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Rethinking Drug Response in Leishmania: Identifying the Genomic Determinants of Persistence

Cel

Drug resistance (DR) in Leishmania is a growing clinical challenge, yet often viewed too simplistically, overlooking the diversity of drug responses and survival strategies. Drug sensitivity (DS) and persistence are among these neglected responses, though essential for optimizing treatment: DS and DR reveal collateral sensitivities, while persistence, a dormant, slow- or non-growing drug response state, could drive treatment relapse. This means persistence enables survival during therapy and regrowth once drug pressure subsides, a state considered a transient, non-genetic adaptation entered stochastically or by stress. However, growing evidence, including our prior work, supports the hypothesis that specific mutations and other genomic pre-adaptations can alter the frequency of parasite subpopulations entering a persister state, challenging its classical genetic separation from DR and DS.
In PERSIST we will test this hypothesis by combining in vitro and in vivo genome-wide CRISPR cytosine base-editing loss-of-function screens developed by my group with persister-labelling and drug-treatment approaches to systematically map the genetic determinants of DS, DR, and persistence in mammalian-stage Leishmania amastigotes. Additionally, using lineage-tracing screens with barcoded parasite populations, we will test whether stochastic and stress-induced persisters exhibit a “memory effect” that predisposes subpopulations toward persistence. Finally, mutants and cell lines with altered persistence frequency will be tested for in vivo survival in sand flies and host niches, and profiled at transcriptomic, epigenetic, and metabolomic levels to uncover key persistence mechanisms.
By revealing the genomic and functional basis of persistence and integrating it with DR and DS, PERSIST will transform our understanding of Leishmania drug response, guide new combination therapies for the neglected tropical disease leishmaniasis, and provide insights into persistence across pathogens.

Dziedzina nauki (EuroSciVoc)

Projekt nie został jeszcze sklasyfikowany według klasyfikacji EuroSciVoc.
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HORIZON-ERC - HORIZON ERC Grants

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Zaproszenie do składania wniosków

(odnośnik otworzy się w nowym oknie) ERC-2026-STG

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Instytucja przyjmująca

JULIUS-MAXIMILIANS-UNIVERSITAT WURZBURG
Wkład UE netto
€ 1 053 561,00
Koszt całkowity
€ 1 053 561,00

Beneficjenci (2)