Project Summary
The natural history of human dermal leishmaniasis caused by Leishmania Viannia species
provides unequivocal evidence of long-term persistence of parasites in asymptomatically as well as
symptomatically infected individuals. Persistent infection can remain asymptomatic, or can be
clinically manifested through the development of mucosal or cutaneous leishmaniasis (ML and CL)
following either asymptomatic infections, or as recurrent disease long after resolution of primary
lesions. Molecular evidence of persistent parasites in the conjunctiva, nasal and oropharyngeal
mucosal tissues, skin and blood monocytes has been documented in as many as 40% of infected
individuals in endemic areas of L. Viannia transmission, however, the role of the host immune
response and parasite subpopulations in promoting and sustaining Leishmania persistence in
humans remains unknown. It is also well established that immune tolerance is an underlying factor
of latent infection and tissue protection in infections by other protozoa such as Plasmodium and
Toxoplasma. Similar host mechanisms of immune tolerance likely contribute to Leishmania
persistence in the absence of signs and symptoms, since disruption of the immune homeostasis by
immunosuppression or local trauma have been identified as contributing factors in recurrent CL. We
hypothesize that Leishmania-host interactions eliciting strong, yet regulated innate immune
responses drive the establishment of local environments of immune tolerance (metabolic and
immunological), that favor Leishmania persistence in humans.
In this project we will characterize the transcriptomes, metabolomes and immunophenotypes
of host tissues and cells associated with persistent infection. We will genotype the corresponding
Leishmania populations, and will assess the participation of immunological tolerance in human
tissues where Leishmania persistence has been detected: nasal mucosa, skin and monocytes.
More specifically, we will 1) Identify the molecular signature of Leishmania persistence in a cohort
of patients with prior history of CL, 2) Characterize the genotype and phenotype of persister
Leishmania sub-populations as they modulate human host cells, and 3) Expand an ex vivo 3D cell
culture system to model the metabolic and immunological microenvironment of Leishmania
persistence. This project will provide critical knowledge on the metabolic and immunological
microenvironments of human tissues permissive for Leishmania persistence, define the signatures
and biomarkers of persistence, and advance ex vivo models of persistent Leishmania infection.