Combined systems approaches reveal highly plastic responses to antimicrobial peptide challenge in Escherichia coli

Obtaining an in-depth understanding of the arms races between peptides comprising the innate immune response and bacterial pathogens is of fundamental interest and will inform the development of new antibacterial therapeutics. We investigated whether a whole organism view of antimicrobial peptide (AMP) challenge on Escherichia coli would provide a suitably sophisticated bacterial perspective on AMP mechanism of action. Selecting structurally and physically related AMPs but with expected differences in bactericidal strategy, we monitored changes in bacterial metabolomes, morphological features and gene expression following AMP challenge at sub-lethal concentrations. For each technique, the vast majority of changes were specific to each AMP, with such a plastic response indicating E. coli is highly capable of discriminating between specific antibiotic challenges. Analysis of the ontological profiles generated from the transcriptomic analyses suggests this approach can accurately predict the antibacterial mode of action, providing a fresh, novel perspective for previous functional and biophysical studies

Het Rijksvaccinatieprogramma in Nederland. Ontwikkelingen in 2006

In 2006 several changes were made in the Dutch National Immunisation Programme (NIP): Hepatitis B vaccination at birth was added for children born to mothers positive for hepatitis B surface antigen; a new vaccine for diphtheria, tetanus, pertussis (a-cellular), poliomyelitis and Haemophilus influenzae (DTaP-IPV/Hib) was introduced; vaccination against pneumococcal disease was added at two, three, four and eleven months; risk groups for hepatitis B receive a combined vaccine for DTaP-IPV/Hib and HBV at the same ages; DT-IPV and aP at the age of four years were combined in one vaccine; and new MMR vaccines were introduced. As new information became available in 2006, the desirability to introduce vaccinations in the NIP for the following diseases could be (re)considered: hepatitis B (universal vaccination), rotavirus, varicella and human papillomavirus. For respiratory syncytial virus and meningococcal serogroup B disease no candidate vaccines are available yet. Extension of the programme with available vaccines for hepatitis A, influenza and tuberculosis is not (yet) recommended. The NIP in the Netherlands is effective and safe. However, continued monitoring of the effectiveness and safety of the NIP is important as changes are made regularly. Maintaining high vaccine uptake is vital to prevent (re)emergence of diseases. Furthermore, the programme should be regularly reviewed as new vaccines become available.In 2006 traden verschillende veranderingen op in het Rijksvaccinatieprogramma (RVP) in Nederland: kinderen die geboren worden uit moeders die chronisch geinfecteerd zijn met hepatitis B krijgen vlak na de geboorte een hepatitis B vaccinatie; er is een ander vaccin geintroduceerd voor difterie, kinkhoest (a-cellulair), tetanus, poliomyelitis en Haemophilus influenzae (DaKTP/Hib); vaccinatie tegen pneumokokken is toegevoegd op de leeftijd van 2, drie, vier en elf maanden; risicogroepen voor hepatitis B krijgen op diezelfde leeftijden een combinatievaccin voor DaKTP/Hib en hepatitis B; DTP en aK zijn gecombineerd in een vaccin op vierjarige leeftijd; en er zijn nieuwe BMR vaccins geintroduceerd. Op basis van informatie die in 2006 beschikbaar is gekomen wordt geadviseerd de introductie van vaccinaties voor de volgende ziekten te overwegen: hepatitis B (universele vaccinatie), rotavirus, waterpokken en humaan papillomavirus. Voor respiratoir syncytieel virus en meningokokken B zijn nog geen kandidaatvaccins beschikbaar en uitbreiding van het RVP met beschikbare vaccins voor hepatitis A, influenza en tuberculose wordt nog niet aanbevolen. Het RVP is effectief en veilig, maar voortdurende bewaking hiervan is groot belang, omdat er regelmatig veranderingen optreden. Handhaven van de hoge vaccinatiegraad is essentieel om terugkeer van ziekten te voorkomen. Verder moet regelmatig bekeken worden of het RVP aangepast moet worden aangezien er steeds nieuwe vaccins beschikbaar komen

Microbial Patterns Signaling via Toll-Like Receptors 2 and 5 Contribute to Epithelial Repair, Growth and Survival

Epithelial cells (ECs) continuously interact with microorganisms and detect their presence via different pattern-recognition receptors (PRRs) including Toll-like receptors (TLRs). Ligation of epithelial TLRs by pathogens is usually associated with the induction of pro-inflammatory mediators and antimicrobial factors. In this study, using human airway ECs as a model, we found that detection of microbial patterns via epithelial TLRs directly regulates tissue homeostasis. Staphylococcus aureus (S. aureus) and microbial patterns signaling via TLR2 and TLR5 induce a set of non-immune epithelial responses including cell migration, wound repair, proliferation, and survival of primary and cancerous ECs. Using small interfering RNA (siRNA) gene targeting, receptor-tyrosine kinase microarray and inhibition studies, we determined that TLR and the epidermal growth factor receptor (EGFR) mediate the stimulating effect of microbial patterns on epithelial repair. Microbial patterns signaling via Toll-like receptors 2 and 5 contribute to epithelial repair, growth and survival. This effect is independent of hematopoietic and other cells as well as inflammatory cytokines suggesting that epithelia are able to regulate their integrity in an autonomous non-inflammatory manner by sensing microbes directly via TLRs

