Gerald SPAETH

Information

Scientific interests and projects

The unit ‘Molecular Parasitolgy and Signaling’ conducts multidisciplinary and internationally highly visible research on Leishmania/macrophage interaction and co-evolution. Our program analyses Leishmania and macrophage regulatory pathways implicated in intracellular parasite development and subversion of host cell functions that qualify as novel drug targets. We will pursue three main axes as part of the ParFrap consortium:

Axis 1 investigates mechanisms of Leishmania differentiation and evolutionary adaptation by conducting systems level and comparative genomics analyses of hamster-derived parasites and clinical isolates with the aim to identify genetic loci that are linked to Leishmania fitness gain in culture and in infected animals;

Axis 2 analyses the signalling role of the Leishmania ecto-kinase CK1.2 and its role in subversion of host cell immune signalling, with the aim to target its exosomal release for anti-leishmanial therapy;

Axis 3 studies mechanisms of Leishmania host subversion using immunological, pharmacological and systems-level investigations, with the aims to (i) discover host-directed, anti-leishmanial hits and (ii) study the impact of intracellular Leishmania infection on macrophage epigenetic regulation, phenotype and functions.

Together these three axes provide important added value to the main ParaFrap scientific work packages, including WP1 on post genomic data exploration (Axes 1 – 3), WP2 on mechanisms of pathogenesis and anti-parasite immunity (Axes 2 and 3), WP3 on parasite molecular and cellular biology (Axes 1 and 3), and WP4 on development of new intervention strategies against parasitic pathogens (Axes 2 and 3).

1. Pescher P, Douché T, Giai-Gianetto Q, Druart K, Kovarova J, Li B, Cokelaer T, Rajan KS, Piel L, Besse C, Boland A, Deleuze JF, Matondo M, Barrett MP, Michaeli S, Späth GF. Five-layer systems analysis of Leishmania stage differentiation reveals an essential role for protein degradation in parasite development. eLife 2026, in press.

2. Bruno F, Castelli G, Li B, Reale S, Carra E, Vitale F, Scibetta S, Calzolari M, Varani S, Ortalli M, Franceschini E, Gennari W, Rugna G, Späth GF. Genomic and epidemiological evidence for the emergence of a L. infantum/L. donovani hybrid with unusual epidemiology in northern Italy. mBio. 2024 Jul 17;15(7):e0099524. doi: 10.1128/mbio.00995-24.

3. Bussotti G, Li B, Pescher P, Vojtkova B, Louradour I, Pruzinova K, Sadlova J, Volf P, Späth GF. Leishmania allelic selection during experimental sand fly infection correlates with mutational signatures of oxidative DNA damage. Proc Natl Acad Sci U S A. 2023 Mar 7;120(10):e2220828120. doi: 10.1073/pnas.2220828120.

4. Piel L, Rajan KS, Bussotti G, Varet H, Legendre R, Proux C, Douché T, Giai-Gianetto Q, Chaze T, Cokelaer T, Vojtkova B, Gordon-Bar N, Doniger T, Cohen-Chalamish S, Rengaraj P, Besse C, Boland A, Sadlova J, Deleuze JF, Matondo M, Unger R, Volf P, Michaeli S, Pescher P, Späth GF. Experimental evolution links post-transcriptional regulation to Leishmania fitness gain. PLoS Pathog. 2022 Mar 16;18(3):e1010375. doi: 10.1371/journal.ppat.1010375.

5. Späth GF, Bussotti G. GIP: an open-source computational pipeline for mapping genomic instability from protists to cancer cells. Nucleic Acids Res. 2022 Apr 8;50(6):e36. doi: 10.1093/nar/gkab1237.