The intersection between host-pathogen interactions and metabolism during Vibrio cholerae infection.

Vibrio cholerae (V. cholerae), the etiological agent of cholera, uses cholera toxin (CT) to cause severe diarrheal disease. Cholera is still a significant cause of mortality worldwide with about half of all cholera cases and deaths occurring in children under five.

Modulation of Host-Microbe Metabolism by Cholera Toxin.

In order for successful fecal-oral transmission, enteric bacterial pathogens have to successfully compete with the intestinal microbiota and reach high concentrations during infection. Vibrio cholerae requires cholera toxin (CT) to cause diarrheal disease, which is thought to promote the fecal-oral transmission of the pathogen. Besides inducing diarrheal disease, the catalytic activity of CT also alters host intestinal metabolism, which promotes the growth of V.

A Potent Inhibitor of the Cystic Fibrosis Transmembrane Conductance Regulator Blocks Disease and Morbidity Due to Toxigenic .

uses cholera toxin (CT) to cause cholera, a severe diarrheal disease in humans that can lead to death within hours of the onset of symptoms. The catalytic activity of CT in target epithelial cells increases cellular levels of 3',5'-cyclic AMP (cAMP), leading to the activation of the cystic fibrosis transmembrane conductance regulator (CFTR), an apical ion channel that transports chloride out of epithelial cells, resulting in an electrolyte imbalance in the intestinal lumen and massive water loss. Here we report that when administered perorally, benzopyrimido-pyrrolo-oxazinedione, (R)-BPO-27), a potent small molecule inhibitor of CFTR, blocked disease symptoms in a mouse model for acute diarrhea caused by toxigenic .

Cholera toxin promotes pathogen acquisition of host-derived nutrients.

Vibrio cholerae is the causative agent of cholera, a potentially lethal enteric bacterial infection. Cholera toxin (CTX), a protein complex that is secreted by V. cholerae, is required for V.

Spore Preparation Protocol for Enrichment of Clostridia from Murine Intestine.

In recent years, many spore-forming commensal Clostridia found in the gut have been discovered to promote host physiology, immune development, and protection against infections. We provide a detailed protocol for rapid enrichment of spore-forming bacteria from murine intestine. Briefly, contents from the intestinal cecum are collected aerobically, diluted and finally treated with chloroform to enrich for Clostridia spores.

Microbiota-activated PPAR-γ signaling inhibits dysbiotic Enterobacteriaceae expansion.

Perturbation of the gut-associated microbial community may underlie many human illnesses, but the mechanisms that maintain homeostasis are poorly understood. We found that the depletion of butyrate-producing microbes by antibiotic treatment reduced epithelial signaling through the intracellular butyrate sensor peroxisome proliferator-activated receptor γ (PPAR-γ). Nitrate levels increased in the colonic lumen because epithelial expression of , the gene encoding inducible nitric oxide synthase, was elevated in the absence of PPAR-γ signaling.

Colonization resistance: The deconvolution of a complex trait.

Carbapenemase-producing Enterobacteriaceae are an emerging threat to hospitals worldwide, and antibiotic exposure is a risk factor for developing fecal carriage that may lead to nosocomial infection. Here, we review how antibiotics reduce colonization resistance against Enterobacteriaceae to pinpoint possible control points for curbing their spread. Recent work identifies host-derived respiratory electron acceptors as a critical resource driving a post-antibiotic expansion of Enterobacteriaceae within the large bowel.

Oxygen as a driver of gut dysbiosis.

Changes in the composition of gut-associated microbial communities may underlie many inflammatory and allergic diseases. However, the processes that help maintain a stable community structure are poorly understood. Here we review topical work elucidating the nutrient-niche occupied by facultative anaerobic bacteria of the family Enterobacteriaceae, whose predominance within the gut-associated microbial community is a common marker of dysbiosis.

Virulence factors enhance Citrobacter rodentium expansion through aerobic respiration.

Citrobacter rodentium uses a type III secretion system (T3SS) to induce colonic crypt hyperplasia in mice, thereby gaining an edge during its competition with the gut microbiota through an unknown mechanism. Here, we show that by triggering colonic crypt hyperplasia, the C. rodentium T3SS induced an excessive expansion of undifferentiated Ki67-positive epithelial cells, which increased oxygenation of the mucosal surface and drove an aerobic C.

