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 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 hostBackground 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 efficiency of the treatment to eliminate also not replicating (“hiding”) parasites.show moreshow less

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Metadaten
Author:Anja Kathrin Wege, Christian Florian, Wolfgang Ernst, Nicole Zimara, Ulrike Schleicher, Frank Hanses, Maximilian Schmid, Uwe Ritter
URN:urn:nbn:de:bvb:29-opus-37304
Title of the journal / compilation:PLoS Neglected Tropical Diseases 6.7 (2012): 30.10.2012 <http://www.plosntds.org/article/info%3Adoi%2F10.1371%2Fjournal.pntd.0001741?>
Document Type:Article
Language:English
Date of Publication (online):2012/10/30
Publishing Institution:Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)
Release Date:2012/10/30
SWD-Keyword:-
Original publication:PLoS Neglected Tropical Diseases 6.7 (2012): 30.10.2012 <http://www.plosntds.org/article/info%3Adoi%2F10.1371%2Fjournal.pntd.0001741?>
Institutes:Medizinische Fakultät -ohne weitere Spezifikation-
Dewey Decimal Classification:610 Medizin und Gesundheit
Collections:Open Access Artikel ohne Förderung 2012

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