PANoptosis in Bacterial Infections: A Double-Edged Sword Balancing Host Immunity and Pathogenesis

Abstract

PANoptosis is a newly identified programmed cell death pathway that integrates characteristics of apoptosis, pyroptosis, and necroptosis. It plays a dual role in the host immune response to bacterial infections. On one hand, PANoptosis acts as a protective mechanism by inducing the death of infected cells to eliminate pathogens and releasing pro-inflammatory cytokines to amplify the immune response. On the other hand, bacteria can exploit PANoptosis to evade host immune defenses. This dual nature underscores the potential of PANoptosis as a target for developing novel therapies against bacterial infections. This review summarizes the molecular mechanisms of PANoptosis, along with the crosstalk and integration of different cell death pathways in response to various bacterial pathogens. We also discuss the dual roles of PANoptosis in bacterial infectious diseases, including sepsis, pulmonary infections, and intestinal infections. Elucidating the molecular mechanisms underlying PANoptosis and how bacteria manipulate this pathway offers critical insights into host-pathogen interactions. These insights provide a foundation for designing targeted antibacterial strategies, modulating inflammation, and advancing precision medicine to improve clinical outcomes.

Keywords: PANoptosis; bacterial infection; bacterial infectious disease; host–pathogen interactions; programmed cell death.

Figure 1

Cellular and biochemical features of pyroptosis, apoptosis, necroptosis, and PANoptosis. This diagram summarizes the key morphological, organelle, DNA, and biochemical changes in pyroptosis, apoptosis, necroptosis, and PANoptosis. Each cell death pathway is characterized by distinct alterations in cell shape, organelle integrity, DNA fragmentation, and the activation of specific biochemical markers. PANoptosis integrates features from all three pathways, exhibiting a variable combination of these changes depending on the specific induction conditions and the interplay of the involved molecular signals.

Figure 2

An overview of PANoptosis molecular mechanisms. The diagram illustrates the progression of PANoptosis, starting with various stimuli, including PAMPs, DAMPs, bacteria, viruses, and LPS. These triggers are recognized by specific sensors, such as NLRP3, ZBP1, AIM2, NLRP12, NLRC5, and RIPK1, leading to the assembly of distinct PANoptosomes, including the NLRP12-PANoptosome, ZBP1-PANoptosome, AIM2-PANoptosome, and RIPK1-PANoptosome. Each PANoptosome complex integrates key components such as ASC, caspase-1, caspase-8, RIPK1, and RIPK3, facilitating the activation of pyroptosis, apoptosis, and necroptosis. The convergence of these pathways culminates in the unified cell death process known as PANoptosis, which serves as a central mediator of regulated inflammatory cell death.

Figure 3

Initiation of PANoptosis during bacterial pathogen invasion. This schematic highlights the molecular mechanisms by which bacterial components trigger PANoptosis. Pathogen-associated molecules, such as LPS, flagellin, T3SS effectors, Z-DNA, and PFTs, activate host sensors including TLR4, TLR5, NAIP/NLRC4, AIM2, ZBP1, and NLRP3. These sensor proteins recruit key downstream adaptors and effectors such as caspase-1, caspase-8, RIPK1, and RIPK3, facilitating the induction of pyroptosis, apoptosis, and necroptosis. The convergence of these distinct cell death pathways results in the execution of PANoptosis, an integrated inflammatory cell death program essential for the host response to bacterial infections.