ORCID Profile
0000-0002-0758-5190
Current Organisation
Universiteit Utrecht
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Publisher: American Society for Microbiology
Date: 03-2013
DOI: 10.1128/IAI.01278-12
Abstract: Influenza A virus (IAV) predisposes in iduals to secondary infections with the bacterium Streptococcus pneumoniae (the pneumococcus). Infections may manifest as pneumonia, sepsis, meningitis, or otitis media (OM). It remains controversial as to whether secondary pneumococcal disease is due to the induction of an aberrant immune response or IAV-induced immunosuppression. Moreover, as the majority of studies have been performed in the context of pneumococcal pneumonia, it remains unclear how far these findings can be extrapolated to other pneumococcal disease phenotypes such as OM. Here, we used an infant mouse model, human middle ear epithelial cells, and a series of reverse-engineered influenza viruses to investigate how IAV promotes bacterial OM. Our data suggest that the influenza virus HA facilitates disease by inducing a proinflammatory response in the middle ear cavity in a replication-dependent manner. Importantly, our findings suggest that it is the inflammatory response to IAV infection that mediates pneumococcal replication. This study thus provides the first evidence that inflammation drives pneumococcal replication in the middle ear cavity, which may have important implications for the treatment of pneumococcal OM.
Publisher: Springer Science and Business Media LLC
Date: 16-02-2017
DOI: 10.1038/SREP42808
Abstract: Advances in genome sequencing technologies and genome-wide association studies (GWAS) have provided unprecedented insights into the molecular basis of microbial phenotypes and enabled the identification of the underlying genetic variants in real populations. However, utilization of genome sequencing in clinical phenotyping of bacteria is challenging due to the lack of reliable and accurate approaches. Here, we report a method for predicting microbial resistance patterns using genome sequencing data. We analyzed whole genome sequences of 1,680 Streptococcus pneumoniae isolates from four independent populations using GWAS and identified probable hotspots of genetic variation which correlate with phenotypes of resistance to essential classes of antibiotics. With the premise that accumulation of putative resistance-conferring SNPs, potentially in combination with specific resistance genes, precedes full resistance, we retrogressively surveyed the hotspot loci and quantified the number of SNPs and/or genes, which if accumulated would confer full resistance to an otherwise susceptible strain. We name this approach the ‘distance to resistance’. It can be used to identify the creep towards complete antibiotics resistance in bacteria using genome sequencing. This approach serves as a basis for the development of future sequencing-based methods for predicting resistance profiles of bacterial strains in hospital microbiology and public health settings.
Publisher: S. Karger AG
Date: 20-08-2013
DOI: 10.1159/000353905
Abstract: It is well established that infection with influenza A virus (IAV) facilitates secondary bacterial disease. However, there is a growing body of evidence that the microbial context in which IAV infection occurs can affect both innate and adaptive responses to the virus. To date, these studies have been restricted to murine models of disease and the relevance of these findings in primary human cells remains to be elucidated. Here, we show that pre-stimulation of primary human monocyte-derived macrophages (MDMs) with the bacterial ligand lipopolysaccharide (LPS) reduces the ability of IAV to infect these cells. The inhibition of IAV infection was associated with a reduced transcription of viral RNA and the ability of LPS to induce an anti-viral/type I interferon response in human MDMs. We demonstrated that this reduced rate of viral infection is associated with a reduced ability to present a model antigen to autologous CD8+ T cells. Taken together, these data provide the first evidence that exposure to bacterial ligands like LPS can play an important role in modulating the immune response of primary human immune cells towards IAV infection, which may then have important consequences for the development of the host's adaptive immune response.
Publisher: American Society for Microbiology
Date: 15-05-2010
DOI: 10.1128/AEM.02938-09
Abstract: Members of the serpin ( ser ine p rotease in hibitor) superfamily have been identified in higher multicellular eukaryotes, as well as in bacteria, although examination of available genome sequences has indicated that homologs of the bacterial serpin-encoding gene ( ser ) are not widely distributed. In members of the genus Bifidobacterium this gene appears to be present in at least 5, and perhaps up to 9, of the 30 species tested. Moreover, phylogenetic analysis using available bacterial and eukaryotic serpin sequences revealed that bifidobacteria produce serpins that form a separate clade. We characterized the ser 210B locus of Bifidobacterium breve 210B, which encompasses a number of genes whose deduced protein products display significant similarity to proteins encoded by corresponding loci found in several other bifidobacteria. Northern hybridization, primer extension, microarray, reverse transcription-PCR (RT-PCR), and quantitative real-time PCR (qRT-PCR) analyses revealed that a 3.5-kb polycistronic mRNA encompassing the ser 210B operon with a single transcriptional start site is strongly induced following treatment of B. breve 210B cultures with some proteases. Interestingly, transcription of other bifidobacterial ser homologs appears to be triggered by different proteases.
