1.1 Models of chronicity, sequestration, treatment response and recrudescence

London School of Hygiene and Tropical Medicine (LSHTM), London, United Kingdom   - Instituto de Higiene e Medicina Tropical (IHMT), Lisboa, Portugal   - Microsens Diagnostic Ltd., London, United Kingdom

Area of research: Diagnostic/Treatment
Research programme: Basic Science

Objectives:

(1) To establish chronic models of virulence and pathogenesis using transgenic bioluminescent Leishmania infections

(2) To track sequestration and recrudescence of chronic transgenic bioluminescent infections in response to sub-curative treatment and immune suppression.

Expected results:

First comparison of the vigour of hybrid, non-hybrid and virus infected Leishmania genotypes in vivo by bioluminescence imaging. Unique insight into the dynamics of parasite sequestration and recrudescence/relapse following treatment failure. 

Summary:

Background:  Leishmania strains with distinct genotypes may differ in virulence, and patients vary in immune competence to combat infection. Traditional experiments for studying comparative pathogenesis require large cohorts of animals, whereas transgenic Leishmania strains and in vivo bioluminescent imaging enable simpler designs5,6. LSHTM has expertise in production of transgenics, IHMT in hybrid phenotyping in vitro and in vivo and SME MICROSENS has unique expertise in antigen detection.   

Methodology: A range of transgenic bioluminescent clones of Leishmania species/strains will be produced. Small groups of hamsters or mice will be infected with bioluminescent strains, including a) parental and hybrid L. donovani, L. infantum/major and L. braziliensis/peruviana b) Leishmania (Viannia) strains with or without Leishmania RNA virus infection. Tissue distributions will be followed sequentially by in vivo imaging and post mortem by bioluminescence or qPCR, and haematological metastasis by antigen detection. Recrudescence of infections will be monitored in vivo following sub-curative treatment or immune suppression. Sites of sequestration and dynamics relapse and opportunistic recrudescence from chronic carrier status will be described.