Cyclopropane Fatty Acids Are Important for Salmonella enterica Serovar Typhimurium Virulence.

A variety of eubacteria, plants, and protozoa can modify membrane lipids by cyclopropanation, which is reported to modulate membrane permeability and fluidity. The ability to cyclopropanate membrane lipids has been associated with resistance to oxidative stress in Mycobacterium tuberculosis, organic solvent stress in Escherichia coli, and acid stress in E. coli and Salmonella. In bacteria, the cfa gene encoding cyclopropane fatty acid (CFA) synthase is induced during the stationary phase of growth. In the present study, we constructed a cfa mutant of Salmonella enterica serovar Typhimurium 14028s (S. Typhimurium) and determined the contribution of CFA-modified lipids to stress resistance and virulence in mice. Cyclopropane fatty acid content was quantified in wild-type and cfa mutant S. Typhimurium. CFA levels in the cfa mutant were greatly reduced compared to CFA levels in the wild type, indicating that CFA synthase is the major enzyme responsible for cyclopropane modification of lipids in Salmonella. S. Typhimurium cfa mutants were more sensitive to extreme acid pH, the protonophore CCCP, and hydrogen peroxide compared to the wild type. In addition, cfa mutants exhibited reduced viability in murine macrophages and could be rescued by the addition of the NADPH phagocyte oxidase inhibitor diphenyleneiodonium (DPI) chloride. S. Typhimurium lacking cfa was also attenuated for virulence in mice. These observations indicate that CFA modification of lipids makes an important contribution to Salmonella virulence.

An unconventional role of an ASB family protein in NF-κB activation and inflammatory response during microbial infection and colitis.

Nuclear factor κB (NF-κB)-mediated signaling pathway plays a crucial role in the regulation of inflammatory process, innate and adaptive immune responses. The hyperactivation of inflammatory response causes host cell death, tissue damage, and autoinflammatory disorders, such as sepsis and inflammatory bowel disease. However, how these processes are precisely controlled is still poorly understood. In this study, we demonstrated that ankyrin repeat and suppressor of cytokine signaling box containing 1 (ASB1) is involved in the positive regulation of inflammatory responses by enhancing the stability of TAB2 and its downstream signaling pathways, including NF-κB and mitogen-activated protein kinase pathways. Mechanistically, unlike other members of the ASB family that induce ubiquitination-mediated degradation of their target proteins, ASB1 associates with TAB2 to inhibit K48-linked polyubiquitination and thereby promote the stability of TAB2 upon stimulation of cytokines and lipopolysaccharide (LPS), which indicates that ASB1 plays a noncanonical role to further stabilize the target protein rather than induce its degradation. The deficiency of Asb1 protects mice from Salmonella typhimurium- or LPS-induced septic shock and increases the survival of mice. Moreover, Asb1-deficient mice exhibited less severe colitis and intestinal inflammation induced by dextran sodium sulfate. Given the crucial role of ASB proteins in inflammatory signaling pathways, our study offers insights into the immune regulation in pathogen infection and inflammatory disorders with therapeutic implications.

Milk Fermented by Lactobacillus paracasei NCC 2461 (ST11) Modulates the Immune Response and Microbiota to Exert its Protective Effects Against Salmonella typhimurium Infection in Mice.

Probiotics form a promising strategy to maintain intestinal health. Milks fermented with probiotic strains, such as the Lactobacillus paracasei ST11, are largely commercialized in Brazil and form a low-cost alternative to probiotic pharmaceutical formulations. In this study, we assessed the probiotic effects of milk fermented by L. paracasei ST11 (administered through fermented milk) in a Salmonella typhimurium infection model in BALB/c mice. We observed in this murine model that the applied probiotic conferred protective effects against S. typhimurium infection, since its administration reduced mortality, weight loss, translocation to target organs (liver and spleen) and ileum injury. Moreover, a reduction in the mRNA expression of pro-inflammatory cytokines such as IFN-γ, IL-6, TNF-α and IL-17 in animals that received the probiotic before challenge was observed. Additionally, the ileum microbiota was better preserved in these animals. The present study highlights a multifactorial protective aspect of this commercial probiotic strain against a common gastrointestinal pathogen.

