PROJECT SUMMARY This is a proposal from early-stage investigator to address the mechanistic underpinnings of host-biofilm interaction in the context of surgical implant-associated complications. It is estimated 10 million women worldwide, including 3 million Americans have breast implants. Over 7 million Americans are living with hip/knee implants. Nearly 300,000 women annually have breast implant surgery in the United States, for reasons including post-mastectomy breast reconstruction (breast cancer and prophylactic mastectomy), revision of prior augmentation/ reconstruction, cosmetic augmentation, and gender affirmation. Over 1 million total hip and total knee replacement surgeries are performed each year in the US. With an aging population, there is a demand for improved mobility and quality of life. The number of joint replacement surgeries are projected to increase considerably in the future. Total joint replacement surgery is expected to continue to be one of the most common elective surgical procedures in the coming decades. There has been increased identification of patients experiencing a constellation of symptoms related to their implants. The symptoms described include myalgias, chronic fatigue, connective-tissue disorders, and a host of other manifestations often associated with autoimmune illnesses. In case of breast implants, these constellations of immune symptoms are named Breast Implant Illness (BII). Similar symptoms have been reported in subjects with orthopedic implants. Metal/plastic implants for arthroplasty and silicone implants for breasts are made of different materials. Thus, the underlying cause of these conditions may be associated with factors other than the implant material. Bacterial biofilms are one of the leading causes of surgical implant failures, infection and revision surgeries. Despite efforts to maintain sterility during surgery, implantable medical devices can become contaminated with the opportunistic bacteria from the host microflora many of which can form biofilm. This proposal aims to investigate the role of bacterial biofilms in the implant-associated illness. Host-biofilm interactions are guided by the local micro-environmental niche of host in which the biofilm reside. Breast and hip joint replacements have a host-microenvironment rich in adipose tissue comprising lipids. The proposal aims to study lipid metabolites formed during biofilm-host interaction. We hypothesize that a lipid metabolite formed due to biofilm called (E)-10-hydroxy-8-octadecenoic acid (10-HOME) can stimulate CD4+ T cell leading to autoimmune-like syndromes. The metabolite 10- HOME is a member of oxylipin formed by biofilm acting on host oleic acid. Oxylipins are oxidized lipids formed from fatty acids by reactions involving dioxygen-dependent oxidation. Oxilipins have been reported to contribute to inflammatory response. The proposal is based on preliminary data derived from patient samples, studied extensively using in vitro and in vivo animal models to understand the mechanistic pathway of CD4+ Th1 subtype activation in presence of oxylipins derived due to host-biofilm interaction.

PROJECT NARRATIVE The proposal aims to study implant-associated immune reactions mediated via bacterial biofilms. Lipid metabolites formed due to host-biofilm interaction can act as immune-modulators. Guided by patient-derived data, this grant application investigates the mechanism of CD4+ T cell activation by biofilm derived 10-HOME.