Publisher: Cold Spring Harbor Laboratory
Date: 05-11-2016
DOI: 10.1101/085720
Abstract: Infection by C ylobacter is recognised as the most common cause of foodborne bacterial illness worldwide. Faecal contamination of meat, especially chicken, during processing represents a key route of transmission to humans. There is currently no licenced vaccine and no C ylobacter -resistant chickens. In addition, preventative measures aimed at reducing environmental contamination and exposure of chickens to C ylobacter jejuni (biosecurity) have been ineffective. There is much interest in the factors/mechanisms that drive C. jejuni colonisation and infection of animals, and survival in the environment. It is anticipated that understanding these mechanisms will guide the development of effective intervention strategies to reduce the burden of C. jejuni infection. Here we present a comprehensive analysis of C. jejuni fitness during growth and survival within and outside hosts. A comparative analysis of transposon (Tn) gene inactivation libraries in three C. jejuni strains by Tn-seq demonstrated that a large proportion, 331 genes, of the C. jejuni genome is dedicated to ( in vitro ) growth. An extensive Tn library in C. jejuni M1cam (~10,000 mutants) was screened for the colonisation of commercial broiler chickens, survival in houseflies and under nutrient-rich and–poor conditions at low temperature, and infection of human gut epithelial cells. We report C. jejuni factors essential throughout its life cycle and we have identified genes that fulfil important roles across multiple conditions, including maf3, fliW, fliD, pflB and capM , as well as novel genes uniquely implicated in survival outside hosts. Taking a comprehensive screening approach has confirmed previous studies, that the flagella are central to the ability of C. jejuni to interact with its hosts. Future efforts should focus on how to exploit this knowledge to effectively control infections caused by C. jejuni . C ylobacter jejuni is the leading bacterial cause of human diarrhoeal disease. C. jejuni encounters and has to overcome a wide range of “stress” conditions whilst passing through the gastrointestinal tract of humans and other animals, during processing of food products, on/in food and in the environment. We have taken a comprehensive approach to understand the basis of C. jejuni growth and within/outside host survival, with the aim to inform future development of intervention strategies. Using a genome-wide transposon gene inactivation approach we identified genes core to the growth of C. jejuni . We also determined genes that were required during the colonisation of chickens, survival in the housefly and under nutrient-rich and –poor conditions at low temperature, and during interaction with human gut epithelial tissue culture cells. This study provides a comprehensive dataset linking C. jejuni genes to growth and survival in models relevant to its life cycle. Genes important across multiple models were identified as well as genes only required under specific conditions. We identified that a large proportion of the C. jejuni genome is dedicated to growth and that the flagella fulfil a prominent role in the interaction with hosts. Our data will aid development of effective control strategies.
