Mutations in STAT3 underlie sporadic and dominant forms of the hyper-IgE syndrome, an immunodeficiency syndrome involving increased innate immune response, recurrent infections, and complex somatic features.

Infections caused by drug-resistant bacteria are a major problem worldwide. Carbapenem-resistant Klebsiella pneumoniae, most notably isolates classified as multilocus sequence type (ST) 258, have emerged as an important cause of hospital deaths. ST258 isolates are predominantly multidrug resistant, and therefore infections caused by them are difficult to treat. It is not known why the ST258 lineage is the most prevalent cause of multidrug-resistant K. pneumoniae infections in the United States and other countries. Here we tested the hypothesis that carbapenem-resistant ST258 K. pneumoniae is a single genetic clone that has disseminated worldwide. We sequenced to closure the genomes of two ST258 clinical isolates and used these genomes as references for comparative genome sequencing of 83 additional clinical isolates recovered from patients at diverse geographic locations worldwide. Phylogenetic analysis of the SNPs in the core genome of these isolates revealed that ST258 K. pneumoniae organisms are two distinct genetic clades. This unexpected finding disproves the single-clone hypothesis. Notably, genetic differentiation between the two clades results from an ∼215-kb region of divergence that includes genes involved in capsule polysaccharide biosynthesis. The region of divergence appears to be a hotspot for DNA recombination events, and we suggest that this region has contributed to the success of ST258 K. pneumoniae. Our findings will accelerate research on novel diagnostic, therapeutic, and vaccine strategies designed to prevent and/or treat infections caused by multidrug resistant K. pneumoniae.antibiotic resistance | carbapenemase | Enterobacteriaceae | plasmid

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Phagocytes are a critical component of the innate immune response in humans and eliminate invading microorganisms through a process known as phagocytosis. Two distinct receptor-linked phagocytic pathways, one with Ab receptors (FcRs; FcR, Fc receptor) and the other complement receptors (CRs), mediate binding and ingestion of pathogens by human polymorphonuclear leukocytes (PMNs). Although progress has been made toward defining complex signal transduction processes that underlie phagocytosis in each pathway, very little is known about gene regulation during or after phagocytosis. Therefore, we used human oligonucleotide microarrays to identify changes in expression of 12,561 genes accompanying FcR-and CR-mediated phagocytosis. Eighty-four percent of 279 differentially expressed genes were induced or repressed 90 min after ingestion of Ab-and͞or complementopsonized particles. Unexpectedly, more than 30 of these genes encoded proteins involved in at least three distinct apoptotic pathways. Ninety-four differentially expressed cell fate-related genes were identified between 180 and 360 min after phagocytosis and most were induced or repressed by PMNs activated through both receptors simultaneously. By using flow cytometry, we found that FcR-and CR-mediated phagocytosis each promoted programmed cell death in human PMNs; however, phagocytosis mediated by the combination of FcRs and CRs induced apoptosis earlier than that by either receptor alone. Our results reveal distinct patterns of receptor-mediated gene expression that define complex inducible apoptotic pathways in activated PMNs. Most significantly, we discovered that programmed cell death is regulated at the level of gene expression. Thus, we hypothesize that gene regulation in PMNs facilitates resolution of inflammatory responses.