Intestinal infection triggers Parkinson's disease-like symptoms in Pink1-/- mice.

Parkinson's disease is a neurodegenerative disorder with motor symptoms linked to the loss of dopaminergic neurons in the substantia nigra compacta. Although the mechanisms that trigger the loss of dopaminergic neurons are unclear, mitochondrial dysfunction and inflammation are thought to have key roles1,2. An early-onset form of Parkinson's disease is associated with mutations in the PINK1 kinase and PRKN ubiquitin ligase genes3. PINK1 and Parkin (encoded by PRKN) are involved in the clearance of damaged mitochondria in cultured cells4, but recent evidence obtained using knockout and knockin mouse models have led to contradictory results regarding the contributions of PINK1 and Parkin to mitophagy in vivo5-8. It has previously been shown that PINK1 and Parkin have a key role in adaptive immunity by repressing presentation of mitochondrial antigens9, which suggests that autoimmune mechanisms participate in the aetiology of Parkinson's disease. Here we show that intestinal infection with Gram-negative bacteria in Pink1-/- mice engages mitochondrial antigen presentation and autoimmune mechanisms that elicit the establishment of cytotoxic mitochondria-specific CD8+ T cells in the periphery and in the brain. Notably, these mice show a sharp decrease in the density of dopaminergic axonal varicosities in the striatum and are affected by motor impairment that is reversed after treatment with L-DOPA. These data support the idea that PINK1 is a repressor of the immune system, and provide a pathophysiological model in which intestinal infection acts as a triggering event in Parkinson's disease, which highlights the relevance of the gut-brain axis in the disease10.

Edwardsiella piscicida Interferes with Classical Endocytic Trafficking and Replicates in a Specialized Replication-Permissive Niche in Nonphagocytic Cells.

Edwardsiella piscicida is an intracellular pathogen within a broad spectrum of hosts. Essential to E. piscicida's virulence is its ability to invade and replicate inside host cells, yet the survival mechanisms and the nature of the replicative compartment remain unknown. Here, we characterized its intracellular lifestyle in nonphagocytic cells and showed that the intracellular replication of E. piscicida in nonphagocytic cells is dependent on its type III secretion system (T3SS) but not its type VI secretion system. Following internalization, E. piscicida is contained in vacuoles that transiently mature into early endosomes but subsequently bypasses the classical endosome pathway and fusion with lysosomes, which depend on its T3SS. Following rapid escape from the degradative pathway, E. piscicida was found to create a specialized replication-permissive niche characterized by endoplasmic reticulum (ER) markers. Furthermore, we found that a T3SS effector, EseJ, is responsible for the intracellular replication of E. piscicida by preventing endosome/lysosome fusion. In vivo experiments also confirmed that EseJ is necessary for bacterial colonization by E. piscicida in the epithelial layer, followed by systemic dissemination in both zebrafish and mice. Thus, this work elucidates the tactics used by E. piscicida to survive and proliferate within host nonphagocytic cells. IMPORTANCEE. piscicida is a facultative intracellular bacterium associated with septicemia and fatal infections in many animals, including fish and humans. However, little is known about its intracellular life, which is important for successful invasion of the host. The present study is the first comprehensive characterization of E. piscicida's intracellular lifestyle in host cells. Upon internalization, E. piscicida is transiently contained in Rab5-positive vacuoles, but the pathogen prevents further endosome maturation and fusion with lysosomes by utilizing a T3SS effector, EseJ. In addition, the bacterium creates a specialized replication niche for rapid growth via an interaction with the ER. Our study provides new insights into the strategies used by E. piscicida to successfully establish an intracellular lifestyle that contributes to its survival and dissemination during infection.

Is systematic fecal carriage screening of extended-spectrum beta-lactamase-producing Enterobacteriaceae still useful in intensive care unit: a systematic review.

