Bacterial pore-forming toxins: mechanisms and implications for host immunity

Pore-forming toxins (PFTs) are an ancient class of protein toxins specialized in membrane disruption and aiding in the pathogenicity of several different pathogens. These versatile toxins are multifunctional virulence factors that manipulate host signaling and immune responses and modulate the cellular fate. The pore-formation mechanism of PFTs proceeds in a stepwise manner, initiated by receptor binding, followed by oligomerization and membrane insertion. Beyond membrane disruption, PFTs trigger a cascade of immune signaling, inflammasome activation, and diverse cell death pathways such as apoptosis, pyroptosis, necroptosis, and ferroptosis. Additionally, there is increasing evidence suggesting that many PFTs undergo endocytosis and traffic to organelles such as mitochondria, lysosomes, the endoplasmic reticulum, and Golgi, where they modulate intracellular functions. Interestingly, some functions of PFTs are also independent of pore formation, highlighting the functional versatility of PFTs. Technological advancements ranging from cryo-electron microscopy and high-speed AFM to AI-guided modeling, single-molecule imaging, and membrane-mimetic systems have been central in providing structural and mechanistic insights into PFT biology. There has been the discovery of new toxins as well as new toxin families; many of them are antibacterial PFTs deployed in the microbial competition. The growing insights into PFT biology have opened new avenues for therapeutic innovation, both by developing strategies to neutralize PFT-mediated pathogenesis and by engineering PFTs for vaccine development and cancer treatment. In this review, we provide a comprehensive overview of PFT biology within the broader context of host-pathogen interactions and highlight the key structural, mechanistic, and cellular questions that remain unresolved.