How bacterial pathogens use type III and type IV secretion systems to facilitate their transmission.

Work on type III or type IV secretion systems (T3SSs or T4SSs) is often focused on elucidating how these sophisticated bacterial virulence factors manipulate host cell physiology to cause disease. But to fully understand their role in pathogen biology, it is important to consider whether the morbidity or mortality they trigger is somehow linked to enhancing communicability of the microbe. Recent work on Salmonella enterica and Brucella abortus provide captivating examples of how manipulation of host cells with T3SSs or T4SSs instigates distant downstream consequences that promote spread of the pathogen.

Energy Taxis toward Host-Derived Nitrate Supports a Salmonella Pathogenicity Island 1-Independent Mechanism of Invasion.

Unlabelled: Salmonella enterica serovar Typhimurium can cross the epithelial barrier using either the invasion-associated type III secretion system (T3SS-1) or a T3SS-1-independent mechanism that remains poorly characterized. Here we show that flagellum-mediated motility supported a T3SS-1-independent pathway for entering ileal Peyer's patches in the mouse model. Flagellum-dependent invasion of Peyer's patches required energy taxis toward nitrate, which was mediated by the methyl-accepting chemotaxis protein (MCP) Tsr.

Depletion of Butyrate-Producing Clostridia from the Gut Microbiota Drives an Aerobic Luminal Expansion of Salmonella.

The mammalian intestine is host to a microbial community that prevents pathogen expansion through unknown mechanisms, while antibiotic treatment can increase susceptibility to enteric pathogens. Here we show that streptomycin treatment depleted commensal, butyrate-producing Clostridia from the mouse intestinal lumen, leading to decreased butyrate levels, increased epithelial oxygenation, and aerobic expansion of Salmonella enterica serovar Typhimurium. Epithelial hypoxia and Salmonella restriction could be restored by tributyrin treatment.

The Periplasmic Nitrate Reductase NapABC Supports Luminal Growth of Salmonella enterica Serovar Typhimurium during Colitis.

The food-borne pathogen Salmonella enterica serovar Typhimurium benefits from acute inflammation in part by using host-derived nitrate to respire anaerobically and compete successfully with the commensal microbes during growth in the intestinal lumen. The S. Typhimurium genome contains three nitrate reductases, encoded by the narGHI, narZYV, and napABC genes.

The Pyromaniac Inside You: Salmonella Metabolism in the Host Gut.

A metabolically diverse microbial community occupies all available nutrient-niches in the lumen of the mammalian intestine, making it difficult for pathogens to establish themselves in this highly competitive environment. Salmonella serovars sidestep the competition by using their virulence factors to coerce the host into creating a novel nutrient-niche. Inflammation-derived nutrients available in this new niche support a bloom of Salmonella serovars, thereby ensuring transmission of the pathogen to the next susceptible host by the fecal-oral route.

Serum Levels of Neurofilament-H are Elevated in Patients Suffering From Severe Burns.

In previous studies, after injury, burn patients experienced an increase in neuro-inflammation, edema, and neuronal cell death. As demonstrated in other brain injury models, fluid-based biomarkers such as phosphorylated neurofilament-H (pNFL-H) have been shown to correlate with injury severity. In this study the authors hypothesized that burn-injured patients have an increase in pNFL-H in the blood during the acute and chronic time-points after injury.

Hypertonic HBOC-201 decreases neutrophil activation after hemorrhagic shock.

Objective: To evaluate neutrophil activation after exposure to standard HBC-201 (suspended in lactate Ringer's solution) versus HBOC-201 suspended in hypertonic 7.5% saline solution.

Methods: We use plasma and tissue obtained from pigs subjected to controlled hemorrhagic shock and an ex vivo model of stimulated human whole blood.

A TREM-1 Polymorphism A/T within the Exon 2 Is Associated with Pneumonia in Burn-Injured Patients.

Background. The triggering receptor expressed in myeloid cells (TREM-1) is a key mediator in the activation of the local inflammatory response during lung infections. We aimed to evaluate the effect of a functionally relevant TREM-1 single nucleotide polymorphism within the exon 2 (A→T) on the development of pneumonia in burn patients.

