An ex vivo splenic explant model system for the identification of small molecule therapeutics for visceral leishmaniasis
Abstract
New therapies for leishmaniasis are needed. We established an ex vivo splenic explant culture system from hamsters infected with luciferase‐transfected Leishmania donovani to screen chemical compounds for leishmanicidal activity. This model has advantages over in vitro systems in that it: 1) includes the cell populations involved in the host‐parasite interaction, 2) is initiated when the permissive immune mechanisms that lead to progressive disease are evident; 3) supports active parasite replication that can be easily measured by detection of parasite‐expressed luciferase; and 4) can be used to identify compounds that have both direct and immune‐mediated activity. The assay showed excellent discrimination between positive and negative controls (Z’ Factor >0.8). A screen of 1,040 small molecules identified 57 hits (Z score > 1.96; p<0.05). One‐third of the compounds were identified by database search as having toxicity; one‐fourth were administered previously to humans. The results were consistent across a 2.5–10 μM concentration range. Further testing of these lead compounds may identify new drugs for the treatment of leishmaniasis. Supported by the Department of Defense.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 01, 2008
- Source ID
- 10.1096/fasebj.22.1_supplement.1136.22
Entities
People
- Bruno L. Travi
- Peter C. Melby
- Yaneth E. Osorio
Organizations
- United States Department of Defense
- University of Texas at Austin