Salmonella enterica subspecies 1 serovar Typhimurium is a principal cause of human enterocolitis. For unknown reasons, in mice serovar Typhimurium does not provoke intestinal inflammation but rather targets the gut-associated lymphatic tissues and causes a systemic typhoid-like infection. The lack of a suitable murine model has limited the analysis of the pathogenetic mechanisms of intestinal salmonellosis. We describe here how streptomycin-pretreated mice provide a mouse model for serovar Typhimurium colitis. Serovar Typhimurium colitis in streptomycin-pretreated mice resembles many aspects of the human infection, including epithelial ulceration, edema, induction of intercellular adhesion molecule 1, and massive infiltration of PMN/ CD18 ؉ cells. This pathology is strongly dependent on protein translocation via the serovar Typhimurium SPI1 type III secretion system. Using a lymphotoxin ␤-receptor knockout mouse strain that lacks all lymph nodes and organized gut-associated lymphatic tissues, we demonstrate that Peyer's patches and mesenteric lymph nodes are dispensable for the initiation of murine serovar Typhimurium colitis. Our results demonstrate that streptomycin-pretreated mice offer a unique infection model that allows for the first time to use mutants of both the pathogen and the host to study the molecular mechanisms of enteric salmonellosis.Salmonella spp. are gram-negative enterobacteria that cause diseases ranging from a self-limiting enterocolitis to systemic infection (typhoid fever). Salmonella enterica serovar Typhimurium evokes a common form of nonsystemic enterocolitis in humans and cattle, whereas mice are intrinsically resistant to serovar Typhimurium enterocolitis (68,81). Although resistant to intestinal salmonellosis, certain susceptible mouse strains that carry mutations in the NRAMP gene develop a disease similar to typhoid fever (30,75).After oral infection of susceptible mice, serovar Typhimurium does not replicate efficiently in the intestine but penetrates the epithelial barrier by invasion of M cells (12,41,64) or (less efficiently) by transport via CD18 ϩ /dendritic cells (67, 80) and possibly by penetration of enterocytes (72). After penetration of the epithelial barrier, Salmonella spp. colonize Peyer's patches and mesenteric lymph nodes and then spread to the liver and spleen, and the mice finally succumb to systemic infection (10,35,75,81). However, mice show few signs of the intestinal inflammation observed in cattle or humans.Due to the lack of a versatile animal model, much less is known about the mechanisms of the enteric salmonellosis (21,33,62,75,81). To overcome these limitations, the pathogenesis of enteric salmonellosis has been studied by extrapolating data from tissue culture (review by Galan [26]) or from intestinal organ culture (1) or by infection of ligated murine and rabbit ileal loops (11,12,20,41,63,64). However, it remains unclear how these results relate to enteric salmonellosis.For this reason, bovine infection models with serovar Typhimurium (and serovar D...

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These changes indicate an adaptive shift toward constitutive expression of genes required for growth under the nutritional and microaerobic conditions created by suppurative secretions in the lungs of patients with CF. In addition, these results provide important clues about the persistence strategies used by P. aeruginosa during progressive CF lung disease.

Limited therapy options due to antibiotic resistance underscore the need for optimization of current diagnostics. In some bacterial species, antimicrobial resistance can be unambiguously predicted based on their genome sequence. In this study, we sequenced the genomes and transcriptomes of 414 drug‐resistant clinical Pseudomonas aeruginosa isolates. By training machine learning classifiers on information about the presence or absence of genes, their sequence variation, and expression profiles, we generated predictive models and identified biomarkers of resistance to four commonly administered antimicrobial drugs. Using these data types alone or in combination resulted in high (0.8–0.9) or very high (> 0.9) sensitivity and predictive values. For all drugs except for ciprofloxacin, gene expression information improved diagnostic performance. Our results pave the way for the development of a molecular resistance profiling tool that reliably predicts antimicrobial susceptibility based on genomic and transcriptomic markers. The implementation of a molecular susceptibility test system in routine microbiology diagnostics holds promise to provide earlier and more detailed information on antibiotic resistance profiles of bacterial pathogens and thus could change how physicians treat bacterial infections.

Pseudomonas aeruginosa persists in patients with cystic fibrosis (CF) and drives CF lung disease progression. P. aeruginosa potently activates the innate immune system, mainly mediated through pathogen-associated molecular patterns, such as flagellin. However, the host is unable to eradicate this flagellated bacterium efficiently. The underlying immunological mechanisms are incompletely understood. Myeloid-derived suppressor cells (MDSCs) are innate immune cells generated in cancer and proinflammatory microenvironments and are capable of suppressing T cell responses. We hypothesized that P. aeruginosa induces MDSCs to escape T cell immunity. In this article, we demonstrate that granulocytic MDSCs accumulate in CF patients chronically infected with P. aeruginosa and correlate with CF lung disease activity. Flagellated P. aeruginosa culture supernatants induced the generation of MDSCs, an effect that was 1) dose-dependently mimicked by purified flagellin protein, 2) significantly reduced using flagellin-deficient P. aeruginosa bacteria, and 3) corresponded to TLR5 expression on MDSCs in vitro and in vivo. Both purified flagellin and flagellated P. aeruginosa induced an MDSC phenotype distinct from that of the previously described MDSC-inducing cytokine GM-CSF, characterized by an upregulation of the chemokine receptor CXCR4 on the surface of MDSCs. Functionally, P. aeruginosa–infected CF patient ex vivo–isolated as well as flagellin or P. aeruginosa in vitro–generated MDSCs efficiently suppressed polyclonal T cell proliferation in a dose-dependent manner and modulated Th17 responses. These studies demonstrate that flagellin induces the generation of MDSCs and suggest that P. aeruginosa uses this mechanism to undermine T cell–mediated host defense in CF and other P. aeruginosa–associated chronic lung diseases.