SUMMARY Virulence of the emerging Community-Associated Methicillin-Resistant Staphylococcus aureus (CA-MRSA) and other highly pathogenic S. aureus depends on the recently discovered phenol-soluble modulin (PSM) peptide toxins, which combine the capacities to attract and lyse neutrophils. The molecular basis of PSM-stimulated neutrophil recruitment has remained unknown. We demonstrate that the human formyl peptide receptor 2 (FPR2/ALX), which has previously been implicated in control of endogenous inflammatory processes, senses PSMs at nanomolar concentrations and initiates proinflammatory neutrophil responses to CA-MRSA. Specific blocking of FPR2/ALX or deletion of PSM genes in CA-MRSA led to severely diminished capacities of neutrophils to detect CA-MRSA. A specific inhibitor of FPR2/ALX and its functional mouse counterpart blocked PSM-mediated leukocyte infiltration in vivo in a mouse model. Thus, the innate immune system uses a new FPR2/ALX-dependent mechanism to sense bacterial peptide toxins and detect highly virulent bacterial pathogens. FPR2/ALX represents an attractive target for new anti-infective or anti-inflammatory strategies.

The complete genome sequences of two Sulfolobus spindle-shaped viruses (SSVs) from acidic hot springs in Kamchatka (Russia) and Yellowstone National Park (United States) have been determined. These nonlytic temperate viruses were isolated from hyperthermophilic Sulfolobus hosts, and both viruses share the spindleshaped morphology characteristic of the Fuselloviridae family. These two genomes, in combination with the previously determined SSV1 genome from Japan and the SSV2 genome from Iceland, have allowed us to carry out a phylogenetic comparison of these geographically distributed hyperthermal viruses. Each virus contains a circular double-stranded DNA genome of ϳ15 kbp with approximately 34 open reading frames (ORFs). These Fusellovirus ORFs show little or no similarity to genes in the public databases. In contrast, 18 ORFs are common to all four isolates and may represent the minimal gene set defining this viral group. In general, ORFs on one half of the genome are colinear and highly conserved, while ORFs on the other half are not. One shared ORF among all four genomes is an integrase of the tyrosine recombinase family. All four viral genomes integrate into their host tRNA genes. The specific tRNA gene used for integration varies, and one genome integrates into multiple loci. Several unique ORFs are found in the genome of each isolate.

Abstract. Transforming growth factor-ß (TGF-ß) is abundantly expressed in malignant gliomas and is crucial for the tumor micromilieu. TGF-ß not only enhances migration and invasion of glioma cells but also inhibits an effective anti-glioma immune response. TGF-ß mediates its biologic effects through interactions with TGF-ß receptors (TßR)-I to -III. Binding of TGF-ß leads to the activation of an intracellular signaling cascade and subsequent phosphorylation of Sma and MADrelated proteins (SMAD). Soluble TGF-ß receptors (TßRs) abrogate the TGF-ß effect by competing for the binding of the ligand to its receptor. Here we used adenoviral gene transfer to express TßR-IIs and -IIIs in human glioma cell lines. TßR-IIs reduced SMAD2 phosphorylation and TGF-ß-dependent reporter activity. Furthermore, it enhanced glioma cell lysis by natural killer cells. TßR-IIIs alone were inactive in these assays, but enhanced the effects of TßR-IIs. Transduction of LN-308 cells with TßRs markedly delayed growth of intracerebral xenografts in nude mice in vivo. These data commend TßRs for possible experimental therapy of gliomas.

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