The impact of granulomatous liver inflammation on miltefosine and 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, necessitating repeated treatments that may obviously facilitate emergence of resistance. As isolates from clinical relapse patients still demonstrate a 'drug susceptible' phenotype, factors other than intrinsic drug resistance may likely influence treatment outcome. Next to some phenotypic parasite traits, such as infectivity and multiplication potential, treatment failure has also been linked to a decreased drug exposure in particular parasite niches, such as in liver granulomas preventing sterile cure upon drug exposure. In this project, the complex interplay between the parasite's (epi-)phenotype, the drug and the host's immune reaction will be explored using syngeneic VL strains derived from a cure, relapse and resistant background. 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, Veterinary medicine