Tissue and host species-specific transcriptional changes in models of experimental visceral leishmaniasis: 4 approved]

Helen Ashwin, Karin Seifert, Sarah Forrester, Najmeeyah Brown, Sandy MacDonald, Sally James, Dimitris Lagos, Jon Timmis, Jeremy C. Mottram, Simon L. Croft, Paul M. Kaye*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Citations (SciVal)

Abstract

Background: Human visceral leishmaniasis, caused by infection with Leishmania donovani or L. infantum, is a potentially fatal disease affecting 50,000-90,000 people yearly in 75 disease endemic countries, with more than 20,000 deaths reported. Experimental models of infection play a major role in understanding parasite biology, host-pathogen interaction, disease pathogenesis, and parasite transmission. In addition, they have an essential role in the identification and pre-clinical evaluation of new drugs and vaccines. However, our understanding of these models remains fragmentary. Although the immune response to Leishmania donovani infection in mice has been extensively characterized, transcriptomic analysis capturing the tissue-specific evolution of disease has yet to be reported. Methods: We provide an analysis of the transcriptome of spleen, liver and peripheral blood of BALB/c mice infected with L. donovani. Where possible, we compare our data in murine experimental visceral leishmaniasis with transcriptomic data in the public domain obtained from the study of L. donovani-infected hamsters and patients with human visceral leishmaniasis. Digitised whole slide images showing the histopathology in spleen and liver are made available via a dedicated website, www.leishpathnet.org. Results: Our analysis confirms marked tissue-specific alterations in the transcriptome of infected mice over time and identifies previously unrecognized parallels and differences between murine, hamster and human responses to infection. We show commonality of interferon-regulated genes whilst confirming a greater activation of type 2 immune pathways in infected hamsters compared to mice. Cytokine genes and genes encoding immune checkpoints were markedly tissue specific and dynamic in their expression, and pathways focused on non-immune cells reflected tissue specific immunopathology. Our data also addresses the value of measuring peripheral blood transcriptomics as a potential window into underlying systemic disease. Conclusions: Our transcriptomic data, coupled with histopathologic analysis of the tissue response, provide an additional resource to underpin future mechanistic studies and to guide clinical research.

Original languageEnglish
Article number135
JournalWellcome Open Research
Volume3
Early online date29 Oct 2018
DOIs
Publication statusPublished - 02 Jan 2019

Keywords

  • Host response
  • Immunopathology
  • Infection
  • Leishmania
  • Transcriptomics

Fingerprint

Dive into the research topics of 'Tissue and host species-specific transcriptional changes in models of experimental visceral leishmaniasis: 4 approved]'. Together they form a unique fingerprint.

Cite this