Role of Lipid Mediators in Complex Host Cell-Microbe Interactions
During infectious inflammation, different host immune cells interact to efficiently clear invading microbes and to restore tissue function which is regulated by lipid mediators (LM). LM comprise oxygenated fatty acids, formed mainly by lipoxygenases (LOX) in complex networks via transcellular metabolism in interacting cells. While some LM members promote host defense against microbes and the return to homeostasis, leukotrienes (LTs) and prostaglandins (PG) exhibit detrimental features promoting inflammation and related diseases. The knowledge of regulation of the biosynthesis of such distinct LM and their individual roles in host cell-microbe interactions is incomplete. Moreover, favorable manipulation of the complex LM network as therapeutic approach is difficult: it requires smart intervention strategies with the connected biosynthetic enzymes in multiple interacting cells, which are not yet established.
We successfully developed a LM metabololipidomics platform that allows determining complex LM signature profiles in single and communicating phagocytes upon exposure to pathogenic bacteria. Knowledge of the formation and role of LM in communicating innate immune cells is of utmost importance for understanding the combat with microbes and offers novel therapeutic approaches against microbial infections. Thus, we will elucidate the regulation of the biosynthesis and functions of LM in host phagocyte-microbe interactions and elaborate manipulation of LM as a concept for improved intervention strategies. We hypothesize that for resolving infections within a tripartite system (A-B-C), the host exploits toxins from bacteria (A) to produce beneficial LM in competent cells (B) such as M2 macrophages which then enable phagocytes (C) such as M1 macrophages or neutrophils for host defense and return to homeostasis. Understanding the complexity of LM biosynthesis and their roles in host cell-microbe interactions allows for manipulation of LM with small molecules to promote beneficial host functions in microbial infections.
Schematic overview of project A04. In a tripartite system (A-B-C), pathogenic bacteria (A) release exotoxins that activate LM producers (B) to generate pro-inflammatory LT/PG or pro-resolving SPM that differentially impact functions of phagocytes (C) leading to deleterious or beneficial effects. Smart manipulation by drugs and natural products may help to shift from LT/PG to SPM formation to promote beneficial host functions in microbial infections. Image was created with Biorender.com.