Transplantation of gasdermin pores by extracellular vesicles propagates pyroptosis to bystander cells.

Pyroptosis mediated by gasdermins (GSDMs) plays crucial roles in infection and inflammation. Pyroptosis triggers the release of inflammatory molecules, including damage-associated molecular patterns (DAMPs). However, the consequences of pyroptosis-especially beyond interleukin (IL)-1 cytokines and DAMPs-that govern inflammation are poorly defined.

A bacterial toxin co-opts caspase-3 to disable active gasdermin D and limit macrophage pyroptosis.

During infections, host cells are exposed to pathogen-associated molecular patterns (PAMPs) and virulence factors that stimulate multiple signaling pathways that interact additively, synergistically, or antagonistically. The net effect of such higher-order interactions is a vital determinant of the outcome of host-pathogen interactions. Here, we demonstrate one such complex interplay between bacterial exotoxin- and PAMP-induced innate immune pathways.

Role of Extracellular Vesicles in Immunity and Host Defense.

Extracellular vesicles (EVs) are membrane-bound structures released by cells and have become significant players in immune system functioning, primarily by facilitating cell-to-cell communication. Immune cells like neutrophils and dendritic cells release EVs containing bioactive molecules that modulate chemotaxis, activate immune cells, and induce inflammation. EVs also contribute to antigen presentation, lymphocyte activation, and immune tolerance.

Host extracellular vesicles confer cytosolic access to systemic LPS licensing non-canonical inflammasome sensing and pyroptosis.

Intracellular surveillance for systemic microbial components during homeostasis and infections governs host physiology and immunity. However, a long-standing question is how circulating microbial ligands become accessible to intracellular receptors. Here we show a role for host-derived extracellular vesicles (EVs) in this process; human and murine plasma-derived and cell culture-derived EVs have an intrinsic capacity to bind bacterial lipopolysaccharide (LPS).

A bacterial autotransporter impairs innate immune responses by targeting the transcription factor TFE3.

Type I interferons (IFNs) are consequential cytokines in antibacterial defense. Whether and how bacterial pathogens inhibit innate immune receptor-driven type I IFN expression remains mostly unknown. By screening a library of enterohemorrhagic Escherichia coli (EHEC) mutants, we uncovered EhaF, an uncharacterized protein, as an inhibitor of innate immune responses including IFNs.

Structural basis for GSDMB pore formation and its targeting by IpaH7.8.

Gasdermins (GSDMs) are pore-forming proteins that play critical roles in host defence through pyroptosis. Among GSDMs, GSDMB is unique owing to its distinct lipid-binding profile and a lack of consensus on its pyroptotic potential. Recently, GSDMB was shown to exhibit direct bactericidal activity through its pore-forming activity.

Shigella "Osp"pression of innate immunity.

Interferons are potent antimicrobial effectors and thus an attractive target for pathogen interference. In this issue of Cell, Alphonse et al. reveal that the Shigella effectors OspC1 and OspC3 employ a surprising mechanism to block interferon signaling and attenuate antibacterial responses, thus securing their replicative niche.

Mechanisms and Consequences of Noncanonical Inflammasome-Mediated Pyroptosis.

The noncanonical inflammasome, comprising inflammatory caspases 4, 5, or 11, monitors the cytosol for bacterial lipopolysaccharide (LPS). Intracellular LPS-elicited autoproteolysis of these inflammatory caspases leads to the cleavage of the pore-forming protein gasdermin D (GSDMD). GSDMD pore formation induces a lytic form of cell death known as pyroptosis and the release of inflammatory cytokines and DAMPs, thereby promoting inflammation.

Hierarchical cell-type-specific functions of caspase-11 in LPS shock and antibacterial host defense.

Caspase-11 sensing of intracellular lipopolysaccharide (LPS) plays critical roles during infections and sepsis. However, the key cell types that sense intracellular LPS and their contributions to the host responses at the organismal level are not completely clear. Here, we show that macrophage/monocyte-specific caspase-11 plays a dominant role in mediating the pathological manifestations of endotoxemia, including gasdermin D (GSDMD) activation, interleukin (IL)-1β, IL-18, and damage-associated molecular pattern (DAMP) release, tissue damage, and death.

Impact of Nutrient Intake on Hydration Biomarkers Following Exercise and Rehydration Using a Clustering-Based Approach.

We investigated the impact of nutrient intake on hydration biomarkers in cyclists before and after a 161 km ride, including one hour after a 650 mL water bolus consumed post-ride. To control for multicollinearity, we chose a clustering-based, machine learning statistical approach. Five hydration biomarkers (urine color, urine specific gravity, plasma osmolality, plasma copeptin, and body mass change) were configured as raw- and percent change.