Authors
S J Forrester1; H Ashwin1; E Clark3; K Seifert2; N Brown1; P Andrews3; S L Croft2; J Timmis3; J Mottram1; P Kaye1;
1 Centre for Immunology and Infection, Dept. of Biology and Hull York Medical School, University of York, York, YO10 5DD, UK; 2 Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK; 3 Simomics Ltd. York, YO31 7TQ
Discussion
Viscerotropic strains of Leishmania donovani and Leishmania infantum are responsible for a significant health burden worldwide, with 200,000 to 400,000 new cases reported annually; however many aspects of the host-parasite interplay during infection have yet to be elucidated. CRACK-IT is a interdisciplinary project that brings together immunological, pharmacological and transcriptomic data in an attempt to understand host-parasite dynamics during infection and following treatment. Based on a published Petri net model of the host response to infection (Albergante et al PLoS Comp. Biol. 9(11):e1003334), we are constructing a multi scale model of infection that will significantly reduce the numbers of animals required for pre-clinical evaluation of drug combination therapies (including immuno-chemotherapy). Here, we discuss issues pertinent to understanding the interplay between host immunity, drug pharmokinetics and parasite genomic plasticity, and how these can be brought together by the use of transcriptome-based analysis. We will describe tissue and disease-stage specific transcriptomic profiles in the blood, liver and spleen, and discuss the approaches we are taking to tease apart the transcriptomic responses observed during therapy and that are due to direct drug-immune interactions from those that represent a confounding effect due to changes in parasite load.
