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.
Highlights
Of the many diseases associated with infection by the protozoan parasite Leishmania, visceral leishmaniasis (VL) represents one of the most challenging to understand in terms of its pathophysiology
Unlike cutaneous leishmaniasis, where parasite growth and the pathological consequences of the ensuing immune response are largely confined to the site of transmission, VL is characterized by systemic spread of parasites, multi-organ involvement and a systemic response that is fatal without treatment
Splenic response to L. donovani infection in BALB/c mice As part of a larger program of research aimed at evaluating multiple aspects of EVL, we infected two cohorts of female BALB/c mice with 2×107 amastigotes of L. donovani (CRACK-IT_1 and CRACKIT_2) and at defined time points corresponding to increased parasite load and architectural changes in the splenic microenvironment (Figure 1), spleen tissues were processed for genome-wide transcriptomic profiling by microarray
Summary
Of the many diseases associated with infection by the protozoan parasite Leishmania, visceral leishmaniasis (VL) represents one of the most challenging to understand in terms of its pathophysiology. The application of transcriptomic profiling has provided valuable insights into the pathogenesis of many infectious and non-infectious diseases[15,16,17,18,19,20,21,22,23,24,25,26], and on the response to drugs, vaccines and other immunotherapeutic interventions[27,28,29,30,31]. The application of whole blood transcriptomic profiling (WBTP) opened a new era in clinical monitoring of disease, fuelled notably by the work of Chaussebel and others that illustrated its potential to provide insights into systemic disease processes and serve as a clinical tool[19,32,33,34]. Studies formally comparing whole blood with the systemic tissue transcriptome are rare[21]
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