Leprosy is no longer designated as a global health problem by the WHO (defined by a registered prevalence of less than one case of leprosy per 10,000 population); however, about 200,000 new cases are still reported each year. Recently several epidemiological reports based on ?find-and-treat? campaigns have indicated under reporting and suggested ?hidden-leprosy?. This, as well as the identification of environmental reservoirs, would explain the continued transmission of the etiological agent, Mycobacterium leprae, in the human population. The most pronounced forms of this disease manifest with sever deformities and physical disabilities that are a result of irreversible nerve damage caused by the pathogen's tropism for peripheral nerves. Specifically, M. leprae has evolved and adapted to infect and survive in Schwann cells (SCs), where defined host-pathogen interactions result in demyelination and nerve fibrosis. The molecular and biochemical interactions of M. leprae and SCs have not been well defined. Thus, elucidating these interactions and their downstream consequences is essential to understand the neuropathogenesis of leprosy and to develop appropriate interventions. The ability of M. leprae to induce lipid droplet formation in SCs has been established as key and fundamental aspect of M. leprae pathogenicity. As such, the focus of the proposed research is to define the molecular interactions that result in lipid droplet formation by M. leprae infected SCs and understand how M. leprae utilizes lipids from these droplets to support its growth and drive pathogenesis. These objectives are based on the unifying hypothesis that, via surface ligands M. leprae gains access to SCs and induces lipid droplet formation. The pathogen modulation of host cell lipid metabolism promotes SC dysfunction and the generation of a permissive innate immune response that facilitates bacilli persistence in the nerve. Further, M. leprae catabolism of the lipid droplet associated cholesterol supports the pathogens intracellular growth, as well as drives cell signaling events that result in impairment of myelin production and stability.

Public Health Relevance

Leprosy, a disease caused by infection from the bacterium Mycobacterium leprae, remains a significant public health issue in various regions across the globe; with ~200,000 new cases reported annually. Of particular concern is peripheral nerve infection that results in damaging neuropathology with consequent irreversible nerve dysfunction that provokes deformities, physical disabilities, and notorious discrimination. The proposed research addresses the molecular interactions between the bacterium and host cells that lead to the neuropathology of leprosy. A specific emphasis will be placed on understanding the interaction between M. leprae and the Schwann cells that produce a protective myelin sheath around neuronal axons. Elucidation of host-pathogen interactions and the downstream biological consequences will provide essential information required to develop therapies to treat and prevent neuropathology in leprosy patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI141526-02
Application #
9978702
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Mendez, Susana
Project Start
2019-07-17
Project End
2024-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Colorado State University-Fort Collins
Department
Microbiology/Immun/Virology
Type
Schools of Veterinary Medicine
DUNS #
785979618
City
Fort Collins
State
CO
Country
United States
Zip Code
80523