103 research outputs found
More than 18,000 effectors in the Legionella genus genome provide multiple, independent combinations for replication in human cells.
The genus Legionella comprises 65 species, among which Legionella pneumophila is a human pathogen causing severe pneumonia. To understand the evolution of an environmental to an accidental human pathogen, we have functionally analyzed 80 Legionella genomes spanning 58 species. Uniquely, an immense repository of 18,000 secreted proteins encoding 137 different eukaryotic-like domains and over 200 eukaryotic-like proteins is paired with a highly conserved type IV secretion system (T4SS). Specifically, we show that eukaryotic Rho- and Rab-GTPase domains are found nearly exclusively in eukaryotes and Legionella Translocation assays for selected Rab-GTPase proteins revealed that they are indeed T4SS secreted substrates. Furthermore, F-box, U-box, and SET domains were present in >70% of all species, suggesting that manipulation of host signal transduction, protein turnover, and chromatin modification pathways are fundamental intracellular replication strategies for legionellae. In contrast, the Sec-7 domain was restricted to L. pneumophila and seven other species, indicating effector repertoire tailoring within different amoebae. Functional screening of 47 species revealed 60% were competent for intracellular replication in THP-1 cells, but interestingly, this phenotype was associated with diverse effector assemblages. These data, combined with evolutionary analysis, indicate that the capacity to infect eukaryotic cells has been acquired independently many times within the genus and that a highly conserved yet versatile T4SS secretes an exceptional number of different proteins shaped by interdomain gene transfer. Furthermore, we revealed the surprising extent to which legionellae have coopted genes and thus cellular functions from their eukaryotic hosts, providing an understanding of how dynamic reshuffling and gene acquisition have led to the emergence of major human pathogens
First insights into the vertical habitat use of the whitespotted eagle ray Aetobatus narinari revealed by popâup satellite archival tags
The whitespotted eagle ray Aetobatus narinari is a tropical to warmâtemperate benthopelagic batoid that ranges widely throughout the western Atlantic Ocean. Despite conservation concerns for the species, its vertical habitat use and diving behaviour remain unknown. Patterns and drivers in the depth distribution of A. narinari were investigated at two separate locations, the western North Atlantic (Islands of Bermuda) and the eastern Gulf of Mexico (Sarasota, Florida, U.S.A.). Between 2010 and 2014, seven popâup satellite archival tags were attached to A. narinari using three methods: a throughâtail suture, an external tailâband and throughâwing attachment. Retention time ranged from 0 to 180âdays, with tags attached via the throughâtail method retained longest. Tagged rays spent the majority of time (82.85â±â12.17% S.D.) within the upper 10 m of the water column and, with one exception, no rays travelled deeper than ~26âm. One Bermuda ray recorded a maximum depth of 50.5 m, suggesting that these animals make excursions off the foreâreef slope of the Bermuda Platform. Individuals occupied deeper depths (7.42â±â3.99âm S.D.) during the day versus night (4.90â±â2.89âm S.D.), which may be explained by foraging and/or predator avoidance. Each individual experienced a significant difference in depth and temperature distributions over the diel cycle. There was evidence that mean hourly depth was best described by location and individual variation using a generalized additive mixed model approach. This is the first study to compare depth distributions of A. narinari from different locations and describe the thermal habitat for this species. Our study highlights the importance of region in describing A. narinari depth use, which may be relevant when developing management plans, whilst demonstrating that diel patterns appear to hold across individuals
Typhoid fever in Fiji: a reversible plague?
Le pays des Ăźles Fidji, avec une population d\u27environ 870 000 personnes, fait face Ă une charge croissante de plusieurs maladies transmissibles, y compris l\u27infection bactĂ©rienne de la fiĂšvre typhoĂŻde. Les donnĂ©es de surveillance indiquent que la fiĂšvre typhoĂŻde est devenue de plus en plus frĂ©quente dans les zones rurales de Fidji et est plus frĂ©quente chez les jeunes adultes. La transmission des organismes qui causent la fiĂšvre typhoĂŻde est facilitĂ©e par la contamination fĂ©cale des aliments ou de l\u27eau et peut ĂȘtre influencĂ©e par les pratiques comportementales locales dans les Ăźles Fidji. Le MinistĂšre fidjien de la SantĂ©, avec le soutien de l\u27aide australienne, a organisĂ© une rĂ©union en aoĂ»t 2012 afin dâĂ©laborer des stratĂ©gies complĂštes de lutte et de prĂ©vention de la fiĂšvre typhoĂŻde Ă Fidji. Les spĂ©cialistes internationaux et locaux ont Ă©tĂ© invitĂ©s Ă partager les donnĂ©es pertinentes et discuter des options de lutte contre la typhoĂŻde. Les recommandations qui en ont rĂ©sultĂ© sont axĂ©es sur lâĂ©tablissement d\u27une vision plus claire de lâĂ©pidĂ©miologie de la fiĂšvre typhoĂŻde Ă Fidji et l\u27exploration de la contribution de potentielles voies de transmission. En outre, le comitĂ© a suggĂ©rĂ© des Ă©tapes telles que l\u27assurance que les doses recommandĂ©es de ciprofloxacine soient appropriĂ©es afin de rĂ©duire le risque possible de rechute et de rĂ©infection dans les cas cliniques, l\u27encouragement d\u27une hygiĂšne correcte des mains pour les manipulateurs d\u27aliments et de boissons, le travail en collaboration avec les agences de l\u27eau et de l\u27assainissement afin d\u27analyser les pratiques actuelles d\u27assainissement et la considĂ©ration d\u27une politique de vaccination ciblant les populations Ă©pidĂ©miologiquement concernĂ©es