A macrophage-based screen identifies antibacterial compounds selective for intracellular Salmonella Typhimurium.

Salmonella Typhimurium (S. Tm) establishes systemic infection in susceptible hosts by evading the innate immune response and replicating within host phagocytes. Here, we sought to identify inhibitors of intracellular S. Tm replication by conducting parallel chemical screens against S. Tm growing in macrophage-mimicking media and within macrophages. We identify several compounds that inhibit Salmonella growth in the intracellular environment and in acidic, ion-limited media. We report on the antimicrobial activity of the psychoactive drug metergoline, which is specific against intracellular S. Tm. Screening an S. Tm deletion library in the presence of metergoline reveals hypersensitization of outer membrane mutants to metergoline activity. Metergoline disrupts the proton motive force at the bacterial cytoplasmic membrane and extends animal survival during a systemic S. Tm infection. This work highlights the predictive nature of intracellular screens for in vivo efficacy, and identifies metergoline as a novel antimicrobial active against Salmonella.

Mycotic aneurysm due to Salmonella species: clinical experiences and review of the literature.

The mortality of patients with mycotic aneurysms is high, especially in East Asia, and infection by Salmonella species is the most common. Our study aimed to improve prognosis of adult mycotic aneurysms with early diagnosis and accurate treatment. Four adult patients with mycotic aneurysm caused by Salmonella were included and analyzed by single-center retrospective analysis. Cases reported in the literature during the past 10 years were also summarized. The average age of the 4 male patients was 61.25 years, while that of the 53 cases reported in the literature was 65.13 years. Hypertension, diabetes, and atherosclerosis were common complications. Most patients presented fever and experienced pain at the corresponding position of the aneurysm. Laboratory examination found an increased number of white blood cells accompanied by an increase in inflammatory markers. Most aneurysms were found in the abdominal aorta, while the rupture of an aneurysm was the most common complication. The mortality rates were 21.43 and 7.14% after open surgery or endovascular aneurysm repair (EVAR) intervention, respectively. The recurrence rates of infection were 0 and 17.85% for both treatments, respectively. The mortality rate of mycotic aneurysm caused by Salmonella infection was high in middle-aged males with hypertension, diabetes, and atherosclerosis. The possibility of a Salmonella-infected aneurysm should be considered in these high-risk groups presenting chills, fever, chest, and back pain. Open surgery was superior to EVAR treatment in the clearance of infected foci and the reduction of postoperative recurrence. The recurrence of postoperative infection can be prevented by intravenous antibiotic therapy for 6 weeks post-surgery.

Mycotic aneurysm due to Salmonella species: clinical experiences and review of the literature

The mortality of patients with mycotic aneurysms is high, especially in East Asia, and infection by Salmonella species is the most common. Our study aimed to improve prognosis of adult mycotic aneurysms with early diagnosis and accurate treatment. Four adult patients with mycotic aneurysm caused by Salmonella were included and analyzed by single-center retrospective analysis. Cases reported in the literature during the past 10 years were also summarized. The average age of the 4 male patients was 61.25 years, while that of the 53 cases reported in the literature was 65.13 years. Hypertension, diabetes, and atherosclerosis were common complications. Most patients presented fever and experienced pain at the corresponding position of the aneurysm. Laboratory examination found an increased number of white blood cells accompanied by an increase in inflammatory markers. Most aneurysms were found in the abdominal aorta, while the rupture of an aneurysm was the most common complication. The mortality rates were 21.43 and 7.14% after open surgery or endovascular aneurysm repair (EVAR) intervention, respectively. The recurrence rates of infection were 0 and 17.85% for both treatments, respectively. The mortality rate of mycotic aneurysm caused by Salmonella infection was high in middle-aged males with hypertension, diabetes, and atherosclerosis. The possibility of a Salmonella-infected aneurysm should be considered in these high-risk groups presenting chills, fever, chest, and back pain. Open surgery was superior to EVAR treatment in the clearance of infected foci and the reduction of postoperative recurrence. The recurrence of postoperative infection can be prevented by intravenous antibiotic therapy for 6 weeks post-surgery.

