Active Infection & Immunity Cancer

Pathways to parasite dissemination in visceral leishmaniasis

Funder Wellcome Charity-funded
Recipient organisation University of York
Funding £2.5M
Period Jul 2022 — Jun 2027

In plain English

AI plain-English summary

The parasite *Leishmania donovani* spreads through the body by hiding inside immune cells called myeloid cells, but no one knows exactly how it moves from one tissue to another. This matters because the parasite’s ability to disseminate—from the initial infection site to the spleen, liver, and bone marrow—is what causes visceral leishmaniasis, a fatal disease if untreated. It also drives the later skin complication, post kala-azar dermal leishmaniasis (PKDL). Yet the cellular and molecular steps of that journey remain a black box. The researchers will map infected human and rodent tissue at single-cell resolution, track parasite populations using genetic tags, and combine modelling with experiments to test how the parasite spreads laterally in the skin. If successful, this fundamental science will reveal the specific changes in myeloid cells that allow the parasite to travel and establish new infection sites. That knowledge could eventually point to host-directed therapies—drugs that block the parasite’s spread by targeting the patient’s own cells rather than the parasite itself. There is no immediate practical application; the work is curiosity-driven. But understanding how a pathogen hijacks immune cells to move through the body could, in the long run, inform strategies for other intracellular infections that rely on similar dissemination routes.

View original technical description
Leishmania donovani infection is characterised by widespread parasite dissemination within and between multiple tissues, a process intimately linked to the parasite’s intracellular lifestyle in myeloid cells. Yet despite dissemination underpinning the pathogenesis of visceral leishmaniasis (VL) and post kala azar dermal leishmaniasis (PKDL), little is known about this critical aspect of parasitism. To address this knowledge gap, we propose a program of research involving: i) comparative in situ analysis of infected human and rodent tissue at single cell resolution (including spatial proteomics / transcriptomics and mass spectroscopy imaging); ii) the application of sequence tag-based analysis of microbial populations to probe parasite within-host population dynamics, and iii) iterative rounds of modelling and experimentation to test hypotheses related to lateral parasite spread in the skin. By applying these orthogonal approaches at key inflection points in the natural history of disease, we will identify key changes in myeloid cell phenotype and function associated with dissemination, discover novel bottlenecks impacting parasite establishment and replication temporally and across different tissues, and gain new insights into the key transition from VL to PKDL. This research will increase our fundamental knowledge of L. donovani-host interactions and provide new targets for host-directed therapy aimed at minimising parasite dissemination.

View the original record at the funder ↗

Researchers

Paul Kaye (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

Characterization of Leishmania-Specific T cells in human skin and blood during cutaneous and mucocutaneous leishmaniasis
Immunology and Immunopathology of visceral leishmaniasis
Leishmania virulence factors and host peptidases associated with visceral leishmaniasis
BBSome trafficking: investigating a novel pathway associated with virulence in Leishmania
Immunopathology and the regulation of immune responses during Leishmania donovani infection

Original classification

Investigator Award in Science

Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.