Dissecting antimicrobial logic: species-specific strategies for intracellular pathogen defense

Control of intracellular pathogens is a critical element of host defense. Defining the molecular mechanisms by which the host restricts or eliminates these pathogens may inform the development of novel immunotherapeutics and antimicrobial strategies, particularly in the face of rising antibiotic resistance. In parallel, understanding how pathogens subvert these immune responses may yield new approaches to disrupt virulence rather than viability. Yet, the precise mechanisms by which primates-and especially humans-achieve intracellular pathogen control remain poorly understood. Five years ago, I reflected on the complexity of interferon-induced control of Legionella pneumophila in a murine infection model. In this review, I revisit those questions considering emerging evidence, highlighting how cross-species comparisons and context-specific immune programs are reshaping our understanding of host-pathogen interactions and the logic of antimicrobial defense.