The in vitro and in vivo protective effects of tannin derivatives against Salmonella enterica serovar Typhimurium infection.

In this study, we investigated the protective effects of tannin-derived components, gallic acid (GA) and tannic acid (TA), in vitro and in vivo against Salmonella infection in mice. Both GA and TA showed antibacterial effects against Salmonella (S.) Typhimurium as well as inhibitory effects on the adherence, invasion, and intracellular growth of the pathogens in macrophages. Following a lethal dose of Salmonella infection in mice, reduced virulence in both GA- and TA-treated groups was observed based on reduced mortality rates. In the non-infected groups, the average weights of the spleens and livers of GA- or TA-treated mice were not significantly different with the control group. In addition, the average weights of these organs in all of the Salmonella-infected groups were not significantly different but the numbers of bacteria in the spleens and livers in both GA- and TA-treated mice were significantly reduced. The levels of cytokine production in non-infected mice revealed that GA-treated and TA-treated mice elicited an increased level of IFN-γ, and both IFN-γ and MCP-1, respectively, as compared with the PBS-treated group. These findings highlight the potential of GA and TA as alternatives for the treatment of salmonellosis and as supplements to conventional antimicrobial food additives.

Human genetic and metabolite variation reveals that methylthioadenosine is a prognostic biomarker and an inflammatory regulator in sepsis.

Sepsis is a deleterious inflammatory response to infection with high mortality. Reliable sepsis biomarkers could improve diagnosis, prognosis, and treatment. Integration of human genetics, patient metabolite and cytokine measurements, and testing in a mouse model demonstrate that the methionine salvage pathway is a regulator of sepsis that can accurately predict prognosis in patients. Pathway-based genome-wide association analysis of nontyphoidal Salmonella bacteremia showed a strong enrichment for single-nucleotide polymorphisms near the components of the methionine salvage pathway. Measurement of the pathway's substrate, methylthioadenosine (MTA), in two cohorts of sepsis patients demonstrated increased plasma MTA in nonsurvivors. Plasma MTA was correlated with levels of inflammatory cytokines, indicating that elevated MTA marks a subset of patients with excessive inflammation. A machine-learning model combining MTA and other variables yielded approximately 80% accuracy (area under the curve) in predicting death. Furthermore, mice infected with Salmonella had prolonged survival when MTA was administered before infection, suggesting that manipulating MTA levels could regulate the severity of the inflammatory response. Our results demonstrate how combining genetic data, biomolecule measurements, and animal models can shape our understanding of disease and lead to new biomarkers for patient stratification and potential therapeutic targeting.

Clinical and microbiological features of invasive nontyphoidal Salmonella associated with HIV-infected patients, Gauteng Province, South Africa.

