Effect of biannual azithromycin distribution on antibody responses to malaria, bacterial, and protozoan pathogens in Niger.

The MORDOR trial in Niger, Malawi, and Tanzania found that biannual mass distribution of azithromycin to children younger than 5 years led to a 13.5% reduction in all-cause mortality (NCT02048007). To help elucidate the mechanism for mortality reduction, we report IgG responses to 11 malaria, bacterial, and protozoan pathogens using a multiplex bead assay in pre-specified substudy of 30 communities in the rural Niger placebo-controlled trial over a three-year period (n = 5642 blood specimens, n = 3814 children ages 1-59 months). Mass azithromycin reduces Campylobacter spp. force of infection by 29% (hazard ratio = 0.71, 95% CI: 0.56, 0.89; P = 0.004) but serological measures show no significant differences between groups for other pathogens against a backdrop of high transmission. Results align with a recent microbiome study in the communities. Given significant sequelae of Campylobacter infection among preschool aged children, our results support an important mechanism through which biannual mass distribution of azithromycin likely reduces mortality in Niger.

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.

Genomic characterization of Salmonella Uzaramo for human invasive infection.

Salmonella is composed of a wide variety of serovars, causing human self-limited gastrointestinal illnesses or invasive infections. Invasive non-typhoidal Salmonella (iNTS) is well documented, with high mortality for children and immunocompromised adults in sub-Saharan Africa and has recently been reported in Southeast Asia. However, iNTS in China remains unknown. In May 2019, a case of invasive infection caused by Salmonella enterica serovar Uzaramo (S. Uzaramo) was reported for the first time in China. Phylogenomic analysis was performed by genomic sequencing the available contextualized isolates, which separated the two Chinese strains into different sublineages. Both phenotypic and genomic characterization demonstrated that the S. Uzaramo isolates showed in general low antimicrobial resistance potential, except one isolated from lake-water in China. Additional comparative genomic analysis and Caenorhabditis elegans killing assays suggested a unique combination of virulence factors, including typhoid toxin and tcf fimbrial adhesin, which might play a role in the invasive infection. This study highlights that the transparency of global surveillance genomic data could accelerate understanding of virulence and antimicrobial resistance makeup of a previously unknown threat.

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.

Cinnamaldehyde inhibits type three secretion system in Salmonella enterica serovar Typhimurium by affecting the expression of key effector proteins.

The increasing understanding of bacterial pathogenesis has revealed many new targets for the development of non-traditional antibacterial drugs. Interference with bacterial virulence has become a new strategy to treat bacteria-mediated diseases. As an important food-borne pathogen, Salmonella enterica serovar Typhimurium uses type III secretion system (T3SS) to facilitate invasion of host cells. In this study, we identified cinnamaldehyde as a Salmonella pathogenicity island 1 (SPI-1) inhibitor which blocks the secretion of several SPI-1 associated effector proteins and consequently exhibits a strong inhibitory effect on SPI-1-mediated invasion of HeLa cells. Further study revealed that cinnamaldehyde significantly reduced the transcription of some SPI-1 genes, such as sipA and sipB, in S. Typhimurium by affecting multiple SPI-1 regulator genes. In an animal infection model, cinnamaldehyde effectively protected infected mice against S. Typhimurium-induced mortality and pathological damages. In summary, this study presented an effective SPI-1 inhibitor, cinnamaldehyde, which reduces the expression of SPI-1 effector proteins by regulating the transcription of main regulator genes.

The global burden of non-typhoidal salmonella invasive disease: a systematic analysis for the Global Burden of Disease Study 2017.