BACKGROUND: Extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) are disseminating worldwide leading to increased hospital length of stay and mortality in intensive care units (ICU). ESBL-E dissemination was first due to outbreaks in hospital settings which led to the implementation of systematic fecal carriage screening to improve hygiene procedures by contact precautions. ESBLs have since spread in the community, and the relevance of contact precautions is questioned. ESBL-E dissemination led to an overuse of carbapenems triggering the emergence of carbapenem-resistant Enterobacteriaceae. Empirical antimicrobial therapy based on ESBL-E fecal carriage has been proposed but is debated as it could increase the consumption of carbapenems among ESBL-E carriers without any clinical benefit. Finally, selective decontamination among ESBL-E fecal carriers is evoked to decrease the risk for subsequent ESBL-E infection, but its efficacy remains debated. We propose to systematically review the evidence to recommend or not such systematic ESBL-E fecal carriage screening in adult ICU. METHODS: Every article focusing on ESBL-E and ICU available on the MEDLINE database was assessed. Articles were included if focusing on cross-transmission, efficacy of hygiene procedures, link between ESBL-E colonization and infection or guidance of empirical therapy or selective decontamination efficacy. RESULTS: Among 330 articles referenced on PubMed, 39 abstracts were selected for full-text assessment and 25 studies were included. Systematic screening of ESBL-E fecal carriage to guide contact precautions do not seem to decrease the rate of ESBL-E cross-transmission. It has a very good negative predictive value for subsequent ESBL-E infections but a positive predictive value between 40 and 50% and so does not help to spare carbapenems. Cessation of ESBL-E carriage systematic screening could decrease the use of carbapenems in ICU without any clinical harm. Nevertheless, further studies are needed to validate these results from monocentric before-after study. Selective decontamination strategy applied to ESBL-E fecal carriers could be helpful, but available data are conflicting. CONCLUSION: Current knowledge lacks of high-quality evidence to strongly recommend in favor of or against a systematic ESBL-E fecal carriage screening policy for ICU patients in a non-outbreak situation. Further evaluation of selective decontamination or fecal microbiota transplantation among ESBL-E fecal carriers is needed.

Characteristics of febrile urinary tract infections in older male adults.

BACKGROUND: Urinary tract infections (UTI) are among the most frequent bacterial infections in older adults. The aim of the study was to analyse the existence of differences in clinical features, microbiological data and risk of infection by multidrug-resistant organisms (MDRO) between older and non-older men with febrile UTI (FUTI). METHODS: This was an ambispective observational study involving older males with a FUTI attended in the Emergency Department. Variables collected included age, comorbidity, diagnostic of healthcare-associated (HCA)-FUTI, clinical manifestations, hospitalization, mortality, and microbiological data. RESULTS: Five hundred fifty-two males with a FUTI, 329 (59.6%) of whom were older adults, were included. Older males had a higher frequency of HCA-FUTI (p <  0.001), increased Charlson scores (p <  0.001), had received previous antimicrobial treatment more frequently (p <  0.001) and had less lower urinary tract symptoms (p <  0.001). Older patients showed a lower frequency of FUTI caused by E. coli (p <  0.001) and a higher rate of those due to Enterobacter spp. (p = 0.003) and P. aeruginosa (p = 0.033). Resistance rates to cefuroxime (p = 0.038), gentamicin (p = 0.043), and fluoroquinolones (p <  0.001) in E. coli isolates and the prevalence of extended-spectrum beta-lactamase and AmpC producing E. coli and Klebsiella spp. strains (p = 0.041) and MDRO (p <  0.001) were increased in older males. Inadequate empirical antimicrobial treatment (p = 0.004), frequency of hospitalization (p <  0.001), and all cause in-hospital mortality (p = 0.007) were higher among older patients. In the multivariate analysis, being admitted from an long term care facility (OR 2.4; 95% CI: 1.06-5.9), having a urinary tract abnormality (OR 2.2; 95% CI: 1.2-3.8) and previous antimicrobial treatment (OR 3.2; 95% CI: 1.9-5.4) were associated to FUTI caused by MDRO. CONCLUSIONS: Older male adults with a FUTI have different clinical characteristics, present specific microbiological features, and antimicrobial resistance rates. In the multivariate analysis being an older male was not associated with an increased risk of FUTI caused by MDRO.