The aim of this study was to define factors associated with HIV-infected versus uninfected patients with invasive nontyphoidal Salmonella (iNTS) and factors associated with mortality, which are inadequately described in Africa.Laboratory-based surveillance for iNTS was undertaken. At selected sentinel sites, clinical data (age, sex, HIV status, severity of illness, and outcome) were collected.Surveillance was conducted in Gauteng, South Africa, from 2003 to 2013. Clinical and microbiological differences between HIV-infected and uninfected patients were defined and risk factors for mortality established.Of 4886 iNTS infections in Gauteng from 2003 to 2013, 3106 (63.5%) were diagnosed at sentinel sites. Among persons with iNTS infections, more HIV-infected persons were aged ≥5 years (χ = 417.6; P < 0.001) and more HIV-infected children were malnourished (χ = 5.8; P = 0.02). Although 760 (30.6%) patients died, mortality decreased between 2003 [97/263 (36.9%)] and 2013 [926/120 (21.7%)]. On univariate analysis, mortality was associated with patients aged 25 to 49 years [odds ratio (OR) = 2.2; 95% confidence interval (CI) = 1.7-2.7; P < 0.001 and ≥50 years (OR = 3.0; 95% CI = 2.2-4.1; P < 0.001) compared with children < 5 years, HIV-infected patients (OR = 2.4; 95% CI = 1.7-3.4; P < 0.001), and severe illness (OR = 5.4; 95% CI = 3.6-8.1; P < 0.001). On multivariate analysis, mortality was associated with patients aged ≥50 years [adjusted OR (AOR) = 3.6, 95% CI = 2.1-6.1, P < 0.001] and severe illness (AOR = 6.3; 95% CI = 3.8-10.5; P < 0.001).Mortality due to iNTS in Gauteng remains high primarily due to disease severity. Interventions must be aimed at predisposing conditions, including HIV, other immune-suppressive conditions, and malignancy.

Salmonella enterica subspecies arizonae infection of adult patients in Southern Taiwan: a case series in a non-endemic area and literature review.

BACKGROUND: The majority of Salmonella arizonae human infections have been reported in southwestern United States, where rattlesnake-based products are commonly used to treat illness; however, little is known in non-endemic areas. We reviewed and analyzed the clinical manifestations and treatment outcomes in adult patients with S. arizonae infection at our institution. METHOD: A retrospective study was conducted at a regional teaching hospital in southern Taiwan from July 2007 to June 2014. All adult patients diagnosed with S. arizonae infections and treated for at least three days at Chia-Yi Christian Hospital were included. Patients were followed till discharge. RESULTS: A total of 18 patients with S. arizonae infections (median age: 63.5 years) were enrolled for analysis, of whom two thirds were male. The three leading underlying diseases were diabetes mellitus, peptic ulcer disease and malignancy. Ten patients had bacteraemia and the most common infection focus was the lower respiratory tract. Most of the patients (72.2%) received third-generation cephalosporins as definitive therapy. In contrast, ampicillin-based regimens (accounting for 45.2%) were the major treatment modalities in previous reports. The crude in-hospital mortality was 5.6%, which was much lower than what was previously reported (22.7%). CONCLUSIONS: Though uncommon, there were cases of S. arizonae infections in Taiwan. Patients receiving third-generation cephalosporins treatment had better prognosis compared with those treated with ampicillin-based regimen.

Cytokine Profiles during Invasive Nontyphoidal Salmonella Disease Predict Outcome in African Children.

Nontyphoidal Salmonella is a leading cause of sepsis in African children. Cytokine responses are central to the pathophysiology of sepsis and predict sepsis outcome in other settings. In this study, we investigated cytokine responses to invasive nontyphoidal Salmonella (iNTS) disease in Malawian children. We determined serum concentrations of 48 cytokines with multiplexed immunoassays in Malawian children during acute iNTS disease (n = 111) and in convalescence (n = 77). Principal component analysis and logistic regression were used to identify cytokine signatures of acute iNTS disease. We further investigated whether these responses are altered by HIV coinfection or severe malnutrition and whether cytokine responses predict inpatient mortality. Cytokine changes in acute iNTS disease were associated with two distinct cytokine signatures. The first is characterized by increased concentrations of mediators known to be associated with macrophage function, and the second is characterized by raised pro- and anti-inflammatory cytokines typical of responses reported in sepsis secondary to diverse pathogens. These cytokine responses were largely unaltered by either severe malnutrition or HIV coinfection. Children with fatal disease had a distinctive cytokine profile, characterized by raised mediators known to be associated with neutrophil function. In conclusion, cytokine responses to acute iNTS infection in Malawian children are reflective of both the cytokine storm typical of sepsis secondary to diverse pathogens and the intramacrophage replicative niche of NTS. The cytokine profile predictive of fatal disease supports a key role of neutrophils in the pathogenesis of NTS sepsis.

