Functional Microbiomics, Inflammation and Pathogenicity

University Of Louisville, Louisville KY

Investigators

Linked publications & trials

Abstract

ABSTRACT Inflammation is essential to protect us against infection. To contain the infection, leukocytes must rapidly sense pathogens and recruit additional immune cells to infected tissues. However, once the infection is contained, inflammation must also be quickly resolved to avoid collateral tissue damage caused by activated immune cells. Therefore, initiation and resolution of inflammation are tightly regulated processes. Lipid mediators of inflammation are essential for both the initiation and resolution of inflammation. Leukotriene B4 (LTB4) is a pro- inflammatory lipid rapidly produced in response to infection. LTB4 binding to the BLT1 receptor recruits and activates resident and circulating leukocytes to sites of infection, and LTB4/BLT1 signaling is required to effectively control infections. However, persistent LTB4 synthesis can also lead to chronic inflammation and tissue damage associated with inflammatory diseases such as gout, asthma, and silicosis. Because dysregulation of LTB4 impacts both acute and chronic inflammation, defining the specific contribution of this potent chemoattractant to the regulation of inflammation is essential to understanding the molecular mechanisms of inflammatory initiation and resolution. We have demonstrated that dysregulation of LTB4-mediated inflammation occurs during both silica-induced sterile inflammation (i.e., persistent LTB4 production) and Yersinia pestis infection (i.e., inhibited LTB4 production). While we have established a role for this signaling pathway in both diseases, the precise nature of this dysregulation and its impact on inflammatory cell programming remains a critical gap in our knowledge pertaining to LTB4 regulation of inflammatory responses. Therefore, the goal of this project is to use the Core Resource Centers at the University of Louisville's COBREs and the Kentucky INBRE to define the temporal and spatial regulation of inflammation during LTB4 dysregulation induced by silica inhalation or Y. pestis infection. We will achieve this through the application of cutting-edge technologies including single cell RNA sequencing and imaging mass cytometry. Defining these mechanisms of regulation is key to understanding how inflammation is properly controlled and can reveal potential therapeutic interventions to better treat infection and diseases resulting from chronic inflammation.