Catfish Bite Case Report.

Although catfish are found worldwide and commonly consumed in the southern United States, fatal infections from catfish are rare. Edwardsiella tarda is a bacterium known to cause gastrointestinal distress most commonly, but extraintestinal infections are a rarely considered danger for those acquiring, preparing, and consuming aquatic animals. Susceptible to all gram-negative active antibiotics, it is easily treated except in immunocompromised hosts, such as those with malignancy, diabetes, and hepatic dysfunction.

A Phase 1 Study To Assess the Pharmacokinetics of Intravenous Plazomicin in Adult Subjects with Varying Degrees of Renal Function.

Plazomicin is an FDA-approved aminoglycoside for the treatment of complicated urinary tract infections. In this open-label study, 24 adults with normal renal function or mild, moderate, or severe renal impairment (n = 6 per group) received a single 7.5-mg/kg of body weight dose of plazomicin as a 30-min intravenous infusion. Total clearance declined with renal impairment, resulting in 1.98-fold and 4.42-fold higher plazomicin exposures, as measured by the area under the concentration-time curve from 0 h to infinity, in subjects with moderate and severe impairment, respectively, than in subjects with normal renal function. (This study has been registered at ClinicalTrials.gov under identifier NCT01462136.).

Carbapenemase-producing Enterobacteriaceae in Mexico: report of seven non-clonal cases in a pediatric hospital.

BACKGROUND: Carbapenemases-producing Enterobacteriaceae (CPE) are a worldwide public health emergency. In Mexico, reports of CPE are limited, particularly in the pediatric population. Here, we describe the clinical, epidemiological, and molecular characteristics of seven consecutive cases in a third-level pediatric hospital in Mexico City over a four-month period during 2016. RESULTS: The Enterobacteriaceae identified were three Escherichia coli strains (producing OXA-232, NDM-1 and KPC-2), two Klebsiella pneumoniae strains (producing KPC-2 and NDM-1), one Klebsiella oxytoca strain producing OXA-48 and one Enterobacter cloacae strain producing NDM-1. The majority of patients had underlying disesases, three were immunocompromised, and three had infections involved the skin and soft tissues. Half patients died as a result of CPE infection. CONCLUSIONS: This study represents the first report of E. coli ST131-O25b clone producing NDM-1 in Latin America. In addition, this study is the first finding of K. oxytoca producing OXA-48 and E. coli producing OXA-232 in Mexican pediatric patients.

Photorhabdus luminescens Toxins TccC3 and TccC5 Affect the Interaction of Actin with Actin-Binding Proteins Essential for Treadmilling.

Actin is one of the most abundant cellular proteins and an essential constituent of the actin cytoskeleton, which by its dynamic behavior participates in many cellular activities. The organization of the actin cytoskeleton is regulated by a large number of proteins and represents one of the major targets of bacterial toxins. A number of bacterial effector proteins directly modify actin: Clostridial bacteria produce toxins, which ADP-ribosylate actin at Arg177 leading to inhibition of actin polymerization. The bacterium Photorhabdus luminescens produces several types of protein toxins, including the high molecular weight Tc toxin complex, whose component TccC3 ADP-ribosylates actin at Thr148 promoting polymerization and aggregation of intracellular F-actin leading to inhibition of several cellular functions, such as phagocytosis. Here, we review recent findings about the functional consequences of these actin modifications and for the Thr148-ADP-ribosylated actin the subsequent alterations in the interaction with actin-binding proteins . In addition, we describe the effects of ADP-ribosylation of Rho GTPases by the TccC5 component.

Induction of Colonic M Cells during Intestinal Inflammation.

