Innate immunity constitutes the first line of defense against infection. In mammals, it has traditionally been understood as a system that detects conserved molecular features of microbes and activates inflammatory responses. However, pathogens do not merely present recognizable molecules — they actively manipulate host cells in order to replicate and evade defense.
In plants and bacteria, immune systems have evolved mechanisms that detect such hostile activities by monitoring the integrity of vulnerable host processes. Whether similar activity-based surveillance mechanisms operate broadly in mammals has remained largely unexplored.
This project investigates the hypothesis that mammalian immune systems can sense pathogen-induced perturbations of critical host pathways — a principle referred to as effector-triggered immunity. The MORC3-MRE pathway serves as a model system to explore this concept. This pathway performs a dual function: it contributes to antimicrobial defense while simultaneously restraining excessive inflammatory activation under steady-state conditions. Because of its antimicrobial activity, it is frequently targeted by pathogens seeking to overcome host restriction. Crucially, when pathogens interfere with this pathway, they disable its anti-inflammatory function, thereby inadvertently triggering a potent inflammatory response. In this way, pathogen attack on a host defense mechanism is converted into an alarm signal that activates immunity.
The overall objective of the project is to define how such activity-based sensing operates at the molecular level, determine its relevance in living organisms, and assess whether this principle represents a general and previously underappreciated dimension of mammalian innate immunity. By expanding the conceptual framework of immune recognition, the project addresses fundamental questions in infection biology, inflammation, and cancer immunity.
