Cellular Reactive Oxygen Species Inhibit MPYS Induction of IFNβ

Many inflammatory diseases, as well as infections, are accompanied by elevation in cellular levels of Reactive Oxygen Species (ROS). Here we report that MPYS, a.k.a. STING, which was recently shown to mediate activation of IFNβ expression during infection, is a ROS sensor. ROS induce intermolecular disulfide bonds formation in MPYS homodimer and inhibit MPYS IFNβ stimulatory activity. Cys-64, -148, -292, -309 and the potential C88xxC91 redox motif in MPYS are indispensable for IFNβ stimulation and IRF3 activation. Thus, our results identify a novel mechanism for ROS regulation of IFNβ stimulation

HSV Infection Induces Production of ROS, which Potentiate Signaling from Pattern Recognition Receptors: Role for S-glutathionylation of TRAF3 and 6

The innate immune response constitutes the first line of defense against infections. Pattern recognition receptors recognize pathogen structures and trigger intracellular signaling pathways leading to cytokine and chemokine expression. Reactive oxygen species (ROS) are emerging as an important regulator of some of these pathways. ROS directly interact with signaling components or induce other post-translational modifications such as S-glutathionylation, thereby altering target function. Applying live microscopy, we have demonstrated that herpes simplex virus (HSV) infection induces early production of ROS that are required for the activation of NF-κB and IRF-3 pathways and the production of type I IFNs and ISGs. All the known receptors involved in the recognition of HSV were shown to be dependent on the cellular redox levels for successful signaling. In addition, we provide biochemical evidence suggesting S-glutathionylation of TRAF family proteins to be important. In particular, by performing mutational studies we show that S-glutathionylation of a conserved cysteine residue of TRAF3 and TRAF6 is important for ROS-dependent activation of innate immune pathways. In conclusion, these findings demonstrate that ROS are essential for effective activation of signaling pathways leading to a successful innate immune response against HSV infection

Comparative evaluation of the inhibitory activities of the novel penicillanic acid sulfone Ro 48-1220 against beta-lactamases that belong to groups 1, 2b, and 2be

The inhibitory activity of the penicillanic acid sulfone Ro 48-1220 against group 1, 2b, and 2be beta-lactamases was evaluated, Ro 48-1220 inhibited TEM and SHV enzymes as effectively as clavulanate and tazobactam. It also inhibited group 1 beta-lactamases at lower concentrations than tazobactam. Ro 48-1220, at a concentration of 4 mu g/ml, protected ceftriaxone and ceftazidime against strains producing group 1 and 2be beta-lactamases

In vitro activity of cefetamet against enterobacteria expressing an SHV-5-type beta-lactamase

The in vitro activity of cefetamet against Escherichia coli, Klebsiella pneumoniae and Serratia marcescens strains expressing an SHV-5-type β-lactamase was evaluated. Most of the examined strains were susceptible to the antibiotic. Cefetamet was found to be considerably more active than ceftazidime and aztreonam. Its activity was comparable to that of cefotaxime. Cefetamet MIC values were related to the quantity of the enzyme expressed. The SHV-5-type enzyme hydrolysed cefetamet with an efficiency (Vmax/Km) similar to that of ceftazidime. © 1996 S. Karger AG, Basel