Intestinal M (microfold) cells are specialized epithelial cells overlying lymphoid tissues in the small intestine. Unlike common enterocytes, M cells lack an organized apical brush border, and are able to transcytose microparticles across the mucosal barrier to underlying antigen-presenting cells. We found that in both the dextran sodium sulfate and Citrobacter rodentium models of colitis, significantly increased numbers of Peyer's patch (PP) phenotype M cells were induced at the peak of inflammation in colonic epithelium, often accompanied by loosely organized lamina propria infiltrates. PP type M cells are thought to be dependent on cytokines, including tumor necrosis factor (TNF)-α and receptor activator of nuclear factor kappa-B ligand; these cytokines were also found to be induced in the inflamed tissues. The induction of M cells was abrogated by anti-TNF-α blockade, suggesting that anti-TNF-α therapies may have similar effects in clinical settings, although the functional consequences are not clear. Our results suggest that inflammatory cytokine-induced PP type M cells may be a useful correlate of chronic intestinal inflammation.

Starvation beneficially influences the liver physiology and nutrient metabolism in Edwardsiella tarda infected red sea bream (Pagrus major).

Dietary compromises, especially food restrictions, possess species-specific effects on the health status and infection control in several organisms, including fish. To understand the starvation-mediated physiological responses in Edwardsiella tarda infected red sea bream, especially in the liver, we performed a 20-day starvation experiment using 4 treatment (2 fed and 2 starved) groups, namely, fed-placebo, starved-placebo, fed-infected, and starved-infected, wherein bacterial exposure was done on the 11th day. In the present study, the starved groups showed reduced hepatosomatic index and drastic depletion in glycogen storage and vacuole formation. The fed-infected fish showed significant (P<0.05) increase in catalase and superoxide dismutase activity in relation to its starved equivalent. Significant (P<0.05) alteration in glucose and energy metabolism, as evident from hexokinase and glucose-6-phosphate dehydrogenase activity, was recorded in the starved groups. Interestingly, coinciding with the liver histology, PPAR (peroxisome proliferator activated receptors) α transcription followed a time-dependent activation in starved groups while PPARγ exhibited an opposite pattern. The transcription of hepcidin 1 and transferrin, initially increased in 0dai (days after infection) starved fish but reduced significantly (P<0.05) at later stages. Two-color immunohistochemistry and subsequent cell counting showed significant increase in P63-positive cells at 0dai and 5dai but later reduced slightly at 10dai. Similar results were also obtained in the lysosomal (cathepsin D) and non-lysosomal (ubiquitin) gene transcription level. All together, our data suggest that starvation exerts multidirectional responses, which allows for better physiological adaptations during any infectious period, in red sea bream.

Streptococcus pneumoniae-induced pneumonia and Citrobacter rodentium-induced gut infection differentially alter vitamin A concentrations in the lung and liver of mice.

In the developing world, vitamin A (VA) deficiency is endemic in populations that are also at great risk of morbidity and mortality because of pneumococcal pneumonia and enteric infections. To better understand how lung and gastrointestinal pathogens affect VA status, we assessed VA concentrations in serum, lung, and liver during an invasive pneumonia infection induced by Streptococcus pneumoniae serotype 3, and a noninvasive gut infection induced by Citrobacter rodentium, in vitamin A-adequate (VAA) and vitamin A-deficient (VAD) mice. For pneumonia infection, mice were immunized with pneumococcal polysaccharide serotype 3 (PPS3), or not (infected-control), 5 d prior to intranasal inoculation with S. pneumoniae. Two days post-inoculation, immunization was protective against systemic infection regardless of VA status as PPS3 immunization decreased bacteremia compared with infected-control mice (P < 0.05). Retinol concentrations in the lung were higher in infected-control VAA mice (15.7 nmol/g: P < 0.05) compared with PPS3-immunized mice (8.23 nmol/g), but this was not associated with increased lung bacterial burden. VAA mice had reduced severity of C. rodentium-induced gut infection as measured by fecal bacterial shedding compared with VAD mice (P < 0.05). Liver retinol and retinyl ester concentrations in VAA mice decreased at the peak of infection (retinol, 8.1 nmol/g; retinyl esters, 985 nmol/g; P < 0.05, compared with uninfected mice; retinol, 29.5 nmol/g; retinyl esters, 1730 nmol/g), whereas tissue VA concentrations were low in VAD mice during both infections. Colonic mucin gene expression was also depressed at peak infection compared with uninfected mice (P < 0.05). Overall, pneumonia had less effect on VA status than gastrointestinal infection, predominantly owing to reduced hepatic VA storage at the peak of gut infection.