New Role for FDA-Approved Drugs in Combating Antibiotic-Resistant Bacteria.

Antibiotic resistance in medically relevant bacterial pathogens, coupled with a paucity of novel antimicrobial discoveries, represents a pressing global crisis. Traditional drug discovery is an inefficient and costly process; however, systematic screening of Food and Drug Administration (FDA)-approved therapeutics for other indications in humans offers a rapid alternative approach. In this study, we screened a library of 780 FDA-approved drugs to identify molecules that rendered RAW 264.7 murine macrophages resistant to cytotoxicity induced by the highly virulent Yersinia pestis CO92 strain. Of these compounds, we identified 94 not classified as antibiotics as being effective at preventing Y. pestis-induced cytotoxicity. A total of 17 prioritized drugs, based on efficacy in in vitro screens, were chosen for further evaluation in a murine model of pneumonic plague to delineate if in vitro efficacy could be translated in vivo Three drugs, doxapram (DXP), amoxapine (AXPN), and trifluoperazine (TFP), increased animal survivability despite not exhibiting any direct bacteriostatic or bactericidal effect on Y. pestis and having no modulating effect on crucial Y. pestis virulence factors. These findings suggested that DXP, AXPN, and TFP may modulate host cell pathways necessary for disease pathogenesis. Finally, to further assess the broad applicability of drugs identified from in vitro screens, the therapeutic potential of TFP, the most efficacious drug in vivo, was evaluated in murine models of Salmonella enterica serovar Typhimurium and Clostridium difficile infections. In both models, TFP treatment resulted in increased survivability of infected animals. Taken together, these results demonstrate the broad applicability and potential use of nonantibiotic FDA-approved drugs to combat respiratory and gastrointestinal bacterial pathogens.

The efficacy of autologous femoropopliteal vein reconstruction for primary aortic and aortic graft infection.

BACKGROUND: The objective of our study was to analyze the efficacy of autologous superficial femoropopliteal vein reconstruction for primary aortic or aortic graft infection. METHODS: We performed a retrospective analysis of 14 patients treated for an infected aortic prosthesis or primary infected aorta between 2012 and 2014. Three patients had a primary mycotic aneurysm caused by a Salmonella or Coxiella burnetti infection. Seven patients were treated previously for aortic aneurysms with a conventional Dacron vascular prosthesis and 4 with an endovascular prosthesis. All infected prostheses were explanted via median laparotomy with subsequent debridement of the aortic aneurysm wall. Aortic reconstruction was performed with 1 or 2 superficial femoropopliteal veins, interpositioning the greater omentum when possible. The primary outcome measure was 30-day mortality. Secondary outcome measures were reoperation, operating time, amputation rate, length of intensive care unit (ICU) and hospital stay, reinfection rate, and limb edema requiring compression therapy. RESULTS: The 30-day mortality was 28%. Two patients died of an abdominal sepsis, one patient of a cerebrovascular accident and another of a hypovolemic shock. One patient died at home 2 years after surgery of unknown cause. Four patients required a reoperation. The median intraoperative blood loss was 1,500 mL (500-8000). Median operating time was 364 min (264-524). Median length of ICU stay was 3.5 days (1-47), and median hospital stay was 20 days (10-47). There were no limb amputations. Mild edema of the donor leg was documented in 2 patients. Compression stockings were not worn by any patients. Postoperative antibiotic treatment was administered for at least 6 weeks. No recurrent infections were diagnosed. CONCLUSIONS: Autologous venous reconstruction of the aorta offers advantages over other therapeutic approaches and deserves a prominent place in the treatment of the primary infected aorta or an infected aortic prosthetic graft.

Loss of the lac operon contributes to Salmonella invasion of epithelial cells through derepression of flagellar synthesis.

