Burgess project: A drug-resistance map for Leishmania populations in Brazil.

Visceral leishmaniasis (VL) is a neglected disease caused by Leishmania infantum/donovani (1). After disease onset, VL is generally fatal if untreated. The main foci of VL are the Indian subcontinent, East Africa and Brazil. There is no vaccine for VL, so case management is reliant on antileishmanial drugs, including Meglumine Antimoniate, liposomal Amphotericin B and Amphotericin B deoxycholate (2). These drugs are problematic; they are toxic and frequently do not completely clear infections, making residual drug resistance from relapsed patients an ongoing clinical concern.
More than 40,000 VL cases were reported in Brazil between 2008-2018. It is likely that L. infantum populations in Brazil already contain drug-resistant parasites, since drug-treatment cure rates are only 70-80% in Brazilian states (3). We have shown that tolerance to miltefosine, a potent anti-antileishmanial, is due to mutations in parasites that were present in Brazil before the first drug trial (4). Drug-induced parasite clearance may vary due to a variety of factors, including parasite overall ‘fitness’ for human infection. For example, macrophage infection rates differ between strains (5), and our unpublished analysis has shown that genetic variation in L. infantum strains influences immune responses.
This PhD project will be supported by world-leading Leishmania expertise at the University of York with established collaborative links to leading Brazilian researchers (see https://yorkleish.org/). The project will use laboratory assays, genome sequencing technology and quantitative genetics to estimate the genetic contributions of drug resistance in L. infantum isolates from Brazil. With collaborators at York and Brazil, you will develop high-throughput methods to measure drug tolerance and cell fitness in Leishmania isolates. Using population genomics data from L. infantum strains from throughout Brazil, you will create a drug-resistance map that will have predictive power to monitor the spread of drug-resistance in South America.
References
1. S. Burza, S. L. Croft, M. Boelaert, Leishmaniasis. Lancet. 392, 951–970 (2018). 2. I. P. S. F. Carvalho, H. M. Peixoto, G. A. S. Romero, M. R. F. Oliveira, Treatment for human visceral leishmaniasis: a cost‐effectiveness analysis for Brazil. Trop. Med. Int. Health. 24, 1064–1077 (2019). 3. G. A. S. Romero, D. L. Costa, C. H. N. Costa, R. P. de Almeida, E. V. de Melo, S. F. G. de Carvalho, A. Rabello, A. L. de Carvalho, A. de Q. Sousa, R. D. Leite, S. S. Lima, T. A. Amaral, F. P. Alves, J. Rode, Collaborative LVBrasil Group, Efficacy and safety of available treatments for visceral leishmaniasis in Brazil: A multicenter, randomized, open label trial. PLoS Negl. Trop. Dis. 11, e0005706 (2017). 4. J. B. T. Carnielli, K. Crouch, S. Forrester, V. C. Silva, S. F. G. Carvalho, J. D. Damasceno, E. Brown, N. J. Dickens, D. L. Costa, C. H. N. Costa, R. Dietze, D. C. Jeffares, J. C. Mottram, A Leishmania infantum genetic marker associated with miltefosine treatment failure for visceral leishmaniasis. EBioMedicine. 5. J. B. T. Carnielli, R. Monti-Rocha, D. L. Costa, A. Molina Sesana, L. N. N. Pansini, M. Segatto, J. C. Mottram, C. H. N. Costa, S. F. G. Carvalho, R. Dietze, Natural Resistance of Leishmania infantum to Miltefosine Contributes to the Low Efficacy in the Treatment of Visceral Leishmaniasis in Brazil. Am. J. Trop. Med. Hyg. 101, 789–794 (2019).

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