Recent advances in ZBP1-derived PANoptosis against viral infections.

Innate immunity is an important first line of defense against pathogens, including viruses. These pathogen- and damage-associated molecular patterns (PAMPs and DAMPs, respectively), resulting in the induction of inflammatory cell death, are detected by specific innate immune sensors. Recently, Z-DNA binding protein 1 (ZBP1), also called the DNA-dependent activator of IFN regulatory factor (DAI) or DLM1, is reported to regulate inflammatory cell death as a central mediator during viral infection. ZBP1 is an interferon (IFN)-inducible gene that contains two Z-form nucleic acid-binding domains (Zα1 and Zα2) in the N-terminus and two receptor-interacting protein homotypic interaction motifs (RHIM1 and RHIM2) in the middle, which interact with other proteins with the RHIM domain. By sensing the entry of viral RNA, ZBP1 induces PANoptosis, which protects host cells against viral infections, such as influenza A virus (IAV) and herpes simplex virus (HSV1). However, some viruses, particularly coronaviruses (CoVs), induce PANoptosis to hyperactivate the immune system, leading to cytokine storm, organ failure, tissue damage, and even death. In this review, we discuss the molecular mechanism of ZBP1-derived PANoptosis and pro-inflammatory cytokines that influence the double-edged sword of results in the host cell. Understanding the ZBP1-derived PANoptosis mechanism may be critical for improving therapeutic strategies.

Integrated NLRP3, AIM2, NLRC4, Pyrin inflammasome activation and assembly drive PANoptosis.

Inflammasomes are important sentinels of innate immune defense; they sense pathogens and induce the cell death of infected cells, playing key roles in inflammation, development, and cancer. Several inflammasome sensors detect and respond to specific pathogen- and damage-associated molecular patterns (PAMPs and DAMPs, respectively) by forming a multiprotein complex with the adapters ASC and caspase-1. During disease, cells are exposed to several PAMPs and DAMPs, leading to the concerted activation of multiple inflammasomes. However, the molecular mechanisms that integrate multiple inflammasome sensors to facilitate optimal host defense remain unknown. Here, we discovered that simultaneous inflammasome activation by multiple ligands triggered multiple types of programmed inflammatory cell death, and these effects could not be mimicked by treatment with a pure ligand of any single inflammasome. Furthermore, NLRP3, AIM2, NLRC4, and Pyrin were determined to be members of a large multiprotein complex, along with ASC, caspase-1, caspase-8, and RIPK3, and this complex drove PANoptosis. Furthermore, this multiprotein complex was released into the extracellular space and retained as multiple inflammasomes. Multiple extracellular inflammasome particles could induce inflammation after their engulfment by neighboring macrophages. Collectively, our findings define a previously unknown regulatory connection and molecular interaction between inflammasome sensors, which drives the assembly of a multiprotein complex that includes multiple inflammasome sensors and cell death regulators. The discovery of critical interactions among NLRP3, AIM2, NLRC4, and Pyrin represents a new paradigm in understanding the functions of these molecules in innate immunity and inflammasome biology as well as identifying new therapeutic targets for NLRP3-, AIM2-, NLRC4- and Pyrin-mediated diseases.

The risk of active tuberculosis among individuals living in tuberculosis-affected households in the Republic of Korea, 2015.

BACKGROUND: In the Republic of Korea (ROK), compared to other high-income countries, tuberculosis (TB) prevalence is relatively high. Active TB and latent TB infection (LTBI) surveillance of individuals living in TB-affected households has been conducted for several years. Although active case finding is an important strategy in low-prevalence, high-income countries, its effectiveness in a high prevalence setting is unclear. This study evaluated the risk of TB in household contact by calculating the incidence of TB among household contacts and comparing it with the general population of the ROK. METHODS: A retrospective cohort study, including 36,133 household-contacts of 17,958 TB patients reported in 2015, was conducted. The data was extracted from the Korean National TB Surveillance System (web-based TB cases notification system, KNTSS). The Cox proportional hazard regression model was used to evaluate risk factors for incidence of TB. A P-value < .05 was considered statistically significant. RESULTS: In this study, 319 (0.9%) of 36,133 household-contacts were reported as having TB within 1 year, which is a higher rate than the rate for the general population in the ROK. The rate of TB reported for contacts that had completed LTBI treatment (0.6%) was lower than for the LTBI group without treatment (4.6%). In multivariate analysis, age older than 65 (p < .001), being a spouse of a TB patient (p = .007), and LTBI without treatment (p = .013) were each a risk factor for TB incidence among contacts. Younger age (p < .001), presence of a cough (p < .001), testing positive for acid-fast bacilli (AFB; p < .001), and cavity on radiograph (p < .001) of the index patient were also statistically significant risk factors. CONCLUSIONS: Individuals living in TB-affected households are at high risk of developing TB in the ROK and active case finding among them is a strategy effective in the early detection and prevention of TB.