Mechanisms of nerve injury in leprosy
Investigator: David Scollard , M.D., Ph.D.
Nerve injury is the major cause of morbidity in leprosy, the major infectious cause of crippling in the world.
The mechanisms of this injury are very poorly understood: human nerves are seldom biopsied, so direct data are minimal, and there have been no animal models until the recent recognition of leprosy neuritis in the armadillo. In this animal, intravenous inoculation of M. leprae results in infection of peripheral nerves.
National Hansen's Disease Program studies of this model suggest that infection begins in epineurial lymphatics and blood vessels, from where it spreads to the well-protected endoneurial compartment. We hypothesize that endothelial cells of the peripheral nerve are the gatekeepers allowing entry of M. leprae but not other bacterial pathogens. Since reagents to study this further in the armadillo have been unavailable, we have proceeded using an in-vitro cell culture model to analyze the effects of M. leprae infection on
- the viability of endothelial cells,
- the permeability of monolayers created with these cells and
- the expression of cell surface molecules involved in cell to cell contact.
Using the armadillo model of Hansen's disease, we are now preparing for immuno-histochemical and molecular studies of armadillo nerves with varying degrees of M. leprae infection. The goal of these studies is to provide the first detailed description of the development of immunity and inflammation in infected nerves, enabling the formulation of specific hypotheses concerning the mechanisms of development and progression of lepromatous neuritis.
Endocrine Changes as Risk Factors for Leprosy Reactions
Investigator: David Scollard, M.D., Ph.D.
Much of the crippling in leprosy results from acute, immunologic "reactions," but the factors that initiate them are unknown. Longstanding clinical observations suggest that hormonal changes may be associated with reactions and are possible precipitating factors, but no good quantitative data exist.
An international, collaborative, prospective study is now underway, with a goal of enrolling approximately 2,700 new patients in three endemic areas: Manaus and Goiania in Brazil , Cebu in The Philippines, and Lalgadh , Nepal .
Levels of several hormones and cytokines will be measured in paired baseline and follow-up blood samples from selected patients, matched using a nested case-control design. Levels will be correlated with reaction status and nerve injury. This novel approach combines the preeminent endocrinology research capabilities of collaborators at the National Institutes of Health with established leprosy expertise in field sites and at the National Hansen's Disease Program.
Antigen discovery and vaccine development
Investigators: Linda Adams, Ph.D., Ramanuj Lahiri Ph.D., Richard Truman, Ph.D.
Despite significant improvement in global control measures for leprosy, new cases of leprosy continue at an incidence of ~200,000 per year. Implementation of worldwide World Health Organization-recommended multidrug therapy (WHO-MDT) has not eliminated the disease and other intervention strategies will be necessary. A high impact intervention strategy would be an effective vaccine against leprosy; however, the fact that M. leprae has not been successfully cultivated in vitro poses a serious challenge to the identification and purification of protective antigens.
Our studies exploring new vaccine candidates may offer improved protection over conventional vaccines. We are also evaluating the utility of gene knockout mice by studying their immune responses to vaccination as well as what immunological cues are necessary to produce protective immunity to M. leprae infection, as well as the armadillo for analyzing vaccine efficacy in preventing neurological damage.
Development of a diagnostic test for early detection of leprosy
Investigator: Ramanuj Lahiri, Ph.D.
Although global prevalence of leprosy is markedly reduced since the introduction of WHO MDT regimens, new case detection rates remains steady suggesting that treatment alone may not be sufficient to block transmission and the need for early detection of cases. A major effort is underway to employ recombinant proteins and synthetic peptides to develop diagnostic assays to detect early infection in animal models. The sensitivity of new diagnostic tests is as important as specificity. These animal studies provide an important interface between antigen development and the expensive field evaluation of these tests in humans.