Identifying factors involved in miltefosine or amphotericin B treatment failure in visceral leishmaniasis.

Amphotericin B (AmB) is currently implemented as first-line treatment for visceral leishmaniasis (VL) in large parts of the world, while the use of miltefosine (MIL) is endorsed as second option, either in mono- or in combination therapy. However, a cumulative number of treatment failures is being reported, requiring the need for repeated treatments that will facilitate emergence of resistance. As isolates from clinical relapse patients generally still demonstrate a 'drug susceptible' phenotype, factors other than intrinsic drug resistance may likely influence treatment outcome. For MIL, increased infectivity and metacyclogenesis potential of the infecting parasites has been suggested, while preliminary observations from our laboratory indicate similarities for AmB. Treatment failure has also been linked to a decreased drug exposure in particular parasite niches, such as in liver granulomas precluding sterile cure upon drug exposure. In this project, the complex interplay between the parasite's (epi-)phenotype, the drug and the host's immune system will be explored using syngeneic VL strains derived from a cure, relapse and resistant background. More in particular, virulence will be compared in the sand fly vector and in in vitro and in vivo laboratory models. The impact of the development of granulomas upon infection with the different strains will be compared in relation to the in vitro and in vivo drug efficacy and relapse potential.

Keywords:LEISHMANIA

Disciplines:Microbiology, Systems biology, Laboratory medicine

Project type:Collaboration project