BACKGROUND: Non-typhoidal salmonella invasive disease is a major cause of global morbidity and mortality. Malnourished children, those with recent malaria or sickle-cell anaemia, and adults with HIV infection are at particularly high risk of disease. We sought to estimate the burden of disease attributable to non-typhoidal salmonella invasive disease for the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017. METHODS: We did a systematic review of scientific databases and grey literature, and estimated non-typhoidal salmonella invasive disease incidence and mortality for the years 1990 to 2017, by age, sex, and geographical location using DisMod-MR, a Bayesian meta-regression tool. We estimated case fatality by age, HIV status, and sociodemographic development. We also calculated the HIV-attributable fraction and estimated health gap metrics, including disability-adjusted life-years (DALYs). FINDINGS: We estimated that 535 000 (95% uncertainty interval 409 000-705 000) cases of non-typhoidal salmonella invasive disease occurred in 2017, with the highest incidence in sub-Saharan Africa (34·5 [26·6-45·0] cases per 100 000 person-years) and in children younger than 5 years (34·3 [23·2-54·7] cases per 100 000 person-years). 77 500 (46 400-123 000) deaths were estimated in 2017, of which 18 400 (12 000-27 700) were attributable to HIV. The remaining 59 100 (33 300-98 100) deaths not attributable to HIV accounted for 4·26 million (2·38-7·38) DALYs in 2017. Mean all-age case fatality was 14·5% (9·2-21·1), with higher estimates among children younger than 5 years (13·5% [8·4-19·8]) and elderly people (51·2% [30·2-72·9] among those aged ≥70 years), people with HIV infection (41·8% [30·0-54·0]), and in areas of low sociodemographic development (eg, 15·8% [10·0-22·9] in sub-Saharan Africa). INTERPRETATION: We present the first global estimates of non-typhoidal salmonella invasive disease that have been produced as part of GBD 2017. Given the high disease burden, particularly in children, elderly people, and people with HIV infection, investigating the sources and transmission pathways of non-typhoidal salmonella invasive disease is crucial to implement effective preventive and control measures. FUNDING: Bill & Melinda Gates Foundation.

Modeling and Cost Benefit Analysis to Guide Deployment of POC Diagnostics for Non-typhoidal Salmonella Infections with Antimicrobial Resistance.

Invasive non-typhoidal Salmonella (NTS) is among the leading causes of blood stream infections in sub-Saharan Africa and other developing regions, especially among pediatric populations. Invasive NTS can be difficult to treat and have high case-fatality rates, in part due to emergence of strains resistant to broad-spectrum antibiotics. Furthermore, improper treatment contributes to increased antibiotic resistance and death. Point of care (POC) diagnostic tests that rapidly identify invasive NTS infection, and differentiate between resistant and non-resistant strains, may greatly improve patient outcomes and decrease resistance at the community level. Here we present for the first time a model for NTS dynamics in high risk populations that can analyze the potential advantages and disadvantages of four strategies involving POC diagnostic deployment, and the resulting impact on antimicrobial treatment for patients. Our analysis strongly supports the use of POC diagnostics coupled with targeted antibiotic use for patients upon arrival in the clinic for optimal patient and public health outcomes. We show that even the use of imperfect POC diagnostics can significantly reduce total costs and number of deaths, provided that the diagnostic gives results quickly enough that patients are likely to return or stay to receive targeted treatment.

An attenuated Salmonella vaccine secreting Lawsonia intracellularis immunogenic antigens confers dual protection against porcine proliferative enteropathy and salmonellosis in a murine model.

Porcine proliferative enteropathy (PPE) caused by Lawsonia intracellularis (LI) is a global cause for substantial economic losses in the swine industry. Here, we constructed live attenuated Salmonella typhimurium (ST) mutant strains expressing and secreting 4 selected immunogenic LI antigens, namely, optA, optB, Lawsonia flagellin (LfliC), and Lawsonia hemolysin (Lhly); the resultant recombinant strains were designated Sal-optA, Sal-optB, Sal-LfliC, or Sal-Lhly, respectively. Using the BALB/c mouse model, we demonstrate that mice vaccinated once orally, either with a mixture of all 4 recombinant strains or with an individual recombinant strain, show significant (p < 0.05) production of LI-specific systemic immunoglobulin (Ig) G and mucosal IgA responses compared to the Salmonella alone group. Upon restimulation of vaccinated splenocytes with the LI-specific antigens, significant (p < 0.05) and comparable production of interferon-γ responses are found in all vaccinated groups, except the Sal-Lhly group, which shows non-significant levels. Challenge studies were performed in C57BL/6 vaccinated mice. On challenge with the LI (106.9 50% tissue culture infectious dose) 14 days post-vaccination, 20% (1/5) of mice in all vaccinated groups, except Sal-Lhly group, show the presence of the LI-specific genomic DNA (gDNA) in stool samples. In contrast, 40% (2/5) and 60% (3/5) of mice vaccinated with the Sal-Lhly strain and the attenuated Salmonella alone, respectively, were found positive for the LI-specific gDNA. Furthermore, 0% mortality was observed in mice vaccinated against the ST challenge compared to the 30% mortality observed in the unvaccinated control group. In conclusion, we demonstrate that the Salmonella-based LI-vaccines induce LI-specific humoral and cell-mediated immunities, and encompass the potential to offer dual protection against PPE and salmonellosis.

