Joshua R. Lacsina, M.D., Ph.D.

We apply systems immunology approaches to investigate human cutaneous leishmaniasis, a disfiguring chronic skin disease caused by the protozoan parasite Leishmania.

Cutaneous leishmaniasis (CL) is endemic and emerging in the southwestern United States and often also affects military personnel who have been deployed to Leishmania-endemic areas. Leishmania parasites are transmitted to humans via the bite of an infected sand fly. As the disease progresses, the immune response to the parasite in the skin can trigger pathologic inflammation that leads to chronic ulceration and permanent scarring. Current therapies for CL are variably effective with increasing reports of drug resistance. A major roadblock to the development of novel therapeutics for CL is our incomplete understanding of human immunity to Leishmania in the skin.

Our group seeks to define the cellular circuits that drive pathologic inflammation and damage to skin tissue in CL. To do this, we employ a variety of experimental and bioinformatic approaches, including single-cell transcriptomics, multiomic spatial profiling, and mechanistic multiscale tissue modeling to map the cell subsets and intercellular signals that drive CL immunopathology. Current efforts are focused on constructing a comprehensive single-cell and spatial atlas of human CL. This work is being performed in collaboration with the NIAID Leishmaniasis Clinic (Principal Investigator: Dr. Elise O’Connell, Laboratory of Parasitic Diseases). Our goal is to develop novel host-directed therapies for CL patients that 1) inhibit the critical signaling circuits driving pathologic inflammation in the skin and 2) enhance immune control of the parasite.

Another major focus of our group is investigating human immunity to vector bites and vector-borne pathogens via controlled human vector challenge studies. The immune response to vector bites profoundly affects the susceptibility of the host to vector-borne pathogens. In collaboration with Dr. Matthew Memoli (Laboratory of Infectious Diseases), we performed a human challenge study using mosquitos and sand flies, which revealed a conserved transcriptomic skin response against highly divergent vector species. We are now using single-cell and spatial profiling to map the cellular circuitry of the human skin response to vector bites. Our goal is to develop novel clinical therapies that co-opt these responses to enhance protection against vector-borne pathogens.