Role of intestinal inflammation in predisposition of Edwardsiella tarda infection in zebrafish (Danio rerio).

Edwardsiella tarda, an enteric opportunistic pathogen, is associated with acute to chronic edwardsiellosis in cultured fish, resulting in heavy losses in aquaculture. To date, the pathogenesis of E. tarda has been extensively studied and a great deal of vaccine candidates have been attempted. However, the research on the predisposition of E. tarda infection is poorly reported. In this study, the effects of intestinal inflammation on E. tarda infection were investigated using a zebrafish model that influenced by perturbation of intestinal microbiota. Featured symptoms of edwardsiellosis were observed in intestinal inflammatory zebrafish compared with healthy fish. Higher bacterial numbers were detected in both mucosal tissues (intestine, skin and gills) and lymphoid tissues (liver, spleen and kidney) of inflammatory zebrafish while the bacterial loads in healthy zebrafish appeared to be relatively lower by 10-100 folds. Moreover, significant up-regulation of IL-1ß, TNF-α and iNOS was noticed in multiple tissues of zebrafish with intestinal inflammation between 6 and 72 h post infection. However, only moderate elevation was observed in the gills and liver of healthy fish. Furthermore, the expression of genes involved in neutrophil recruitment (mpx, IL-8 and LECT2) and antimicrobial response (ß-defensin and hepcidin) showed notable up-regulation in the intestine of inflammatory zebrafish. These results demonstrate that fish with intestinal inflammation is more susceptible to E. tarda and the antimicrobial response during E. tarda infection might inhibit the growth of intestinal microbiota. Our results suggest that maintaining good management to avoid intestinal inflammation is a feasible prevention measure against edwardsiellosis.

Evidence of functional cross talk between the Notch and NF-κB pathways in nonneoplastic hyperproliferating colonic epithelium.

The Notch and NF-κB signaling pathways regulate stem cell function and inflammation in the gut, respectively. We investigate whether a functional cross talk exists between the two pathways during transmissible murine colonic hyperplasia (TMCH) caused by Citrobacter rodentium (CR). During TMCH, NF-κB activity and subunit phosphorylation in colonic crypts of NIH Swiss mice at days 6 and 12 were associated with increases in downstream target CXC chemokine ligand (CXCL)-1/keratinocyte-derived chemokine (KC) expression. Blocking Notch signaling acutely for 5 days with the Notch blocker dibenzazepine (DBZ) failed to inhibit crypt NF-κB activity or CXCL-1/KC expression. Chronic DBZ administration for 10 days, however, blocked Notch and NF-κB signaling in the crypts and abrogated hyperplasia. Intriguingly, chronic Notch inhibition was associated with significant increases in IL-1α, granulocyte colony-stimulating factor, monocyte chemoattractant protein 1, macrophage inflammatory protein 2, and KC in the crypt-denuded lamina propria or whole distal colon, with concomitant increases in myeloperoxidase activity. In core-3(-/-) mice, which are defective in intestinal mucin, DBZ administration replicated the results of NIH Swiss mice; in Apc(Min/+) mice, which are associated with CR-induced elevation of NF-κB-p65(276) expression, DBZ reversed the increase in NF-κB-p65(276), which may have blocked rapid proliferation of the mutated crypts. DBZ further blocked reporter activities involving the NF-κB-luciferase reporter plasmid or the Toll-like receptor 4/NF-κB/SEAPorter HEK-293 reporter cell line, while ectopic expression of Notch-N(ICD) reversed the inhibitory effect. Dietary bael (Aegle marmelos) extract (4%) and curcumin (4%) restored Notch and NF-κB cross talk in NIH Swiss mice, inhibited CR/DBZ-induced apoptosis in the crypts, and promoted crypt regeneration. Thus functional cross talk between the Notch and NF-κB pathways during TMCH regulates hyperplasia and/or inflammation in response to CR infection.