Publisher: American Society for Microbiology
Date: 08-03-2017
Abstract: To improve our understanding about the severity of invasive pneumococcal disease (IPD), we investigated the association between the genotype of Streptococcus pneumoniae and disease outcomes for 349 bacteremic patients. A pneumococcal genome-wide association study (GWAS) demonstrated a strong correlation between 30-day mortality and the presence of the phage-derived gene pblB , encoding a platelet-binding protein whose effects on platelet activation were previously unknown. Platelets are increasingly recognized as key players of the innate immune system, and in sepsis, excessive platelet activation contributes to microvascular obstruction, tissue hypoperfusion, and finally multiorgan failure, leading to mortality. Our in vitro studies revealed that pblB expression was induced by fluoroquinolones but not by the beta-lactam antibiotic penicillin G. Subsequently, we determined pblB induction and platelet activation by incubating whole blood with the wild type or a pblB knockout mutant in the presence or absence of antibiotics commonly administered to our patient cohort. pblB -dependent enhancement of platelet activation, as measured by increased expression of the α-granule protein P-selectin, the binding of fibrinogen to the activated αIIbβ3 receptor, and the formation of platelet-monocyte complex occurred irrespective of antibiotic exposure. In conclusion, the presence of pblB on the pneumococcal chromosome potentially leads to increased mortality in patients with an invasive S. pneumoniae infection, which may be explained by enhanced platelet activation. This study highlights the clinical utility of a bacterial GWAS, followed by functional characterization, to identify bacterial factors involved in disease severity. IMPORTANCE The exact mechanisms causing mortality in invasive pneumococcal disease (IPD) patients are not completely understood. We examined 349 patients with IPD and found in a bacterial genome-wide association study (GWAS) that the presence of the phage-derived gene pblB was associated with mortality in the first 30 days after hospitalization. Although pblB has been extensively studied in Streptococcus mitis , its consequence for the interaction between platelets and Streptococcus pneumoniae is largely unknown. Platelets are important in immunity and inflammation, and excessive platelet activation contributes to microvascular obstruction and multiorgan failure, leading to mortality. We therefore developed this study to assess whether the expression of pblB might increase the risk of death for IPD patients through its effect on enhanced platelet activation. This study also shows the value of integrating extensive bacterial genomics and clinical data in predicting and understanding pathogen virulence, which in turn will help to improve prognosis and therapy.
Publisher: Oxford University Press (OUP)
Date: 08-02-2016
DOI: 10.1093/BFGP/ELV063
Abstract: The minimal subset of genes required for cellular growth, survival and viability of an organism are classified as essential genes. Knowledge of essential genes gives insight into the core structure and functioning of a cell. This might lead to more efficient antimicrobial drug discovery, to elucidation of the correlations between genotype and phenotype, and a better understanding of the minimal requirements for a (synthetic) cell. Traditionally, constructing a catalog of essential genes for a given microbe involved costly and time-consuming laboratory experiments. While experimental methods have produced abundant gene essentiality data for model organisms like Escherichia coli and Bacillus subtilis, the knowledge generated cannot automatically be extrapolated to predict essential genes in all bacteria. In addition, essential genes identified in the laboratory are by definition 'conditionally essential', as they are essential under the specified experimental conditions: these might not resemble conditions in the microorganisms' natural habitat(s). Also, large-scale experimental assaying for essential genes is not always feasible because of the time investment required to setup these assays. The ability to rapidly and precisely identify essential genes in silico is therefore important and has great potential for applications in medicine, biotechnology and basic biological research. Here, we review the advances made in the use of computational methods to predict microbial gene essentiality, perspectives for the future of these techniques and the possible practical applications of essential genes.
Publisher: Cold Spring Harbor Laboratory
Date: 30-07-2017
DOI: 10.1101/169722
Abstract: Different clinical manifestations of invasive pneumococcal disease (IPD) have thus far mainly been explained by patient characteristics. Here we studied the contribution of pneumococcal genetic variation to IPD phenotype. The index cohort consisted of 349 patients admitted to two Dutch hospitals between 2000-2011 with pneumococcal bacteraemia. We performed genome-wide association studies to identify pneumococcal lineages, genes and allelic variants associated with 23 clinical IPD phenotypes. The identified associations were validated in a nationwide (n=482) and a post-pneumococcal vaccination cohort (n=121). The contribution of confirmed pneumococcal genotypes to the clinical IPD phenotype, relative to known clinical predictors, was tested by regression analysis. The presence of pneumococcal gene slaA was a nationwide confirmed independent predictor of meningitis (OR=10.5, p=0.001), as was sequence cluster 9 (OR=3.68, p=0.057). A set of 4 pneumococcal genes co-located on a prophage was a confirmed independent predictor of 30-day mortality (OR=3.4, p=0.003). We could detect the pneumococcal variants of concern in these patients’ blood s les by molecular lification. In the post-vaccination cohort where the distribution of both patient characteristics and pneumococcal serotypes had changed, the relative importance of the prophage was no longer supported. Knowledge of pneumococcal genotypic variants improved our clinical risk assessment for detrimental manifestations of IPD. This provides us with novel opportunities to target, anticipate or avert the pathogenic effects that are related to particular pneumococcal variants. Therefore, future diagnostics should facilitate prompt appreciation of pathogen ersity in clinical sepsis management. Ongoing surveillance is warranted to monitor the clinical value of information on pathogen variants in dynamic microbial and susceptible host populations. None.