Examination with next-generation sequencing technology of the bacterial microbiota in bronchoalveolar lavage samples after traumatic injury.

Background: We examined the microbiota of bronchoalveolar lavage (BAL) samples with next-generation sequencing (NGS) technology to determine whether its results correlate with those of standard culture methods or affect patient outcome or both.

Methods: We collected BAL samples in the surgical intensive care unit (SICU) as part of the standard of care for intubated individuals who had a Clinical Pulmonary Infection Score (CPIS)≥6 points. A portion of the BAL fluid was sequenced for the 16S region of ribosomal deoxyribonucleic acid (rDNA) with the Roche 454 FLX Titanium sequencer.

Salmonella uses energy taxis to benefit from intestinal inflammation.

Chemotaxis enhances the fitness of Salmonella enterica serotype Typhimurium (S. Typhimurium) during colitis. However, the chemotaxis receptors conferring this fitness advantage and their cognate signals generated during inflammation remain unknown.

Phage-mediated acquisition of a type III secreted effector protein boosts growth of salmonella by nitrate respiration.

Information on how emerging pathogens can invade and persist and spread within host populations remains sparse. In the 1980s, a multidrug-resistant Salmonella enterica serotype Typhimurium clone lysogenized by a bacteriophage carrying the sopE virulence gene caused an epidemic among cattle and humans in Europe. Here we show that phage-mediated horizontal transfer of the sopE gene enhances the production of host-derived nitrate, an energetically highly valuable electron acceptor, in a mouse colitis model.

IL-10 polymorphism associated with decreased risk for mortality after burn injury.

Objective: Evaluation of single nucleotide polymorphisms (SNPs) in the interleukin-10 promoter (-592 and -819) on risk for death after burn injury.

Methods: Association between the IL-10 SNPs and outcome after burn injury was evaluated in a cohort of 265 patients from Parkland Hospital, Dallas, TX with ≥ 15% TBSA burns without non-burn trauma (ISS ≤ 16), traumatic or anoxic brain injury or spinal cord injury, who survived >48 h under an IRB-approved protocol. Clinical data were collected prospectively and genotyping was conducted by TaqMan assay.

Soluble triggering receptor expressed on myeloid cells-1 is an early marker of infection in the surgical intensive care unit.

Background: To determine the value of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in early differentiation of systemic inflammatory response syndrome (SIRS) from infection in patients in a surgical intensive care unit (ICU).

Methods: Patients were enrolled if there was clinical suspicion of infection and they fulfilled at least two criteria of SIRS at the time of admission to the ICU. The patients were classified as having SIRS (no infection; n = 37) or infection (n = 56) on the basis of the decision of the treating physician and bacteriological evidence of infection.

Inflammatory mediators of liver ischemia-reperfusion injury.

Liver ischemia and reperfusion--which cause liver damage that is significant in a variety of diseases, injuries, and procedures (including but not limited to trauma and transplant)--have been the focus of many investigations in recent years. Although the mechanisms of ischemia-reperfusion injury are numerous and complex, many advances in treatment have been made. The following review considers recent advances in the understanding of hepatic ischemia-reperfusion injury and focuses on inflammatory mediators of significance.

Role of p38 and JNK in liver ischemia and reperfusion.

Background/purpose: The signal transduction of mitogen-activated protein kinases (MAPKs) has appeared to be an important mediator of ischemic-related events. Because of this, we analyzed the participation of p38 and JNK in liver ischemia and reperfusion, as two individual members of the MAPK family of proteins.

Methods: All papers referred to in PubMed for the past 15 years were analyzed to determine how and when these MAPKs were considered to be an intricate part of the ischemic event.

Resuscitation from hemorrhagic shock comparing standard hemoglobin-based oxygen carrier (HBOC)-201 versus 7.5% hypertonic HBOC-201.

Background: Hemoglobin-based oxygen carrier (HBOC) resuscitation has been associated with increased systemic and pulmonary vascular resistances (SVR, PVR), which may result in reduced blood flow and severe pulmonary hypertension. The physiologic and immunologic properties of 7.5% hypertonic saline solution (HTS), such as reduction of SVR and PVR, as well as inhibition of neutrophil and endothelial activation may be beneficial in reducing some of these undesirable effects of HBOCs.