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Understanding the genetic basis of natural resistance to miltefosine in Leishmania infantum in Brazil


Project Description

The drug Miltefosine has been used successfully to treat the neglected tropical disease visceral leishmaniasis in India, but it was unsuccessful for VL in a clinical trial in Brazil (Carnielli et al., 2019 Am J Trop Med Hyg 101, 789). Following whole genome sequence analysis of Leishmania infantum parasites isolated from treated and relapse patients, we identified a molecular marker for miltefosine treatment failure, the Miltefosine Sensitivity Locus (MSL) (Carnielli et al., 2018 EBioMedicine 36, 83). A genotyping survey of L. infantum showed that the frequency of MSL varies in a cline from 95% in North East Brazil to <5% in the South East. Population genetics analysis also indicates that the MSL is genetically stable and is a new deletion that occurred in South America. We hypothesise that loss of one or more of the four genes within the MSL leads to resistance of the parasites to miltefosine and that this natural resistance is not under positive selection. In this project we will address several questions. 1. What is the molecular basis for resistance to miltefosine in MSL negative strains? 2. How is the MSL distributed in L. infantum isolates in South America? 3. Does sexual exchange contribute to the spread of MSL negative strains in South America? We will use population genetic and molecular genetic approaches to address these questions.

Funding Notes

This is a studentship fully funded for three years and covers: (i) a tax-free annual stipend at the standard Research Council rate (£15,009 estimated for 2020 entry), (ii) research costs, and (iii) tuition fees at the UK/EU rate.

Interviews will take place in May 2020 on a date to be confirmed. The PhD start date is 1st October 2020.

References

ENTRY REQUIREMENTS: Students applying for postgraduate study in our Department should normally have obtained an upper second class honours degree (or equivalent). If your first language is not English you will need to show evidence that you meet our English language requirements. We welcome applications from students with backgrounds in any biological, chemical, and/or physical science, or students with mathematical backgrounds who are interested in using their skills in addressing biological questions.

ELIGIBILITY: This studentship is available to UK/EU students only (Tier 4 visa holders are not eligible)

How good is research at University of York in Biological Sciences?

FTE Category A staff submitted: 44.37

Research output data provided by the Research Excellence Framework (REF)

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