Role of Mycobacterium leprae proteins and RNAs in initiating neuropathy

Peripheral neuropathy is a major global health problem affecting millions of people with clinical symptoms of sensory and motor function loss, and results from disease conditions, aging, injury or infection. A classic example of infectious neuropathies is leprosy neuropathy, which is caused primarily by Mycobacterium leprae (ML) infection of the Schwann cells, the glial cells or supporting cells for the axons of the adult PNS. Since ML uniquely infect adult Schwann cells and progressively causes neuropathic conditions in humans after extremely long incubation period, this bacterial infection provides an excellent model to delineate how altered Schwann cells, as a result of infection, contribute to the initiation of the axonal degeneration and demyelination of sensory and motor neurons. Recently, we discovered that ML hijacks the notable plasticity of adult Schwann cells and reprograms infected cells to progenitor/stem cell-like cells that precedes the activation of innate immune factors. In this project, we propose that Immune factors generated within Schwann cells by ML proteins and ML RNAs can directly affect the enclosing or surrounding nerves and recruite inflammatory cells, leading to the initiation of sensory and motor nerve damage. Similarly, we also propose that the damage to sensory nerve endings in the epidermis is due to release of immune factors from ML infected epidermal keratinocytes, independent of Schwann cell involvement. Thus, we plan to identify candidate ML proteins and RNAs with the capacity to elicit innate immune genes/factors and determine their role in axonal degeneration in tissue culture models and zebrafish model, which has been well characterized to study neurodegeneration process in living animals. Based on these results we will select most promising candidate ML proteins and RNAs and generate transgenic mouse models, which are likely to recapitulate how ML naturally initiates axonal degeneration leading to neuropathic conditions. We anticipate that the knowledge gain from this model will eventually permit us to test small molecule drugs with the ability to alleviate axonal degeneration and demyelination, and thus develop new therapeutics to halt nervedegeneration in leprosy neuropathy, and may also have implications for other neuropathic conditions and diseases.

Neuropathic diseases and pain due to degeneration of axons in peripheral nerves (PN) represents a significant clinical problem globally. However, much less is known about the mechanisms by which glial cells in the adult PN contribute to the initiation of axonal degeneration leading to neuropathies. In this project, we propose to gain new understanding of early events of axonal degeneration of sensory and motor neurons, the common features of neuropathic diseases, using gene products of Mycobacterium leprae (ML) which naturally infect Schwann cells and causes one of the classical examples of neuropathies, leprosy neuropathy. Proposed research will identify ML gene products, proteins and RNAs that induce innate immune factors in Schwann cells and their role in perturbing Schwann cell support to and interaction with axons of sensory and motor neurons in ex-vivo, and in vivo zebrafish models. We will also plan to study how the nerve ending damage in the epidermis without Schwann cells leads to sensory loss in the skin and the potential role of immune factors released by epidermal keratinocytes in response to ML proteins and RNAs. Based on these studies we will select the most relevant candidate ML protein and RNAs to generate transgenic mice expressing these candidate ML gene products in adult Schwann cells initiating early neuropathic conditions, which eventually permit us to test small molecule drugs with the ability to alleviate axonal degeneration, and thus develop common new therapeutics not only for leprosy neuropathy but also for other neuropathic conditions and pain.

Understanding how axonal degeneration process initiates and progresses in neuropathic conditions is an immense strategic importance with broader implications for the management of peripheral neuropathies and pain. In this project, we propose to gain new understanding of early events of axonal degeneration of sensory and motor neurons, key common features of neuropathic diseases, using gene products of leprosy bacterium which causes one of the classical examples of neuropathies, leprosy neuropathy. Proposed research should provide detailed mechanistic insights into how ML gene products initiate axonal degeneration in sensory nerves, and potential leads to the use of ML gene products as tools for new interventions. Thus, our proposed research is of clinical and strategic importance, and has a potential to translate to patient, family and societal benefits and fits well with MRC's mission.
Staff/students: Research staff employed and students working on this project will receive high quality training and highly specialist skills. The skills set in the lab is unique as we bring together several themes of fields to our research, infection biology, neurobiology, stem cell biology with wide range of tissue culture and in vivo animal models as well as next generation genome-wide studies. Staff and students will be uniquely fused with such a combination of different fields which bring broader scientific lens that they can look through to get a bigger picture of science they do. In terms of career progression and diversification, the university of Edinburgh is recognized by the UK Research Council as a center of Excellence for generic and transferable skills training.
Public interest: Our lab webpage and news we posted about recent discoveries together guided by our Centre's outreach team we often engage with the public. We explain science to school pupils, fundraisers, teachers, and patients. We liaise with the University Press Office and give interviews to local press.
Patients: Patients with neurodegenerative diseases of the PNS, and particularly leprosy neuropathy: Our work has the potential to develop early interventions and biomarkers for neuropathic diseases, particular leprosy neuropathy. If achievable, our work will impact on a broad group of patients with peripheral neuropathies including diabetes and millions of patients suffering from past and present leprosy worldwide. From the point of view of global challenges of combating neglected infectious diseases, leprosy neuropathy remains a major challenge to global health due to continuing detection of new cases in endemic countries and extreme difficulty of diagnosing infected individuals at the early stage. There are about 250,000 new leprosy cases are diagnosed annually with estimated 2 million people living with visible deformities (WHO report), which include significant number of children worldwide. More global dissemination of M. leprae infection is also possible due to unprecedented influx of migrant population with potentially undiagnosed infected individuals from endemic countries. Thus, this project has the potential of enhancing quality of life and health of many groups of patients and to reduce global incidence of disability, which is currently known to be contributed largely by leprosy.
Patients' families: Neuropathies are devastating conditions that also immensely affect the wellbeing of patients' relatives. Curative treatments will undoubtedly have a major positive impact on these beneficiaries and their function in the society.
Exploitation and dissemination: The proposed research may lead to commercially exploitable results if we develop technologies to alleviate axonal degeneration. Candidate ML gene products and their potential to initiate axonal degeneration in vivo models will allow use to identify critical degenerative pathways that can potentially be arrested by small molecule drugs, which could be develop to a therapeutics for neuropathy.