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.</p

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

Het Rijksvaccinatieprogramma in Nederland: huidige situatie en ontwikkelingen

The national immunisation programme in the Netherlands is very effective and safe. To improve the success and effectiveness of the immunisation programme, vaccination of other (age)groups is indicated. Extension of the programme with new target diseases can result in considerable health gain for some diseases. The target diseases are largely under control. However, monitoring the effectiveness of the programme is important. Maintaining high vaccin uptake is vital to prevent (re)emergence of disease. Vaccination of (young) adults now (pertussis) and in the future (mumps, measles, rubella, hepatitis B) could give further improvement. Also other vaccination strategies need attention such as maternal or newborn vaccination for pertussis. The switch to a DTPa-IPV/Hib combination vaccine in 2005 should be monitored carefully both for pertussis and other components. The national immunisation programme could be extended with new target diseases. Pneumococcal vaccination for children is expected to give important health gain. The desirability to introduce varicella vaccination - possibly in combination with mumps, measles and rubella - needs further study. When effective and safe vaccines become available for meningococcal serogroup B, respiratory syncytial virus and human papillomavirus, extension of the immunisation programme might be advisable. Extension of the programme with available vaccines for influenza, hepatitis A or tuberculosis is not (yet) recommended. For these diseases the current policy needs to be continued, possibly with lowering the age of influenza vaccination from 65 years to 50 years of age. The desirability to vaccinate children against influenza needs additional investigation, like pneumococcal vaccination for elderly. Vaccination against HSV-2 or rotavirus is not possible yet. The health gain is expected to be limited for HSV-2. When a vaccine for rotavirus comes available a cost-effectiveness analysis is needed.Het Rijksvaccinatieprogramma in Nederland is zeer effectief en veilig. Om het succes en de effectiviteit van het vaccinatieprogramma te vergroten, is vaccinatie van andere (leeftijds)groepen aan te bevelen. Uitbreiding van het programma met nieuwe doelziekten kan voor een aantal ziekten aanzienlijke gezondheidswinst opleveren. De ziekten waartegen wordt gevaccineerd zijn grotendeels onder controle, maar bewaking van de effectiviteit van het programma is van groot belang. Handhaven van de hoge vaccinatiegraad is essentieel om terugkeer van de ziekten te voorkomen. Vaccinatie van (jong) volwassenen nu (kinkhoest) of in de toekomst (bof, mazelen, rodehond, hepatitis B) zal verder verbetering kunnen geven. Ook andere vaccinatiestrategieen verdienen aandacht, zoals vaccinatie van pasgeborenen of aanstaande ouders. De vervanging van het huidige difterie, tetanus, poliomyelitis, hele-cel kinkhoest en Haemophilus influenzae vaccin (DKTP/Hib) door een combinatievaccin met een a-cellulaire kinkhoestcomponent (DKATP/Hib) ingevoerd begin 2005 moet nauwkeurig worden gemonitored, zowel voor kinkhoest als de overige vaccincomponenten. Het Rijksvaccinatieprogramma kan met vaccins tegen andere ziekten uitgebreid worden. Pneumokokken-vaccinatie van kinderen levert belangrijke gezondheidswinst op. De wenselijkheid om waterpokken-vaccinatie te introduceren - mogelijk in een combinatievaccin met bof, mazelen en rodehond - moet bestudeerd worden. Als tegen meningokokken B, respiratoir syncytieel virus en humaan papillomavirus effectieve en veilige vaccins op de markt komen, is uitbreiding van het vaccinatieprogramma naar verwachting raadzaam. Dit geldt (nog) niet (of in mindere mate) voor de al beschikbare vaccins tegen influenza, hepatitis A en tuberculose. Voor deze ziekten is continuering van het huidige beleid nodig met mogelijke verlaging van de leeftijd voor influenzavaccinatie van 65 jaar naar 50 jaar. De wenselijkheid van vaccinatie van kinderen tegen influenza is een punt voor nader onderzoek, evenals pneumokokken-vaccinatie van ouderen. Vaccinatie tegen herpes simplex virus-2 en rotavirus is nog niet mogelijk. Vaccinatie levert naar verwachting relatief beperkte gezondheidswinst op voor herpes simplex virus-2. Als een rotavirus vaccin beschikbaar komt is een kosten-effectiviteitsanalyse aangewezen