Impact of the prone position in an animal model of unilateral bacterial pneumonia undergoing mechanical ventilation.

BACKGROUND: The prone position (PP) has proven beneficial in patients with severe lung injury subjected to mechanical ventilation (MV), especially in those with lobar involvement. We assessed the impact of PP on unilateral pneumonia in rabbits subjected to MV. METHODS: After endobronchial challenge with Enterobacter aerogenes, adult rabbits were subjected to either "adverse" (peak inspiratory pressure = 30 cm H2O, zero end-expiratory pressure; n = 10) or "protective" (tidal volume = 8 ml/kg, 5 cm H2O positive end-expiratory pressure; n = 10) MV and then randomly kept supine or turned to the PP. Pneumonia was assessed 8 h later. Data are presented as median (interquartile range). RESULTS: Compared with the supine position, PP was associated with significantly lower bacterial concentrations within the infected lung, even if a "protective" MV was applied (5.93 [0.34] vs. 6.66 [0.86] log10 cfu/g, respectively; P = 0.008). Bacterial concentrations in the spleen were also decreased by the PP if the "adverse" MV was used (3.62 [1.74] vs. 6.55 [3.67] log10 cfu/g, respectively; P = 0.038). In addition, the noninfected lung was less severely injured in the PP group. Finally, lung and systemic inflammation as assessed through interleukin-8 and tumor necrosis factor-α measurement was attenuated by the PP. CONCLUSIONS: The PP could be protective if the host is subjected to MV and unilateral bacterial pneumonia. It improves lung injury even if it is utilized after lung injury has occurred and nonprotective ventilation has been administered.

Brain-gut interactions increase peripheral nociceptive signaling in mice with postinfectious irritable bowel syndrome.

BACKGROUND & AIMS: To investigate the peripheral sensory effects of repeated stress in patients with postinfectious irritable bowel syndrome (IBS), we tested whether stress following self-limiting bacterial colitis increases colonic dorsal root ganglia (DRG) nociceptive signaling. METHODS: C57BL/6 mice were infected with Citrobacter rodentium. Stress was induced using a 9-day water avoidance paradigm (days 21-30 after infection). Colonic DRG neuronal excitability was measured using perforated patch clamp techniques, in vitro multi-unit afferent recordings, and measurements of visceromotor reflexes. RESULTS: Combined stress and prior infection increased corticosterone and epinephrine levels, compared with infected animals, but did not alter the resolution of colonic inflammation. These changes were associated with increased neuronal excitability and parallel changes in multi-unit afferent recordings and visceromotor reflex thresholds. Protease activity was increased at day 30 following infection with C rodentium. Protease inhibitors markedly reduced the effects of colonic supernatants on neuronal excitability from C rodentium but not stressed animals. Colonic DRG neurons expressed messenger RNAs for the ß(2) adrenergic and glucocorticoid receptors; incubation with stress mediators recapitulated the effects on neuronal excitability observed with chronic stress alone. PAR2 activation with concentrations of the activating peptide SLIGRL that had no effect on neuronal excitability in controls caused marked increases in excitability when applied to neurons from chronically stressed animals. CONCLUSIONS: Stress, combined with prior acute colitis, results in exaggerated peripheral nociceptive signaling. Proteases and stress mediators can signal directly to colonic DRG neurons; further analysis of these pathways could provide new targets for treatment of patients with postinfectious IBS.

Role of neutrophils and macrophages in the pathogenesis of necrotizing enterocolitis caused by Cronobacter sakazakii.