Salmonella, a genus that is closely related to Escherichia coli, includes many pathogens of humans and other animals. A notable feature that distinguishes Salmonella from E. coli is lactose negativity, because the lac operon is lost in most Salmonella genomes. Here, we expressed the lac operon in Salmonella enterica serovar Typhimurium and compared the virulence of the Lac(+) strain to that of the wild-type strain in a murine model, invasion assays, and macrophage replication assays. We showed that the Lac(+) strain is attenuated in vivo and the attenuation of virulence is caused by its defect in epithelial cell invasion. However, the invasion-defective phenotype is unrelated to lactose utilization. Through sequencing and the comparison of the transcriptome profile between the Lac(+) and wild-type strains during invasion, we found that most flagellar genes were markedly downregulated in the Lac(+) strain, while other genes associated with invasion, such as the majority of genes encoded in Salmonella pathogenicity island 1, were not differentially expressed. Moreover, we discovered that lacA is the major repressor of flagellar gene expression in the lac operon. In conclusion, these data demonstrate that the lac operon decreases Salmonella invasion of epithelial cells through repression of flagellar biosynthesis. As the ability to invade epithelial cells is a critical virulence determinant of Salmonella, our results provide important evidence that the loss of the lac operon contributes to the evolution of Salmonella pathogenicity.

Treatment of infected abdominal aortic aneurysm caused by Salmonella.

BACKGROUND: We reviewed the outcomes of patients treated for nontyphoidal Salmonella-infected abdominal aortic aneurysm (AAA) treatment at a single center. METHODS: This was a retrospective chart review of 26 patients with nontyphoidal Salmonella-infected AAA. Four patients underwent medical therapy alone, while 22 patients underwent surgical therapy. Revascularization method selection was dependent on preoperative antibiotic response in the surgical therapy group. RESULTS: The in-hospital mortality rate for the surgical therapy group was 14%, while the rate for the medical therapy group was 100%. Overall survival for the surgical therapy group was 82%, while the reinfection rate was 9%. In the surgical therapy group, 2 patients had periaortic abscesses and underwent in situ prosthetic graft replacement; none developed graft-related complications or died in the hospital. Kaplan-Meier analysis and log-rank testing revealed no significant differences in graft-related complication and overall survival rates between in situ prosthetic graft group and extra-anatomic bypass group. Salmonella choleraesuis had a higher antimicrobial resistance rate than other isolates. The predictors of survival were clinical presentation of abdominal pain and receiving surgical therapy. CONCLUSIONS: If patients with Salmonella-infected AAAs have good responses to preoperative antibiotic therapy, in situ prosthetic graft replacement is a viable revascularization method, even in the situation of periaortic abscess presentation formation.

Suppression of hepcidin expression and iron overload mediate Salmonella susceptibility in ankyrin 1 ENU-induced mutant.

Salmonella, a ubiquitous Gram-negative intracellular bacterium, is a food borne pathogen that infects a broad range of hosts. Infection with Salmonella Typhimurium in mice is a broadly recognized experimental model resembling typhoid fever in humans. Using a N-ethyl-N-nitrosurea (ENU) mutagenesis recessive screen, we report the identification of Ity16 (Immunity to Typhimurium locus 16), a locus responsible for increased susceptibility to infection. The position of Ity16 was refined on chromosome 8 and a nonsense mutation was identified in the ankyrin 1 (Ank1) gene. ANK1 plays an important role in the formation and stabilization of the red cell cytoskeleton. The Ank1(Ity16/Ity16) mutation causes severe hemolytic anemia in uninfected mice resulting in splenomegaly, hyperbilirubinemia, jaundice, extramedullary erythropoiesis and iron overload in liver and kidneys. Ank1(Ity16/Ity16) mutant mice demonstrated low levels of hepcidin (Hamp) expression and significant increases in the expression of the growth differentiation factor 15 (Gdf15), erythropoietin (Epo) and heme oxygenase 1 (Hmox1) exacerbating extramedullary erythropoiesis, tissue iron deposition and splenomegaly. As the infection progresses in Ank1(Ity16/Ity16), the anemia worsens and bacterial load were high in liver and kidneys compared to wild type mice. Heterozygous Ank1(+/Ity16) mice were also more susceptible to Salmonella infection although to a lesser extent than Ank1(Ity16/Ity16) and they did not inherently present anemia and splenomegaly. During infection, iron accumulated in the kidneys of Ank1(+/Ity16) mice where bacterial loads were high compared to littermate controls. The critical role of HAMP in the host response to Salmonella infection was validated by showing increased susceptibility to infection in Hamp-deficient mice and significant survival benefits in Ank1(+/Ity16) heterozygous mice treated with HAMP peptide. This study illustrates that the regulation of Hamp and iron balance are crucial in the host response to Salmonella infection in Ank1 mutants.