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.

Non-Typhi, non-Paratyphi Salmonella-related hospitalisations in Spain: trends, clinical aspects, risk factors for worse prognosis and hospital costs.

This study reviews non-typhoid Salmonella (NTS)-related hospitalisations at National level in Spain between 2010 and 2015. NTS hospitalisations were obtained from the National Registry of Hospitalisations. A descriptive analysis of the hospitalisations was performed, including hospitalisation rates (HR) and case-fatality rates (CFR%) calculation. For those with NTS as Main Diagnosis logistic regression were used to estimate the relationship between the different factors and death outcome. 21,660 registered NTS-related hospitalisations were described (88.8% with Salmonella coded as Main Diagnosis). Average HR2010-2015 was 7.7 (range, 7.3 to 8.1) hospitalisations/100,000 population. Those with NTS infections as Secondary Diagnosis were on average (p < 0.001) older (47.9 vs. 36.5 years), presented worse Charlson Comorbidity Index (2.1 vs. 1.2), higher CFR% (4.8% vs. 0.7%), spent more days hospitalised (15.1 vs. 5.8 days), and generated more costs (6173 vs. 4272 euros/per hospitalisation) than those with NTS as Main Diagnosis. For those with NTS as Main Diagnosis increased risk of death was related to being > 64 years old (OR = 20.99; p < 0.001); presenting septicaemia (OR = 15.82; p < 0.001) or localised infections (OR = 3.98; p = 0.061); Charlson Comorbidity Index > 3 (OR = 4.57; p < 0.001); a non-HIV co-infection (OR = 1.80; p = 0.013); other risk factors (OR = 5.70; p < 0.001); bowel perforation (OR = 70.30; p < 0.001); or acute renal failure (OR = 1.95; p = 0.001). In those with Salmonella as Main Diagnosis, among all complications, bowel perforation presented the strongest association with death outcome. Clinical practice guidelines can help to identify patients at risk of bowel perforation to reduce the fatality of the disease.

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.

Health Outcomes from Multidrug-Resistant Salmonella Infections in High-Income Countries: A Systematic Review and Meta-Analysis.

BACKGROUND: Salmonella is a leading cause of foodborne enterocolitis worldwide. Antimicrobial use in food animals is the driving force for antimicrobial resistance among Salmonella particularly in high-income countries. Nontyphoidal Salmonella (NTS) infections that are multidrug resistant (MDR) (nonsusceptible to ≥1 agent in ≥3 antimicrobial categories) may result in more severe health outcomes, although these effects have not been systematically examined. We conducted a systematic review and meta-analysis to examine impacts of MDR NTS on disease outcomes in high-income settings. METHODS: We systematically reviewed the literature from scientific databases, including PubMed, Scopus, and grey literature sources, using preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. We included peer-reviewed publications of case-control and cohort studies, outbreak investigations, and published theses, imposing no language restriction. We included publications from January 1, 1990 through September 15, 2016 from high-income countries as classified by the World Bank, and extracted data on duration of illness, hospitalization, morbidity and mortality of MDR, and pan-susceptible NTS infections. RESULTS: After removing duplicates, the initial search revealed 4258 articles. After further screening, 16 eligible studies were identified for the systematic review, but, only 9 of these were included in the meta-analysis. NTS serotypes differed among the reported studies, but serotypes Typhimurium, Enteritidis, Newport, and Heidelberg were the most often reported MDR pathogens. Salmonella infections that were MDR were associated with excess bloodstream infections (odds ratio [OR] 1.73; 95% confidence interval [CI] 1.32-2.27), more frequent hospitalizations (OR 2.51; 95% CI 1.38-4.58), and higher mortality (OR 3.54; 95% CI 1.10-11.40) when compared with pan-susceptible isolates. CONCLUSIONS: Our study suggests that MDR NTS infections have more serious health outcomes compared with pan-susceptible strains. With the emergence of MDR Salmonella strains in high-income countries, it is crucial to reduce the use of antimicrobials in animals and humans, and intervene to prevent foodborne infections.