BACKGROUND: Cronobacter sakazakii (CS) is a highly virulent gram-negative opportunistic pathogen that has been implicated in clinical outbreaks of necrotizing enterocolitis (NEC). The role of mucosal immune cells in CS infection is not well understood. In this study, we sought to elucidate the role of neutrophils (polymorphonuclear leukocytes; PMNs) and macrophages in the pathogenesis of NEC induced by CS using a novel newborn mouse model. MATERIALS AND METHODS: PMNs and macrophages were depleted in newborn mice using Gr-1 antibody and carrageenan, respectively, and then infected with 10(3) CFU of CS. The development of NEC in these mice was assessed by a pathologist based on the morphologic changes in the intestine. Cytokine production was determined in the serum and intestinal homogenates of infected mice by enzyme-linked immunosorbent assay (ELISA). Inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production was determined by flow cytometry and Greiss method, respectively. RESULTS: Depletion of PMNs and macrophages in newborn mice led to increased recruitment of dendritic cells (DCs) in the intestine compared with wild-type mice upon infection with CS. PMN- and macrophage-depleted mice showed increased bacterial load, production of pro-inflammatory cytokines, iNOS expression, and NO production in the intestines in comparison to wild-type mice fed with CS. In addition, depletion of PMNs and macrophages prior to infection in mice resulted in severe inflammation, villus destruction, and enhanced enterocyte apoptosis in the intestines compared with CS-infected wild-type mice. CONCLUSIONS: Our data suggest that depletion of PMNs and macrophages from the lamina propria (LP) exacerbates experimental NEC, indicating that both of these immunocytes play an important role in the clearance of CS during the initial stages of infection. The increased mucosal cytokine response and NO production in the absence of these immunocytes may be responsible for the observed increase in mucosal injury. Understanding how CS manipulates these cells, employing novel mouse model of NEC reported in this study, will provide significant insights for the development of novel therapeutic and preventive strategies to combat NEC.

Infective endocarditis by Enterobacter cloacae: a systematic review and meta-analysis.

Enterobacter species are Gram-negative, non-spore-forming, facultative anaerobes typically motile due to the presence of peritrichous flagella. E. cloacae, the species responsible for the majority of Enterobacter infections in humans, is part of the intestinal microbiota and may cause infection in patients that have previously received antimicrobial therapy or who have been admitted to the Intensive Care Unit. E. cloacae may cause several infections, such as pneumonia, urinary tract, skin and soft tissue and intravascular infections. Infective Endocarditis (IE) is a rare disease with notable morbidity and mortality. Even though IE is rarely caused by E. cloacae, these infections can be problematic due to the relative lack of experience in their management. The purpose of this study was to systematically review all published cases of IE by E. cloacae in the literature. A systematic review of PubMed, Scopus and Cochrane library (through 14th November 2020) for studies providing epidemiological, clinical, microbiological as well as treatment data and outcomes of IE by E. cloacae was performed. A total of 20 studies, containing data of 20 patients, were included. A prosthetic valve was present in 27.8%. Mitral valve was the commonest infected site, followed by aortic valve. Diagnosis was facilitated by transthoracic and transesophageal echocardiography in 38.5% each, while the diagnosis was set at autopsy in 10%. Fever, sepsis, shock and immunologic phenomena were the most common clinical presentations, followed by heart failure. Aminoglycosides, cephalosporins and carbapenems were the most common antimicrobials used. Clinical cure was noted in 75%, while overall mortality was 30%. Development of shock and treatment with the combination of piperacillin with tazobactam were associated with overall mortality.

Dissecting the role of the Tir:Nck and Tir:IRTKS/IRSp53 signalling pathways in vivo.