Publisher: Springer Science and Business Media LLC
Date: 28-04-2017
DOI: 10.1038/S41598-017-01133-4
Abstract: C ylobacter is the most common cause of foodborne bacterial illness worldwide. Faecal contamination of meat, especially chicken, during processing represents a key route of transmission to humans. There is a lack of insight into the mechanisms driving C . jejuni growth and survival within hosts and the environment. Here, we report a detailed analysis of C . jejuni fitness across models reflecting stages in its life cycle. Transposon (Tn) gene-inactivation libraries were generated in three C . jejuni strains and the impact on fitness during chicken colonisation, survival in houseflies and under nutrient-rich and –poor conditions at 4 °C and infection of human gut epithelial cells was assessed by Tn-insertion site sequencing (Tn-seq). A total of 331 homologous gene clusters were essential for fitness during in vitro growth in three C . jejuni strains, revealing that a large part of its genome is dedicated to growth. We report novel C . jejuni factors essential throughout its life cycle. Importantly, we identified genes that fulfil important roles across multiple conditions. Our comprehensive screens showed which flagella elements are essential for growth and which are vital to the interaction with host organisms. Future efforts should focus on how to exploit this knowledge to effectively control infections caused by C . jejuni .
Publisher: Oxford University Press (OUP)
Date: 17-05-2018
DOI: 10.1093/CID/CIY417
Abstract: Different clinical manifestations of invasive pneumococcal disease (IPD) have thus far mainly been explained by patient characteristics. Here we studied the contribution of pneumococcal genetic variation to IPD phenotype. The index cohort consisted of 349 patients admitted to 2 Dutch hospitals between 2000-2011 with pneumococcal bacteremia. We performed genome-wide association studies to identify pneumococcal lineages, genes, and allelic variants associated with 23 clinical IPD phenotypes. The identified associations were validated in a nationwide (n = 482) and a post-pneumococcal vaccination cohort (n = 121). The contribution of confirmed pneumococcal genotypes to the clinical IPD phenotype, relative to known clinical predictors, was tested by regression analysis. Among IPD patients, the presence of pneumococcal gene slaA was a nationwide confirmed independent predictor of meningitis (odds ratio [OR], 10.5 P = .001), as was sequence cluster 9 (serotype 7F: OR, 3.68 P = .057). A set of 4 pneumococcal genes co-located on a prophage was a confirmed independent predictor of 30-day mortality (OR, 3.4 P = .003). We could detect the pneumococcal variants of concern in these patients' blood s les. In this study, knowledge of pneumococcal genotypic variants improved the clinical risk assessment for detrimental manifestations of IPD. This provides us with novel opportunities to target, anticipate, or avert the pathogenic effects related to particular pneumococcal variants, and indicates that information on pneumococcal genotype is important for the diagnostic and treatment strategy in IPD. Ongoing surveillance is warranted to monitor the clinical value of information on pneumococcal variants in dynamic microbial and susceptible host populations.
Publisher: Springer Science and Business Media LLC
Date: 23-10-2015
DOI: 10.1038/SREP14952
Abstract: The 7-valent pneumococcal conjugated vaccine (PCV7) has affected the genetic population of Streptococcus pneumoniae in pediatric carriage. Little is known however about pneumococcal population genomics in adult invasive pneumococcal disease (IPD) under vaccine pressure. We sequenced and serotyped 349 strains of S. pneumoniae isolated from IPD patients in Nijmegen between 2001 and 2011. Introduction of PCV7 in the Dutch National Immunization Program in 2006 preluded substantial alterations in the IPD population structure caused by serotype replacement. No evidence could be found for vaccine induced capsular switches. We observed that after a temporary bottleneck in gene ersity after the introduction of PCV7, the accessory gene pool re-expanded mainly by genes already circulating pre-PCV7. In the post-vaccine genomic population a number of genes changed frequency, certain genes became overrepresented in vaccine serotypes, while others shifted towards non-vaccine serotypes. Whether these dynamics in the invasive pneumococcal population have truly contributed to invasiveness and manifestations of disease remains to be further elucidated. We suggest the use of whole genome sequencing for surveillance of pneumococcal population dynamics that could give a prospect on the course of disease, facilitating effective prevention and management of IPD.
Publisher: Springer Science and Business Media LLC
Date: 05-11-2014
Location: Ireland
No related grants have been discovered for Aldert Zomer.