An African Salmonella Typhimurium ST313 sublineage with extensive drug-resistance and signatures of host adaptation
Abstract: Bloodstream infections by Salmonella enterica serovar Typhimurium constitute a major health burden in sub-Saharan Africa (SSA). These invasive non-typhoidal (iNTS) infections are dominated by isolates of the antibiotic resistance-associated sequence type (ST) 313. Here, we report emergence of ST313 sublineage II.1 in the Democratic Republic of the Congo. Sublineage II.1 exhibits extensive drug resistance, involving a combination of multidrug resistance, extended spectrum ÎČ-lactamase production and azithromycin resistance. ST313 lineage II.1 isolates harbour an IncHI2 plasmid we name pSTm-ST313-II.1, with one isolate also exhibiting decreased ciprofloxacin susceptibility. Whole genome sequencing reveals that ST313 II.1 isolates have accumulated genetic signatures potentially associated with altered pathogenicity and host adaptation, related to changes observed in biofilm formation and metabolic capacity. Sublineage II.1 emerged at the beginning of the 21st century and is involved in on-going outbreaks. Our data provide evidence of further evolution within the ST313 clade associated with iNTS in SSA
Genomic and phenotypic variation in epidemic-spanning Salmonella enterica serovar Enteritidis isolates.
BACKGROUND: Salmonella enterica serovar Enteritidis (S. Enteritidis) has caused major epidemics of gastrointestinal infection in many different countries. In this study we investigate genome divergence and pathogenic potential in S. Enteritidis isolated before, during and after an epidemic in Uruguay. RESULTS: 266 S. Enteritidis isolates were genotyped using RAPD-PCR and a selection were subjected to PFGE analysis. From these, 29 isolates spanning different periods, genetic profiles and sources of isolation were assayed for their ability to infect human epithelial cells and subjected to comparative genomic hybridization using a Salmonella pan-array and the sequenced strain S. Enteritidis PT4 P125109 as reference. Six other isolates from distant countries were included as external comparators.Two hundred and thirty three chromosomal genes as well as the virulence plasmid were found as variable among S. Enteritidis isolates. Ten out of the 16 chromosomal regions that varied between different isolates correspond to phage-like regions. The 2 oldest pre-epidemic isolates lack phage SE20 and harbour other phage encoded genes that are absent in the sequenced strain. Besides variation in prophage, we found variation in genes involved in metabolism and bacterial fitness. Five epidemic strains lack the complete Salmonella virulence plasmid. Significantly, strains with indistinguishable genetic patterns still showed major differences in their ability to infect epithelial cells, indicating that the approach used was insufficient to detect the genetic basis of this differential behaviour. CONCLUSION: The recent epidemic of S. Enteritidis infection in Uruguay has been driven by the introduction of closely related strains of phage type 4 lineage. Our results confirm previous reports demonstrating a high degree of genetic homogeneity among S. Enteritidis isolates. However, 10 of the regions of variability described here are for the first time reported as being variable in S. Enteritidis. In particular, the oldest pre-epidemic isolates carry phage-associated genetic regions not previously reported in S. Enteritidis. Overall, our results support the view that phages play a crucial role in the generation of genetic diversity in S. Enteritidis and that phage SE20 may be a key marker for the emergence of particular isolates capable of causing epidemics
Low-dose salinomycin induces anti-leukemic responses in AML and MLL
Development of anti-cancer drugs towards clinical application is costly and inefficient. Large screens of drugs, efficacious for non-cancer disease, are currently being used to identify candidates for repurposing based on their anti-cancer properties. Here, we show that low-dose salinomycin, a coccidiostat ionophore previously identified in a breast cancer screen, has anti-leukemic efficacy. AML and MLLr cell lines, primary cells and patient samples were sensitive to submicromolar salinomycin. Most strikingly, colony formation of normal hematopoietic cells was unaffected by salinomycin, demonstrating a lack of hemotoxicity at the effective concentrations. Furthermore, salinomycin treatment of primary cells resulted in loss of leukemia repopulation ability following transplantation, as demonstrated by extended recipient survival compared to controls. Bioinformatic analysis of a 17-gene signature identified and validated in primary MLLr cells, uncovered immunomodulatory pathways, hubs and protein interactions as potential transducers of low dose salinomycin treatment. Additionally, increased protein expression of p62/Sqstm1, encoded for by one of the 17 signature genes, demonstrates a role for salinomycin in aggresome/vesicle formation indicative of an autophagic response.Together, the data support the efficacy of salinomycin as an anti-leukemic at non-hemotoxic concentrations. Further investigation alone or in combination with other therapies is warranted for future clinical trial
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Ventilator-associated pneumonia in critically ill patients with COVID-19