Salmonellosis in Poland in 2015 and 2016

THE AIM: The aim of the study is to assess the epidemiological situation of salmonellosis in 2015-2016 in Poland, compared to the previous years. MATERIAL AND METHODS: The assessment of the epidemiological situation was performed on the basis of data from bulletins "Infectious diseases and poisonings in Poland", information from the laboratories of Sanitaryepidemiological Stations and data from epidemiological investigations of outbreaks which were provided by Sanitary-epidemiological Stations through the Register of Epidemic Outbreaks (ROE) to the Department of Epidemiology of Infectious Diseases and Surveillance as well as data from the Department of Demographic Studies of the Central Statistical Office. Cases were classified according to the implemented case definitions. RESULTS: In 2015, a total of 8 650 cases salmonellosis were reported. Among them 8 418 were cases of intestinal salmonellosis and 232 of extraintestinal one. Total incidence was 22.5/100 000. 8235 (95,2%) cases met the criteria for confirmed case and 415 cases were classified as probable. In comparison to 2014, the percentage of hospitalized persons increased slightly and remained at a high level of 71.8%. The increase of salmonellosis cases, as in previous years, occurred in the summer months. In 2015 he highest incidence was recorded in the Malopolskie and Mazowieckie voivodeships, and the lowest in the Lubuskie. Children 0-4 were most often affected, especially at the age of 2 and 3 years old. Number of reported foodborne outbreaks caused by Salmonella was 190. Among them 154 were caused by Salmonella Enteritidis. This serotype, as in previous years was the most frequently isolated. Out of the 433 571 tested people who were working with food, 0.2% were infected with Salmonella. In 2016, the total number of reported cases of salmonellosis was 10,027 cases, which was close to 16% increase in cases compared to the previous year and over 19% increase compared to 2014. There were registered 9,701 cases of intestinal and 326 extraintestinal infections. 9,713 cases were classified as confirmed, accounting for 96.9% of all and 314 cases were classified as probable ones. The percentage of hospitalizations in 2016 remained at a similar level as in previous years (71.1%). The peak of incidence as in the previous year was in July. The highest numbers of cases were recorded in the Malopolskie and Mazowieckie voivodeships, which accounted for 23% of all reported cases. As in previous years, most often affected were children at the age 0-4. In 2016 number of reported outbreaks of foodborne infections caused by Salmonella sp. was 240. In 85% of them S. Enteritidis serotype was isolated, which as in previous years was the serotype most frequently isolated in outbreaks and sporadic diseases. Among 443 419 people working with food who were tested for Salmonella 0,2% were positive, as in the previous year. CONCLUSIONS: The increase in the incidence of salmonellosis in 2015-2016 in Poland may be related to the outbreak detected in 2016, covering more than a dozen EU countries, associated with eggs originating in Poland. Observed in the last several years high percentage of hospitalizations due to salmonellosis is a consequence of rare laboratory testing for salmonellosis by GPs of patients with gastroenteritis. It also results in the low sensitivity of salmonella surveillance in Poland.

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.

Presentation of life-threatening invasive nontyphoidal Salmonella disease in Malawian children: A prospective observational study.

