Enhancing immunity by protecting lymphatic muscle cells from MRSA-Induced dysfunction

Recent data suggest that skin and soft tissue infections may lead to the onset of lymphedema, a debilitating and incurable disease of lymphatic vessel insufficiency that annually affects 10 million Americans. However, mechanisms underlying infection-driven impairment of lymphatic vessel function are not completely understood.

The overall goal of the project is to elucidate the mechanisms responsible for the sustained impairment of lymphatic vessel contractility and lymph flow. By identifying and understanding these mechanisms, we aim to develop targeted interventions that can restore fluid balance and boost immune function to aid in the clearance

of primary and recurrent bacterial infections. Lymphatic muscle cells (LMCs) facilitate autonomous lymphatic vessel contraction, but our recent studies and work from others demonstrate pathological impairment of LMC function. In Aim 1, we will use lineage tracing to evaluate the regulation of LMCs following bacterial infection. Further, we will use single-cell RNA sequencing to

investigate whether bacteria alter the transcriptional and functional signatures of LMCs. We will also perform calcium imaging studies to test whether LMCs exposed to bacteria or bacterial virulence factors exhibit impaired contractility, and whether their function can be improved by existing pharmacological agents. In Aim 2, we will

test whether pharmacological inhibitors of bacterial virulence preserve lymphatic contractility, causing the expansion of bacteria-specific T cells that protect against subsequent infections. Through the Boston University Education, Advising and Mentoring in STEM-Medicine (BEAMS) program, we propose to continue and expand a summer program for historically underrepresented minorities from a Boston

public high school. This program will leverage the resources, infrastructure, and expertise of Boston University faculty members (Dr. Kelley and Dr. Dominguez) who currently lead initiatives for underrepresented high school and college students. During their first summer in the program, participants will receive a didactic experience

focused on enhancing their understanding of scientific concepts through comprehensive lectures, problem- based learning, and laboratory practicums. During their second summer, students will engage in immersive research projects within Boston University laboratories, under the guidance of investigators who have shown a

strong dedication to mentoring. These experiences are designed to foster scientific literacy and readiness for college-level science courses. Furthermore, a structured mentoring program is intended to increase the students’ likelihood of attending college and pursuing careers in biomedical research.