Curcumin reduces the antimicrobial activity of ciprofloxacin against Salmonella typhimurium and Salmonella typhi.

OBJECTIVES: Typhoidal and non-typhoidal infection by Salmonella is a serious threat to human health. Ciprofloxacin is the last drug of choice to clear the infection. Ciprofloxacin, a gyrase inhibitor, kills bacteria by inducing chromosome fragmentation, SOS response and reactive oxygen species (ROS) in the bacterial cell. Curcumin, an active ingredient from turmeric, is a major dietary molecule among Asians and possesses medicinal properties. Our research aimed at investigating whether curcumin modulates the action of ciprofloxacin. METHOD: We investigated the role of curcumin in interfering with the antibacterial action of ciprofloxacin in vitro and in vivo. RT-PCR, DNA fragmentation and confocal microscopy were used to investigate the modulation of ciprofloxacin-induced SOS response, DNA damage and subsequent filamentation by curcumin. Chemiluminescence and nitroblue tetrazolium reduction assays were performed to assess the interference of curcumin with ciprofloxacin-induced ROS. DNA binding and cleavage assays were done to understand the rescue of ciprofloxacin-mediated gyrase inhibition by curcumin. RESULTS: Curcumin interferes with the action of ciprofloxacin thereby increasing the proliferation of Salmonella Typhi and Salmonella Typhimurium in macrophages. In a murine model of typhoid fever, mice fed with curcumin had an increased bacterial burden in the reticuloendothelial system and succumbed to death faster. This was brought about by the inhibition of ciprofloxacin-mediated downstream signalling by curcumin. CONCLUSIONS: The antioxidant property of curcumin is crucial in protecting Salmonella against the oxidative burst induced by ciprofloxacin or interferon γ (IFNγ), a pro-inflammatory cytokine. However, curcumin is unable to rescue ciprofloxacin-induced gyrase inhibition. Curcumin's ability to hinder the bactericidal action of ciprofloxacin and IFNγ might significantly augment Salmonella pathogenesis.

Control of a Salmonella virulence locus by an ATP-sensing leader messenger RNA.

The facultative intracellular pathogen Salmonella enterica resides within a membrane-bound compartment inside macrophages. This compartment must be acidified for Salmonella to survive within macrophages, possibly because acidic pH promotes expression of Salmonella virulence proteins. We reasoned that Salmonella might sense its surroundings have turned acidic not only upon protonation of the extracytoplasmic domain of a protein sensor but also by an increase in cytosolic ATP levels, because conditions that enhance the proton gradient across the bacterial inner membrane stimulate ATP synthesis. Here we report that an increase in cytosolic ATP promotes transcription of the coding region for the virulence gene mgtC, which is the most highly induced horizontally acquired gene when Salmonella is inside macrophages. This transcript is induced both upon media acidification and by physiological conditions that increase ATP levels independently of acidification. ATP is sensed by the coupling/uncoupling of transcription of the unusually long mgtC leader messenger RNA and translation of a short open reading frame located in this region. A mutation in the mgtC leader messenger RNA that eliminates the response to ATP hinders mgtC expression inside macrophages and attenuates Salmonella virulence in mice. Our results define a singular example of an ATP-sensing leader messenger RNA. Moreover, they indicate that pathogens can interpret extracellular cues by the impact they have on cellular metabolites.