Nontyphoidal Salmonellae commonly cause invasive disease in African children that is often fatal. The clinical diagnosis of these infections is hampered by the absence of a clear clinical syndrome. Drug resistance means that empirical antibiotic therapy is often ineffective and currently no vaccine is available. The study objective was to identify risk factors for mortality among children presenting to hospital with invasive Salmonella disease in Africa. We conducted a prospective study enrolling consecutive children with microbiologically-confirmed invasive Salmonella disease admitted to Queen Elizabeth Central Hospital, Blantyre, in 2006. Data on clinical presentation, co-morbidities and outcome were used to identify children at risk of inpatient mortality through logistic-regression modeling. Over one calendar year, 263 consecutive children presented with invasive Salmonella disease. Median age was 16 months (range 0-15 years) and 52/256 children (20%; 95%CI 15-25%) died. Nontyphoidal serovars caused 248/263 (94%) of cases. 211/259 (81%) of isolates were multi-drug resistant. 251/263 children presented with bacteremia, 6 with meningitis and 6 with both. Respiratory symptoms were present in 184/240 (77%; 95%CI 71-82%), 123/240 (51%; 95%CI 45-58%) had gastrointestinal symptoms and 101/240 (42%; 95%CI 36-49%) had an overlapping clinical syndrome. Presentation at <7 months (OR 10.0; 95%CI 2.8-35.1), dyspnea (OR 4.2; 95%CI 1.5-12.0) and HIV infection (OR 3.3; 95%CI 1.1-10.2) were independent risk factors for inpatient mortality. Invasive Salmonella disease in Malawi is characterized by high mortality and prevalence of multi-drug resistant isolates, along with non-specific presentation. Young infants, children with dyspnea and HIV-infected children bear a disproportionate burden of the Salmonella-associated mortality in Malawi. Strategies to improve prevention, diagnosis and management of invasive Salmonella disease should be targeted at these children.

Epidemiology of Salmonella enterica Serotype Dublin Infections among Humans, United States, 1968-2013.

Salmonella enterica serotype Dublin is a cattle-adapted bacterium that typically causes bloodstream infections in humans. To summarize demographic, clinical, and antimicrobial drug resistance characteristics of human infections with this organism in the United States, we analyzed data for 1968-2013 from 5 US surveillance systems. During this period, the incidence rate for infection with Salmonella Dublin increased more than that for infection with other Salmonella. Data from 1 system (FoodNet) showed that a higher percentage of persons with Salmonella Dublin infection were hospitalized and died during 2005-2013 (78% hospitalized, 4.2% died) than during 1996-2004 (68% hospitalized, 2.7% died). Susceptibility data showed that a higher percentage of isolates were resistant to >7 classes of antimicrobial drugs during 2005-2013 (50.8%) than during 1996-2004 (2.4%).

Enteric Salmonella in humans and food in the Middle East and North Africa: protocol of a systematic review.

INTRODUCTION: Non-typhoidal Salmonella is considered one of the leading causes of foodborne disease worldwide. This protocol provides methods that will be used to synthesise available epidemiological data on non-typhoidal enteric Salmonella in humans and food in Middle East and North Africa (MENA) region and to characterise the morbidity of human salmonellosis in this region. METHODS AND ANALYSIS: A systematic review will be conducted based on the Cochrane Collaboration handbook and will be reported following the items outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We will search PubMed, Embase, CAB Direct and Global Health Library (WHO) databases in order to identify relevant reports. Additionally, the literature search will be supplemented by checking references of the included reports and the identified reviews. Furthermore, we will hand-search conference proceedings and Ministry of Health's website of each country of the MENA region. We will use comprehensive search criteria with no time and no language restrictions. We will extract data on report and study characteristics, biological assay characteristics, individuals' demographic characteristics and on primary and secondary outcomes of interest. If appropriate, meta-analysis will be conducted in order to estimate pooled prevalence measures using DerSimonian and Laird random-effects models. We will conduct meta-regression analysis to explore the effect of study-level characteristics as potential sources of heterogeneity. ETHICS AND DISSEMINATION: The results of the systematic review will be disseminated in a peer-reviewed journal and presented at relevant conferences. TRIAL REGISTRATION NUMBER: The trial registration number is CRD42016046360.

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.