Attaching and effacing (A/E) lesions and actin polymerization, the hallmark of enteropathogenic Escherichia coli (EPEC), enterohemorrhagic E. coli (EHEC) and Citrobacter rodentium (CR) infections, are dependent on the effector Tir. Phosphorylation of Tir(EPEC/CR) Y474/1 leads to recruitment of Nck and neural Wiskott-Aldrich syndrome protein (N-WASP) and strong actin polymerization in cultured cells. Tir(EPEC/CR) also contains an Asn-Pro-Tyr (NPY(454/1)) motif, which triggers weak actin polymerization. In EHEC the NPY(458) actin polymerization pathway is amplified by TccP/EspF(U), which is recruited to Tir via IRSp53 and/or insulin receptor tyrosine kinase substrate (IRTKS). Here we used C. rodentium to investigate the different Tir signalling pathways in vivo. Following infection with wild-type C. rodentium IRTKS, but not IRSp53, was recruited to the bacterial attachment sites. Similar results were seen after infection of human ileal explants with EHEC. Mutating Y471 or Y451 in Tir(CR) abolished recruitment of Nck and IRTKS respectively, but did not affect recruitment of N-WASP or A/E lesion formation. This suggests that despite their crucial role in actin polymerization in cultured cells the Tir:Nck and Tir:IRTKS pathways are not essential for N-WASP recruitment or A/E lesion formation in vivo. Importantly, wild-type C. rodentium out-competed the tir tyrosine mutants during mixed infections. These results uncouple the Tir:Nck and Tir:IRTKS pathways from A/E lesion formation in vivo but assign them an important in vivo role.

Activation of the contact-phase system on bacterial surfaces--a clue to serious complications in infectious diseases.

Fever, hypotension and bleeding disorders are common symptoms of sepsis and septic shock. The activation of the contact-phase system is thought to contribute to the development of these severe disease states by triggering proinflammatory and procoagulatory cascades; however, the underlying molecular mechanisms are obscure. Here we report that the components of the contact-phase system are assembled on the surface of Escherichia coli and Salmonella through their specific interactions with fibrous bacterial surface proteins, curli and fimbriae. As a consequence, the proinflammatory pathway is activated through the release of bradykinin, a potent inducer of fever, pain and hypotension. Absorption of contact-phase proteins and fibrinogen by bacterial surface proteins depletes relevant coagulation factors and causes a hypocoagulatory state. Thus, the complex interplay of microbe surface proteins and host contact-phase factors may contribute to the symptoms of sepsis and septic shock.

Drosophila EGFR pathway coordinates stem cell proliferation and gut remodeling following infection.

BACKGROUND: Gut homeostasis is central to whole organism health, and its disruption is associated with a broad range of pathologies. Following damage, complex physiological events are required in the gut to maintain proper homeostasis. Previously, we demonstrated that ingestion of a nonlethal pathogen, Erwinia carotovora carotovora 15, induces a massive increase in stem cell proliferation in the gut of Drosophila. However, the precise cellular events that occur following infection have not been quantitatively described, nor do we understand the interaction between multiple pathways that have been implicated in epithelium renewal. RESULTS: To understand the process of infection and epithelium renewal in more detail, we performed a quantitative analysis of several cellular and morphological characteristics of the gut. We observed that the gut of adult Drosophila undergoes a dynamic remodeling in response to bacterial infection. This remodeling coordinates the synthesis of new enterocytes, their proper morphogenesis and the elimination of damaged cells through delamination and anoikis. We demonstrate that one signaling pathway, the epidermal growth factor receptor (EGFR) pathway, is key to controlling each of these steps through distinct functions in intestinal stem cells and enterocytes. The EGFR pathway is activated by the EGF ligands, Spitz, Keren and Vein, the latter being induced in the surrounding visceral muscles in part under the control of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Additionally, the EGFR pathway synergizes with the JAK/STAT pathway in stem cells to promote their proliferation. Finally, we show that the EGFR pathway contributes to gut morphogenesis through its activity in enterocytes and is required to properly coordinate the delamination and anoikis of damaged cells. This function of the EGFR pathway in enterocytes is key to maintaining homeostasis, as flies lacking EGFR are highly susceptible to infection. CONCLUSIONS: This study demonstrates that restoration of normal gut morphology following bacterial infection is a more complex phenomenon than previously described. Maintenance of gut homeostasis requires the coordination of stem cell proliferation and differentiation, with the incorporation and morphogenesis of new cells and the expulsion of damaged enterocytes. We show that one signaling pathway, the EGFR pathway, is central to all these stages, and its activation at multiple steps could synchronize the complex cellular events leading to gut repair and homeostasis.