Dorzolamide suppresses PKCδ -TIRAP-p38 MAPK signaling axis to dampen the inflammatory response.

Sepsis is a syndrome due to microbial infection causing impaired multiorgan function. Its underlying cause is immune dysfunction and macrophages play an essential role. TIRAP interaction with PKCδ in macrophage was studied, revealing downstream signaling by Western blot and quantitative reverse transcriptase PCR.

Ready, STAT3, Go! Bacteria in the race for M2 macrophage polarisation.

Despite macrophages representing professional immune cells that are integral to the host defences against microbial threats, several intracellular bacteria not only infect, but survive, replicate and often persist in these cells. This is perhaps possible because not all macrophages are the same. Instead, macrophages are loosely divided into two classes: the M1 'classically activated' pro-inflammatory subset and the M2 'alternatively activated' cells that are generally anti-inflammatory and infection-permissive.

persisters undermine host immune defenses during antibiotic treatment.

Many bacterial infections are hard to treat and tend to relapse, possibly due to the presence of antibiotic-tolerant persisters. In vitro, persister cells appear to be dormant. After uptake of species by macrophages, nongrowing persisters also occur, but their physiological state is poorly understood.

Growth inhibition of cytosolic Salmonella by caspase-1 and caspase-11 precedes host cell death.

Sensing bacterial products in the cytosol of mammalian cells by NOD-like receptors leads to the activation of caspase-1 inflammasomes, and the production of the pro-inflammatory cytokines interleukin (IL)-18 and IL-1β. In addition, mouse caspase-11 (represented in humans by its orthologs, caspase-4 and caspase-5) detects cytosolic bacterial LPS directly. Activation of caspase-1 and caspase-11 initiates pyroptotic host cell death that releases potentially harmful bacteria from the nutrient-rich host cell cytosol into the extracellular environment.

TBK1 directs WIPI2 against Salmonella.

Defense of the mammalian cell cytosol against Salmonella invasion is reliant upon capture of the infiltrating bacteria by macroautophagy (hereafter autophagy), a process controlled by the kinase TBK1. In our recent study we showed that recruitment of TBK1 activity to Salmonella stabilizes the key autophagy regulator WIPI2 on those bacteria, a novel and essential function for TBK1 in the control of the early steps of antibacterial autophagy. Substantial redundancy exists in the precise recruitment mechanism for TBK1 because engagement with any of several Salmonella-associated 'eat-me' signals, including host-derived glycans, and K48- and K63-linked ubiquitin chains, suffices to recruit TBK1 functionality.

Recruitment of TBK1 to cytosol-invading Salmonella induces WIPI2-dependent antibacterial autophagy.

Mammalian cells deploy autophagy to defend their cytosol against bacterial invaders. Anti-bacterial autophagy relies on the core autophagy machinery, cargo receptors, and "eat-me" signals such as galectin-8 and ubiquitin that label bacteria as autophagy cargo. Anti-bacterial autophagy also requires the kinase TBK1, whose role in autophagy has remained enigmatic.

Cytosolic Replication of Group A Streptococcus in Human Macrophages.

Unlabelled: As key components of innate immune defense, macrophages are essential in controlling bacterial pathogens, including group A Streptococcus(GAS). Despite this, only a limited number of studies have analyzed the recovery of GAS from within human neutrophils and macrophages. Here, we determined the intracellular fate of GAS in human macrophages by using several quantitative approaches.

Cleavage by signal peptide peptidase is required for the degradation of selected tail-anchored proteins.

The regulated turnover of endoplasmic reticulum (ER)-resident membrane proteins requires their extraction from the membrane lipid bilayer and subsequent proteasome-mediated degradation. Cleavage within the transmembrane domain provides an attractive mechanism to facilitate protein dislocation but has never been shown for endogenous substrates. To determine whether intramembrane proteolysis, specifically cleavage by the intramembrane-cleaving aspartyl protease signal peptide peptidase (SPP), is involved in this pathway, we generated an SPP-specific somatic cell knockout.

Salmonella inhibits retrograde trafficking of mannose-6-phosphate receptors and lysosome function.

Salmonella enterica is an intracellular bacterial pathogen that replicates within membrane-bound vacuoles through the action of effector proteins translocated into host cells. Salmonella vacuoles have characteristics of lysosomes but are reduced in hydrolytic enzymes transported by mannose-6-phosphate receptors (MPRs). We found that the effector SifA subverted Rab9-dependent retrograde trafficking of MPRs, thereby attenuating lysosome function.

Galectin 8 targets damaged vesicles for autophagy to defend cells against bacterial invasion.

Autophagy defends the mammalian cytosol against bacterial infection. Efficient pathogen engulfment is mediated by cargo-selecting autophagy adaptors that rely on unidentified pattern-recognition or danger receptors to label invading pathogens as autophagy cargo, typically by polyubiquitin coating. Here we show in human cells that galectin 8 (also known as LGALS8), a cytosolic lectin, is a danger receptor that restricts Salmonella proliferation.

The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria.

Cell-autonomous innate immune responses against bacteria attempting to colonize the cytosol of mammalian cells are incompletely understood. Polyubiquitylated proteins can accumulate on the surface of such bacteria, and bacterial growth is restricted by Tank-binding kinase (TBK1). Here we show that NDP52, not previously known to contribute to innate immunity, recognizes ubiquitin-coated Salmonella enterica in human cells and, by binding the adaptor proteins Nap1 and Sintbad, recruits TBK1.