Inducible antibacterial responses in macrophages

Abstract

Macrophages destroy bacteria and other microorganisms through phagocytosis-coupled antimicrobial responses, such as the generation of reactive oxygen species and the delivery of hydrolytic enzymes from lysosomes to the phagosome. However, many intracellular bacteria subvert these responses, escaping to other cellular compartments to survive and/or replicate. Such bacterial subversion strategies are countered by a range of additional direct antibacterial responses that are switched on by pattern-recognition receptors and/or host-derived cytokines and other factors, often through inducible gene expression and/or metabolic reprogramming. Our understanding of these inducible antibacterial defence strategies in macrophages is rapidly evolving. In this Review, we provide an overview of the broad repertoire of antibacterial responses that can be engaged in macrophages, including LC3-associated phagocytosis, metabolic reprogramming and antimicrobial metabolites, lipid droplets, guanylate-binding proteins, antimicrobial peptides, metal ion toxicity, nutrient depletion, autophagy and nitric oxide production. We also highlight key inducers, signalling pathways and transcription factors involved in driving these different antibacterial responses. Finally, we discuss how a detailed understanding of the molecular mechanisms of antibacterial responses in macrophages might be exploited for developing host-directed therapies to combat antibiotic-resistant bacterial infections. Macrophages are innate immune sentinels providing frontline defence against infection. This Review describes the inducible mechanisms used by macrophages to kill bacterial pathogens and/or inhibit their growth and outlines how this knowledge might be exploited in the design of host-directed therapies.