Abstract: Background: Pandemic COVID-19 caused by the coronavirus SARS-CoV-2 has a high incidence of patients with severe acute respiratory syndrome (SARS). Many of these patients require admission to an intensive care unit (ICU) for invasive ventilation and are at significant risk of developing a secondary, ventilator-associated pneumonia (VAP). Objectives: To study the incidence of VAP and bacterial lung microbiome composition of ventilated COVID-19 and non-COVID-19 patients. Methods: In this retrospective observational study, we compared the incidence of VAP and secondary infections using a combination of microbial culture and a TaqMan multi-pathogen array. In addition, we determined the lung microbiome composition using 16S RNA analysis in a subset of samples. The study involved 81 COVID-19 and 144 non-COVID-19 patients receiving invasive ventilation in a single University teaching hospital between March 15th 2020 and August 30th 2020. Results: COVID-19 patients were significantly more likely to develop VAP than patients without COVID (Cox proportional hazard ratio 2.01 95% CI 1.14â3.54, p = 0.0015) with an incidence density of 28/1000 ventilator days versus 13/1000 for patients without COVID (p = 0.009). Although the distribution of organisms causing VAP was similar between the two groups, and the pulmonary microbiome was similar, we identified 3 cases of invasive aspergillosis amongst the patients with COVID-19 but none in the non-COVID-19 cohort. Herpesvirade activation was also numerically more frequent amongst patients with COVID-19. Conclusion: COVID-19 is associated with an increased risk of VAP, which is not fully explained by the prolonged duration of ventilation. The pulmonary dysbiosis caused by COVID-19, and the causative organisms of secondary pneumonia observed are similar to that seen in critically ill patients ventilated for other reasons
Food Insecurity Prevalence Across Diverse Sites During COVID-19: A Year of Comprehensive Data
Key Findings NFACT includes 18 study sites in 15 states as well as a national poll, collectively representing a sample size of more than 26,000 people. Some sites have implemented multiple survey rounds, here we report results from 22 separate surveys conducted during the year since the COVID-19 pandemic began in March 2020. 18 out of 19 surveys in 14 sites with data for before and since the pandemic began found an increase in food insecurity since the start of the COVID-19 pandemic as compared to before the pandemic. In nearly all surveys (18/19) that measured food insecurity both before and during the pandemic, more Black, Indigenous, and People of Color (BIPOC) were classified as food insecure during the pandemic as compared to before it began. Prevalence of food insecurity for BIPOC respondents was higher than the overall population in the majority of surveys (19/20) sampling a general population. In almost all surveys (21/22), the prevalence of food insecurity for households with children was higher than the overall prevalence of food insecurity. Food insecurity prevalence was higher for households experiencing a negative job impact during the pandemic (i.e. job loss, furlough, reduction in hours) in nearly all surveys and study sites (21/22). Food insecurity prevalence in most sites was significantly higher before COVID-19 than estimates from that time period. Reporting a percent change between pre and during COVID-19 prevalence may provide additional information about the rate of change in food insecurity since the start of the pandemic, which absolute prevalence of food insecurity may not capture. Results highlight consistent trends in food insecurity outcomes since the start of the COVID-19 pandemic, across diverse study sites, methodological approaches, and time
Ventilator-associated pneumonia in critically ill patients with COVID-19
Abstract: Background: Pandemic COVID-19 caused by the coronavirus SARS-CoV-2 has a high incidence of patients with severe acute respiratory syndrome (SARS). Many of these patients require admission to an intensive care unit (ICU) for invasive ventilation and are at significant risk of developing a secondary, ventilator-associated pneumonia (VAP). Objectives: To study the incidence of VAP and bacterial lung microbiome composition of ventilated COVID-19 and non-COVID-19 patients. Methods: In this retrospective observational study, we compared the incidence of VAP and secondary infections using a combination of microbial culture and a TaqMan multi-pathogen array. In addition, we determined the lung microbiome composition using 16S RNA analysis in a subset of samples. The study involved 81 COVID-19 and 144 non-COVID-19 patients receiving invasive ventilation in a single University teaching hospital between March 15th 2020 and August 30th 2020. Results: COVID-19 patients were significantly more likely to develop VAP than patients without COVID (Cox proportional hazard ratio 2.01 95% CI 1.14â3.54, p = 0.0015) with an incidence density of 28/1000 ventilator days versus 13/1000 for patients without COVID (p = 0.009). Although the distribution of organisms causing VAP was similar between the two groups, and the pulmonary microbiome was similar, we identified 3 cases of invasive aspergillosis amongst the patients with COVID-19 but none in the non-COVID-19 cohort. Herpesvirade activation was also numerically more frequent amongst patients with COVID-19. Conclusion: COVID-19 is associated with an increased risk of VAP, which is not fully explained by the prolonged duration of ventilation. The pulmonary dysbiosis caused by COVID-19, and the causative organisms of secondary pneumonia observed are similar to that seen in critically ill patients ventilated for other reasons
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