This proposal describes a five-year mentored training program for the career development of a translational scientist to examine the mechanism by which a cutaneous pathogen, mycobacterium leprae (mLEP), causes the expansion of immunosuppressive myeloid derived suppressor cells (MDSC) and M2 macrophages (M?) that produce interleukin (IL)-10, a factor critical for failure of host defense and pathogen persistence in lepromatous leprosy (L-lep) patients. We will compare the MDSC from L-lep patients with the similar cells seen in the self-limiting or tuberculoid (T-lep) form of disease. We have identified IL-34 as a potential factor that leads to the production of the immunosuppressive myeloid cells. This project addresses several goals of NIAMS using leprosy as a translational model to study mechanisms that impact cutaneous immunity, including: 1) identifying how induction of IL-34 can lead to the production of immunosuppressive myeloid populations (MDSC and M2 M?) that contribute to immune tolerance during cutaneous infection and 2) evaluating how MDSC and M2 M? affect immune responses in leprosy (eg. T cell responses). I completed a PhD investigating the generation of innate immune responses to self-RNAs associated with lupus autoantigens, and have completed two postdoctoral fellowships. My first fellowship examined the importance of myeloid cell development and type I interferon responses in murine sepsis. My second fellowship studied the contribution of type I interferon to IL-10 production in leprosy. Through this proposal, I will develop new molecular techniques, including high throughput RNA sequencing with the computational analytical skills required to understand transcriptional regulation, as well as confocal microscopy. I will also expand my clinical translational skills, by performing experiments involving skin from healthy controls and leprosy patients, by regular meetings with clinicians and coursework in translational research. These new techniques and skills can be applied to virtually any skin disorder. This critical mentored phase of training will be performed under the mentorship of Robert Modlin, MD, a pioneer in translational cutaneous immunology research, who has trained a number of independent investigators. Dr. Modlin will help to guide me through the necessary steps to becoming an independent researcher. The research proposed herein will improve the understanding of how novel myeloid cells develop and contribute to cutaneous immune tolerance to infection. This program will allow me to develop all of the skills and tools needed to embark upon this research project as well as future research projects, with the guidance of a successful mentor capable of assisting me into becoming a successful independent investigator.
Leprosy is a human skin disease caused by the bacteria Mycobacterium leprae (mLEP) that presents with a range of clinical systems that correlate with the immune response to the bacteria making it a great model to study skin immunity; in both the progressive and self-limited form of the disease, myeloid cells of similar phenotypes develop. In this proposal, we will investigate factors, including interleukin-34 that render these immune cells unable to appropriately combat mLEP in the progressive form of the disease while these same cells can effectively control the infection in the self-limited form. Studying mechanisms leading to differences in the two forms of leprosy has the potential to lead to novel therapies for cutaneous inflammatory diseases.
