Open Peer Review Any reports and responses or comments on the article can be found at the end of the article. RESEARCH ARTICLE Tissue-specific transcriptomic changes associated with AmBisome® treatment of BALB/c mice with experimental visceral leishmaniasis [version 1; peer review: awaiting peer review] Sarah Forrester , Karin Siefert , Helen Ashwin , Najmeeyah Brown , Andrea Zelmar , Sally James , Dimitris Lagos , Jon Timmis , Mitali Chatterjee , Jeremy C. Mottram , Simon L. Croft , Paul M. Kaye 1 York Biomedical Research Institute, University of York, York, YO10 5DD, UK Department of Immunology and Infection, London School of Hygiene & Tropical Medicine, London, WC1E 7HT, UK Biosciences Technology Facility, University of York, York, YO10 5DD, UK Department of Electronic Engineering, University of York, UK, York, YO10 5DD, UK Department of Pharmacology, Jawaharlal Institute of Post Graduate Medical Education and Research, Kolkata, 700 020, India Abstract Liposomal amphotericin B (AmBisome®) as a treatment Background: modality for visceral leishmaniasis (VL) has had significant impact on patient care in some but not all regions where VL is endemic. As the mode of action of AmBisome® is poorly understood, we compared the in vivo tissue-specific transcriptome in drug-treated vs untreated mice with experimental VL. BALB/c mice infected with ere treated with 8mg/kg Methods: L. donovani w AmBisome®, resulting in parasite elimination from liver and spleen over a 7-day period. At day 1 and day 7 post treatment (R +1 and R +7), transcriptomic profiling was performed on spleen and liver tissue from treated and untreated mice and uninfected mice. BALB/c mice infected with BCG (an organism resistant to amphotericin B) were analysed M. bovis to distinguish between direct effects of AmBisome® and those secondary to parasite death. AmBisome® treatment lead to rapid parasitological clearance. At Results: R +1, spleen and liver displayed only 46 and 88 differentially expressed (DE) genes (P<0.05; 2-fold change) respectively. In liver, significant enrichment was seen for pathways associated with TNF, fatty acids and sterol biosynthesis. At R +7, the number of DE genes was increased (spleen, 113; liver 400). In spleen, these included many immune related genes known to be involved in anti-leishmanial immunity. In liver, changes in transcriptome were largely accounted for by loss of granulomas. PCA analysis indicated that treatment only partially restored homeostasis. Analysis of BCG-infected mice treated with AmBisome® revealed a pattern of immune modulation mainly targeting macrophage function. 1 2 1 1 2 3 1 4 5 1 2 1 1 2 3 4 5 Reviewer Status AWAITING PEER REVIEW 10 Dec 2019, :198 ( First published: 4 ) https://doi.org/10.12688/wellcomeopenres.15606.1 10 Dec 2019, :198 ( Latest published: 4 ) https://doi.org/10.12688/wellcomeopenres.15606.1 v1 x x x x Page 1 of 16 Wellcome Open Research 2019, 4:198 Last updated: 10 DEC 2019