Prostaglandin E2 (PGE2) is an important lipid mediator in inflammatory and immune responses during acute and chronic infections. Upon stimulation by various proinflammatory stimuli such as lipopolysaccharide (LPS), interleukin (IL)-1β, and tumor necrosis factor (TNF)-α, PGE2 synthesis is upregulated by the expression of cyclooxygenases. Biologically active PGE2 is then able to signal through four primary receptors to elicit a response. PGE2 is a critical molecule that regulates the activation, maturation, migration, and cytokine secretion of several immune cells, particularly those involved in innate immunity such as macrophages, neutrophils, natural killer cells, and dendritic cells. Both Gram-negative and Gram-positive bacteria can induce PGE2 synthesis to regulate immune responses during bacterial pathogenesis. This review will focus on PGE2 in innate immunity and how bacterial pathogens influence PGE2 production during enteric and pulmonary infections. The conserved ability of many bacterial pathogens to promote PGE2 responses during infection suggests a common signaling mechanism to deter protective pro-inflammatory immune responses. Inhibition of PGE2 production and signaling during infection may represent a therapeutic alternative to treat bacterial infections. Further study of the immunosuppressive effects of PGE2 on innate immunity will lead to a better understanding of potential therapeutic targets within the PGE2 pathway.

Background:The Pseudomonas aeruginosa cytotoxin ExoU localizes to the plasma membrane in eukaryotic cells. Results: ExoU and related proteins utilize a conserved four-helical bundle to bind the lipid phosphatidylinositol 4,5-bisphosphate for localization. Conclusion:The membrane localization domain of ExoU represents a novel phosphoinositide binding domain. Significance: This is the first report of a four-helical bundle with specificity for phosphatidylinositol 4,5-bisphosphate.

Burkholderia pseudomallei is a Gram-negative, facultative intracellular bacillus and the etiologic agent of melioidosis, a severe disease in Southeast Asia and Northern Australia. Like other multidrug-resistant pathogens, the inherent antibiotic resistance of B. pseudomallei impedes treatment and highlights the need for alternative therapeutic strategies that can circumvent antimicrobial resistance mechanisms. In this work, we demonstrate that host prostaglandin E2 (PGE2) production plays a regulatory role in the pathogenesis of B. pseudomallei. PGE2 promotes B. pseudomallei intracellular survival within macrophages and bacterial virulence in a mouse model of pneumonic melioidosis. PGE2-mediated immunosuppression of macrophage bactericidal effector functions is associated with increased arginase 2 (Arg2) expression and decreased nitric oxide (NO) production. Treatment with a commercially-available COX-2 inhibitor suppresses the growth of B. pseudomallei in macrophages and affords significant protection against rapidly lethal pneumonic melioidosis when administered post-exposure to B. pseudomallei-infected mice. COX-2 inhibition may represent a novel immunotherapeutic strategy to control infection with B. pseudomallei and other intracellular pathogens.

Microbial competition is most often studied at the genus or species level, but interstrain competition has been less thoroughly examined. Klebsiella pneumoniae is an important pathogen in the context of hospital-acquired pneumonia, and a better understanding of strain competition in the lungs could explain why some strains of this bacterium are more frequently isolated from pneumonia patients than others. We developed a barcode-free method called "StrainSeq" to simultaneously track the abundances of 10 K. pneumoniae strains in a murine pneumonia model. We demonstrate that one strain (KPPR1) repeatedly achieved a marked numerical dominance at 20 h postinoculation during pneumonia but did not exhibit a similar level of dominance in in vitro mixed-growth experiments. The emergence of a single dominant strain was also observed with a second respiratory pathogen, Acinetobacter baumannii, indicating that the phenomenon was not unique to K. pneumoniae. When KPPR1 was removed from the inoculum, a second strain emerged to achieve high numbers in the lungs, and when KPPR1 was introduced into the lungs 1 h after the other nine strains, it no longer exhibited a dominant phenotype. Our findings indicate that certain strains of K. pneumoniae have the ability to outcompete others in the pulmonary environment and cause severe pneumonia and that a similar phenomenon occurs with A. baumannii. In the context of the pulmonary microbiome, interstrain competitive fitness may be another factor that influences the success and spread of certain lineages of these hospital-acquired respiratory pathogens.

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