Understanding the Immunometabolic Regulatory Networks That Allow Bacterial Pathogens to Survive Phagocytosis and Evade Killing by Neutrophils
Abstract
This basic science research project is relevant to the Fiscal Year 2018 Peer Reviewed Medical Research Program topic areas of antimicrobial resistance and emerging infectious diseases. The research aims to understand, at the molecular level, how metabolic pathways and the flow of small molecule metabolites through these cellular pathways, which are normally used by cells to generate energy or to synthesize larger cellular components, impact the immune cell functions of neutrophils. The long-term objectives are to generate a fundamental understanding of the biochemical mechanisms by which antibiotic resistant pathogens exploit the cross-talk between metabolism and innate immune cell function to survive and overcome the antimicrobial defenses of neutrophils. Neutrophil immune cells, also called polymorphonuclear leukocytes or PMNs, are the most abundant type of wide blood cells in the body and the first line of defense against invading bacteria. Human neutrophils are essential to mount effective defenses against infectious wound-colonizing bacteria. Many infectious microbes, however, including antibiotic methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Pseudomonas aeruginosa and Acinobacter baumannii, i.e., microorganisms commonly found in injury-induced and poorly or non-healing wounds, have developed efficient strategies to evade the immune surveillance of PMNs. The diversity of mechanisms used by bacterial pathogens to evade PMN killing is however incompletely understood. Exciting discoveries have shown that central metabolism not only supplies cells with cellular energy and biosynthetic precursors, but is also a critical mediator of immune cell function. Despite these interesting findings, very little is known about the broad influence of metabolism on PMNs. Most of the studies have focused on other types of immune cells including macrophages and T cells. This research is one of the first to undertake a comprehensive study of the immunometabolic properties (i.e., the concept that intracellular metabolic pathways in immune cells alter their functions) of human neutrophils, and to initiate experiments aimed at understanding, at the cellular level, how the immunometabolic regulatory networks of PMNs impact their ability to eradicate antibiotic resistant host pathogens. The current project is founded on the hypothesis that the metabolic landscapes of PMNs (i.e., metabolomes) are diagnostic of their cellular and functional status. Two research objectives are proposed to demonstrate ?proof of principles? regarding the significance of metabolism in modulating PMN immune responses. The research will employ state-of-the-art analytical technologies to identify and quantify a broad spectrum of small molecule metabolites. The metabolite information will be integrated with gene expression profiles and PMN activity assays to create a global map of cellular (genes, proteins, metabolites) networks regulating the transition of PMNs from inactive resting state to an activated state, whereby PMNs respond to ingestion of UV-killed, metabolically inactive, bacteria or human serum-coated latex beads (no bacteria) by producing antimicrobial reactive oxygen species (ROS) and inflammatory molecules. These studies will lay the foundations for future, larger-scale experiments aimed at identifying the molecular processes by which infectious (live) bacterial pathogens such as S. aureus reprogram the metabolism of neutrophils to promote pathogen survival and immune cell defense evasion. Innovation: The impact and role of central metabolism on the antimicrobial functions of neutrophils are not well understood. The hypothesis that bacterial pathogens exploit the metabolism of neutrophils to avoid destruction by PMNs presents a creative angle that warrants further fundamental, basic research studies. Results from this project may uncover mechanistic paradigm shifts regarding the processes by which metabolit
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 05, 2019
- Source ID
- W81XWH1910001
Entities
People
- Valerie Copie
Organizations
- Montana State University
- United States Army