Treatment of primary infected aortic aneurysm without aortic resection.

BACKGROUND: We sought to determine the safety and efficacy of two different treatment strategies for patients with primary infected aortic aneurysms, including antibiotic treatment alone and endovascular aneurysm repair (EVAR) with aggressive antibiotic treatment, as alternatives to the established treatment of open surgical repair. METHODS: We conducted a retrospective chart review of patients who were treated for infected aortic aneurysm without undergoing aortic resection from January 2000 to December 2010 at a single institution. RESULTS: A total of 40 patients underwent traditional open repair during the study period. Sixteen patients with infected aortic aneurysm (11 men; median age, 70; range, 44-80 years) were identified as not having undergone aortic resection during the 11 years reviewed in the study. Nine patients received antibiotic treatment only (group I) and seven patients underwent EVAR with aggressive antibiotic treatment (group II). Salmonella species were isolated from seven patients in group I, and oxacillin-resistant Staphylococcus aureus was isolated from the remaining two patients. In group II, six patients had blood culture results showing Salmonella species and one patient had a blood culture result showing Escherichia coli. Group I (7 of 9 patients; 78%) had a higher hospital mortality rate than group II (0%; P = .003). Mean follow-up among survivors was 10 ± 15 months (range, 1-37 months). One patient in group II developed a reinfection episode (14%). There was no significant difference between group I (67%; SE, 27.2%) and group II (86%; SE, 13.2%) in the 3-month survival rates (log-rank, P = .39). CONCLUSIONS: Our results support the premise that EVAR is beneficial for the patients with infected aortic aneurysm. Treating an infected aortic aneurysm with antibiotics alone could not stop aneurysm expansion and eradicate the aortic infection before the aneurysm ruptures. For the patients with infected aortic aneurysms who have limited life expectancy and multiple comorbidities, EVAR with aggressive antibiotic treatment should be considered preferentially over antibiotic treatment alone.

Non-typhoidal Salmonella bacteremia among adults: an adverse prognosis in patients with malignancy.

BACKGROUND: Clinical information about non-typhoidal Salmonella (NTS) bacteremia in patients with malignancy has rarely been described. This study investigated clinical characteristics and prognostic variables of patients with malignancy while complicated with NTS bacteremia. METHODS: The study included demographic data, clinical information, and outcome in adults (≥18 years old) with and without malignancy complicated with NTS bacteremia at a medical center from 2000 to 2009. RESULTS: There were 206 patients with NTS bacteremia. The serogroups of NTS isolates included group B (40.2%), group D (30.9%), group C (26.5%), and group E (1.5%). Extraintestinal infections were noted in 66 (32.4%) patients and were mainly endovascular (26/206, 12.7%) or pleuropulmonary (17/206, 8.3%) infections. On multivariate analysis, independent factors for in-hospital mortality included shock (odds ratio [OR] 9.13; 95% confidence interval [CI] 3.81-21.83; p < 0.001), malignancy (OR 8.42; 95% CI 3.12-22.71; p < 0.001), and acute renal failure (OR 2.63; 95% CI 1.11-6.22; p = 0.028). Different clinical presentations and outcome were noted in 74 (36.2%) patients with malignancy and 130 without malignancy. The former had more leucopenia and thrombocytopenia at initial presentation and fewer extraintestinal infections (20.2% vs. 39.2%, p = 0.005), endovascular infections (2.7% vs. 18.5%; p = 0.002), and serovar Choleraesuis (10.8% vs. 27.7%; p = 0.005). An elevated in-hospital mortality rate was noted in patients with malignancy compared to those without malignancy (40.5% vs. 17.7%, p < 0.001). Among patients with malignancy, multivariate analysis revealed that shock was the only independent factor associated with in-hospital mortality (OR 7.52; 95% CI, 2.38-23.80; p = 0.001). CONCLUSION: Malignancy is an adverse prognostic factor in patients with NTS bacteremia. Food safety in patients with malignancy should be emphasized to prevent salmonellosis.