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- Laabei, M., et al.
(författare)
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Predicting the virulence of MRSA from its genome sequence
- 2014
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051. ; 24:5, s. 839-849
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Tidskriftsartikel (refereegranskat)abstract
- Microbial virulence is a complex and often multifactorial phenotype, intricately linked to a pathogen's evolutionary trajectory. Toxicity, the ability to destroy host cell membranes, and adhesion, the ability to adhere to human tissues, are the major virulence factors of many bacterial pathogens, including Staphylococcus aureus. Here, we assayed the toxicity and adhesiveness of 90 MRSA (methicillin resistant S. aureus) isolates and found that while there was remarkably little variation in adhesion, toxicity varied by over an order of magnitude between isolates, suggesting different evolutionary selection pressures acting on these two traits. We performed a genome-wide association study (GWAS) and identified a large number of loci, as well as a putative network of epistatically interacting loci, that significantly associated with toxicity. Despite this apparent complexity in toxicity regulation, a predictive model based on a set of significant single nucleotide polymorphisms (SNPs) and insertion and deletions events (indels) showed a high degree of accuracy in predicting an isolate's toxicity solely from the genetic signature at these sites. Our results thus highlight the potential of using sequence data to determine clinically relevant parameters and have further implications for understanding the microbial virulence of this opportunistic pathogen.
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- Abu-Elyazeed, R R, et al.
(författare)
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Safety and immunogenicity of a glycoprotein D genital herpes vaccine in healthy girls 10-17 years of age : results from a randomised, controlled, double-blind trial
- 2013
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Ingår i: Vaccine. - : Elsevier BV. - 0264-410X .- 1873-2518. ; 31:51, s. 6136-6143
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The investigational AS04-adjuvanted herpes simplex virus type 2 (HSV-2) glycoprotein D (gD2) subunit prophylactic vaccine ('HSV vaccine'; GlaxoSmithKline Vaccines) has been shown to be well tolerated in adults, but limited data exist for pre-teen and adolescent girls, a likely target population. The primary objective of this study was to compare the occurrence of serious adverse events (SAEs) over 12 months between HSV vaccine recipients and saline recipients (placebo control group) in pre-teen and adolescent girls. The immunogenicity of the HSV vaccine was also assessed.METHODS: Healthy girls aged 10-17 years, stratified by age (10-15 years; 16-17 years), were randomised 2:1:1 to receive the HSV vaccine, a hepatitis A vaccine (Havrix™; HAV control) or placebo (saline) according to a 0-, 1-, 6-month schedule. Participants and study personnel not involved in the preparation or administration of vaccines were blinded to treatment. Safety and immunogenicity analyses were performed overall and by age (10-15 years; 16-17 years) and HSV serostatus.RESULTS: No statistically significant difference in the percentage of subjects with SAEs was observed between the HSV and saline group, or between the HSV and pooled control (HAV and saline) groups. The HSV vaccine was well tolerated, although a higher incidence of solicited local symptoms was observed in the HSV group than in the control group. Neither age nor HSV serostatus at the time of study entry had an impact on the safety profile of this vaccine. The HSV vaccine was immunogenic regardless of pre-vaccination HSV serostatus. Higher anti-gD geometric mean concentrations were observed in HSV-1 seropositive participants than in HSV-1 seronegative participants.CONCLUSION: The HSV vaccine had an acceptable safety profile, and was well tolerated and immunogenic when administered to girls aged 10-17 years regardless of age or HSV pre-vaccination serostatus.
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- Au, A. E., et al.
(författare)
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Proinflammatory microenvironment promotes lymphoma progression in mice with high megakaryocyte and TPO levels
- 2023
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 7:8, s. 1560-1571
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Tidskriftsartikel (refereegranskat)abstract
- Platelets have been shown to enhance the survival of lymphoma cell lines, but it is unclear if they play a role in lymphoma. Here we investigate a potential role for platelets and/or megakaryocytes in Eµ-myc lymphoma progression. Eµ-myc tumour cells were transplanted into recipient wild-type control mice, Mpl-/-, or TpoTg mice, which exhibit normal, low and high platelet and megakaryocyte counts, respectively. Transplanted TpoTg mice exhibited enhanced lymphoma progression with increased WBC counts, spleen and lymph node weights and enhanced liver infiltration when compared to wild-type. Conversely, tumour bearing Mpl-/- mice presented with reduced WBC counts, lymph node weights and less liver infiltration when compared to wild-type. Utilizing a Mpl-deficient thrombocytopenic immunocompromised mouse model, our results were confirmed with the human NHL GRANTA cell line. While we found that platelets and platelet released molecules supported Eµ-myc tumour cell survival in vitro, pharmacological inhibition of platelet function or anticoagulation in Eµ-myc transplanted wild-type mice did not improve disease outcome. Furthermore, transient platelet depletion or sustained Bcl-xL dependent thrombocytopenia did not alter lymphoma progression. Cytokine analysis of the bone marrow fluid microenvironment revealed increased levels of the proinflammatory molecule interleukin (IL)-1 in TpoTg mice, whereas levels were lowered in Mpl-/- mice. Moreover, RNA sequencing of blood-resident Eµ-myclymphoma cells from TpoTgand wild-type mice after tumour transplant revealed upregulation of hallmark gene sets associated with inflammatory response in TpoTg mice. We propose that a pro-inflammatory microenvironment in TpoTgmice promoted lymphoma progression.
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- Kenny, J. G., et al.
(författare)
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Mannitol Utilisation is Required for Protection of Staphylococcus aureus from Human Skin Antimicrobial Fatty Acids
- 2013
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 8:7
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Tidskriftsartikel (refereegranskat)abstract
- Mannitol (Mtl) fermentation, with the subsequent production of acid, is a species signature of Staphylococcus aureus, and discriminates it from most other members of the genus. Inactivation of the gene mtlD, encoding Mtl-1-P dehydrogenase was found to markedly reduce survival in the presence of the antimicrobial fatty acid, linoleic acid. We demonstrate that the sugar alcohol has a potentiating action for this membrane-acting antimicrobial. Analysis of cellular metabolites revealed that, during exponential growth, the mtlD mutant accumulated high levels of Mtl and Mtl-P. The latter metabolite was not detected in its isogenic parent strain or a deletion mutant of the entire mtlABFD operon. In addition, the mtlD mutant strain exhibited a decreased MIC for H2O2, however virulence was unaffected in a model of septic arthritis.
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