Lipopolysaccharide Potentiates Insulin-Driven Hypoglycemic Shock.

Critically ill patients typically present with hyperglycemia. Treatment with conventional insulin therapy (targeting 144-180 mg/dl) improves patient survival; however, intensive insulin therapy (IIT) targeting normal blood glucose levels (81-108 mg/dl) increases the incidence of moderate and severe hypoglycemia, and increases mortality. Septic patients are especially prone to IIT-induced hypoglycemia, but the mechanism remains unknown.

WildCARDs: inflammatory caspases directly detect LPS.

Inflammasomes are sensors that serve as activation platforms for caspase-1 - a mechanism that set the prevailing paradigm for inflammatory caspase activation. A recent Nature paper by Shi et al. upends this paradigm by describing an unprecedented model for caspase activation whereby caspase-4, -5, and -11 directly bind their agonist, cytosolic LPS, triggering auto-activation and subsequent pyroptotic cell death.

Guanylate binding proteins promote caspase-11-dependent pyroptosis in response to cytoplasmic LPS.

IFN receptor signaling induces cell-autonomous immunity to infections with intracellular bacterial pathogens. Here, we demonstrate that IFN-inducible guanylate binding protein (Gbp) proteins stimulate caspase-11-dependent, cell-autonomous immunity in response to cytoplasmic LPS. Caspase-11-dependent pyroptosis is triggered in IFN-activated macrophages infected with the Gram-negative bacterial pathogen Legionella pneumophila.

Detection of cytosolic bacteria by inflammatory caspases.

The sanctity of the cytosolic compartment is rigorously maintained by a number of innate immune mechanisms. Inflammasomes detect signatures of microbial infection and trigger caspase-1 or caspase-11 activation, culminating in cytokine secretion and obliteration of the replicative niche via pyroptosis. Recent studies have examined inflammatory caspase responses to cytosolic bacteria, including Burkholderia, Shigella, Listeria, Francisella, and Mycobacterium species.

Cytoplasmic LPS activates caspase-11: implications in TLR4-independent endotoxic shock.

Inflammatory caspases, such as caspase-1 and -11, mediate innate immune detection of pathogens. Caspase-11 induces pyroptosis, a form of programmed cell death, and specifically defends against bacterial pathogens that invade the cytosol. During endotoxemia, however, excessive caspase-11 activation causes shock.

Burkholderia BcpA mediates biofilm formation independently of interbacterial contact-dependent growth inhibition.

Contact-dependent growth inhibition (CDI) is a phenomenon in which Gram-negative bacteria use the toxic C-terminus of a large surface-exposed exoprotein to inhibit the growth of susceptible bacteria upon cell-cell contact. Little is known about when and where bacteria express the genes encoding CDI system proteins and how these systems contribute to the survival of bacteria in their natural niche. Here we establish that, in addition to mediating interbacterial competition, the Burkholderia thailandensis CDI system exoprotein BcpA is required for biofilm development.

Caspase-11 protects against bacteria that escape the vacuole.

Caspases are either apoptotic or inflammatory. Among inflammatory caspases, caspase-1 and -11 trigger pyroptosis, a form of programmed cell death. Whereas both can be detrimental in inflammatory disease, only caspase-1 has an established protective role during infection.

Membrane damage during Listeria monocytogenes infection triggers a caspase-7 dependent cytoprotective response.

The cysteine protease caspase-7 has an established role in the execution of apoptotic cell death, but recent findings also suggest involvement of caspase-7 during the host response to microbial infection. Caspase-7 can be cleaved by the inflammatory caspase, caspase-1, and has been implicated in processing and activation of microbial virulence factors. Thus, caspase-7 function during microbial infection may be complex, and its role in infection and immunity has yet to be fully elucidated.

A complex lipoate utilization pathway in Listeria monocytogenes.

Although a complete pathway of lipoic acid metabolism has been established in Escherichia coli, lipoic acid metabolism in other bacteria is more complex and incompletely understood. Listeria monocytogenes has been shown to utilize two lipoate-protein ligases for lipoic acid scavenging, whereas only one of the ligases can function in utilization of host-derived lipoic acid-modified peptides. We report that lipoic acid scavenging requires not only ligation of lipoic acid but also a lipoyl relay pathway in which an amidotransferase transfers lipoyl groups to the enzyme complexes that require the cofactor for activity.