humanized mice might be beneficial for future preclinical chemotherapeutic studies in systemic (visceral) leishmaniasis allowing the investigation of human immune response, side effects of the drug due to cytokine production of activated humane immune cells and the ... |
format |
Article in Journal/Newspaper |
author |
Anja Kathrin Wege Christian Florian Wolfgang Ernst Nicole Zimara Ulrike Schleicher Frank Hanses Maximilian Schmid Uwe Ritter |
author_facet |
Anja Kathrin Wege Christian Florian Wolfgang Ernst Nicole Zimara Ulrike Schleicher Frank Hanses Maximilian Schmid Uwe Ritter |
author_sort |
Anja Kathrin Wege |
title |
Leishmania major infection in humanized mice induces systemic infection and provokes a nonprotective human immune response. |
title_short |
Leishmania major infection in humanized mice induces systemic infection and provokes a nonprotective human immune response. |
title_full |
Leishmania major infection in humanized mice induces systemic infection and provokes a nonprotective human immune response. |
title_fullStr |
Leishmania major infection in humanized mice induces systemic infection and provokes a nonprotective human immune response. |
title_full_unstemmed |
Leishmania major infection in humanized mice induces systemic infection and provokes a nonprotective human immune response. |
title_sort |
leishmania major infection in humanized mice induces systemic infection and provokes a nonprotective human immune response. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2012 |
url |
https://doi.org/10.1371/journal.pntd.0001741 https://doaj.org/article/69d6847b385e497a9113653c81b31bac |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 6, Iss 7, p e1741 (2012) |
op_relation |
http://europepmc.org/articles/PMC3404120?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0001741 https://doaj.org/article/69d6847b385e497a9113653c81b31bac |
op_doi |
https://doi.org/10.1371/journal.pntd.0001741 |
container_title |
PLoS Neglected Tropical Diseases |
container_volume |
6 |
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7 |
container_start_page |
e1741 |
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1766345008123740160 |