Below you can find a description of the research topics that are currently under investigation by the Host-Microbe Interactomics group.
1. Innate defence mechanisms in the small intestine
Certain commensal and probiotic bacteria also engage in active cross-talk with the host epithelium to promote epithelial development, homeostasis and protection of barrier disruption by infection with pathogenic bacteria. At HMI, we identify and study molecular mechanisms by which probiotics and other commensal bacteria activate mechanisms that protect against epithelial permeability caused by pro-inflammatory cytokines or pathogens. Additionally we investigate the role and function of the RegIII family proteins expressed in the intestine in response to bacterial colonization (Thesis Loonen), role of Aryl hydrocarbon receptor (Ahr) and the role of the Muc2-layer, which mediates many interactions of the microbiota with the gut epithelium (link to project). Parts of this work are supported by the Top Institute Food and Nutrition.
2. Probiotic interactions with host cells.
Modulation of the immune system is one of the most plausible mechanistic concepts of probiotic function. In vitro studies suggest that probiotic bacteria stimulate several intestinal cell protective responses, including enhancement of epithelial barrier function, defensin production, mucin synthesis and secretion, inhibition of pathogen binding and cell survival and proliferation.To understand the mechanisms involved, detailed research is needed to determine the bacterial factors and cellular receptors responsible for the immunomodulatory effects of specific probiotic strains. Our main interest is in the interaction of bacteria with dendritic cells (DC) which regulate both tolerance and adaptive responses in mucosal tissues. We have been investigating the role of innate receptors found on DC (thesis Meijerink) and the role of putative probiotic factors using defined mutants in vivo (link to project). Parts of this work are performed in collaboration with the Top Institute Food and Nutrition and with Jolanda van Bilsen (TNO) and NIZO Food Research. We are investigating functionality of next generation probiotics (clostridia and other butyrate-producing human commensal bacteria) with external partners.
3. Discovery of novel antimicrobials
Resistance to multiple antibiotics has built up slowly over the past 20 years but has come to a head in the last five years. Consequently, we are seeing more frequent and persistent disease outbreaks caused by multi-resistant bacteria. Unless strategies for the development of alternative antibiotics are initiated soon, this will have an enormous social impact on the sustainability of other developments in modern medicine and quality of life worldwide. In this project we are aiming to develop novel inhibitors of the essential two-component signal transduction system YycFG (also known as WalKR) that is conserved in several Gram-positive bacterial pathogens, including Staphylococcus aureus, Streptococcus pneumoniae and Enterococcus faecalis. Together with industry and other academic partners we are exploiting recently obtained three-dimensional structures of YycFG homologues and in silico structure based drug discovery to identify putative inhibitors.(link to project) Additionally we are continuing to investigate the role and function of YycFG in S. suis using genetic (transposing mutagenesis together with RNA sequencing or Tn-Seq) and biochemical approaches. We are also evaluating the antibiotic efficacy of antimicrobial frog peptides on a broad panel of bacterial pathogens together with the Medical Microbiology group of Erasmus University Medical Centre, Rotterdam, and are currently following up on lead antibiotics produced by pig microbiota (link to project) together with the group of Colin Hill at University College Cork, Ireland.
To search for novel antibiotics, we are part of National Center of One Health, Antimicrobial Resistance (NCOH-AMR)
4. Virulence factors of Streptococcus suis and disease pathogenesis.
Streptococcus suis is one of the most important pathogens affecting the swine industry and can cause septicemia, meningitis, pneumonia and arthritis in young pigs. S. suis has also been reported to cause sporadic cases of meningitis and sepsis in humans. Current vaccines only protect against a limited range of strains. At HMI we have studied the role of surface proteins in virulence and pathogenesis by comparing the behavior and properties of isogenic mutants in different experimental models (thesis Ferrando). Some of the surface proteins are part of two-component systems, attractive antimicrobial targets (link to project). We have unravelled the natural competence system of S. suis and have identified a short peptide that dramatically increases our ability to genetically transform S. suis. (link to article) We are investigating methods to control S. suis proliferation in pigs using natural antimicrobials produced by pig microbiota and will evaluate if such compounds to be used as pig feed supplements. Parts of our research are in collaboration with Astrid de Greeff at WBR, Lelystad.
We are currently coordinating an EU project PIGSs (Program for Innovative Global Prevention of Streptococcus suis) (link to PIGSs website)
5. Using -omics technologies and network biology to investigate host-microbe interactions
In this research we are developing networks and pathway models to investigate responses of intestinal epithelial cells and tissues to interactions with microbes, both probiotics and microbiota, also using animal models. Throughout the HMI projects, we apply transcriptomics, metabolomics and high-content microscopy approaches to investigate cellular and tissue responses to microbes. Ultimately the developed network models and reconstructed signalling pathway models will provide new insights into the regulatory events in cells and tissues and help to identify microbial and host molecules that mediate host-microbe interactions in health and disease.
6. Analysis of molecular mechanisms establishing microbiota-host interactions
At HMI, we are investigating the molecular mechanisms that mediate specific interactions between specific parts of the microbiota and their hosts using next generation sequencing and metabolic intestinal and systemic blood parameters using unbiased, holistic -omics technologies to search for correlations between abundance of specific microbial groups and health and disease of human and different animal hosts including pigs and mice. Parts of this research are in collaboration with NIZO Food Research and the Netherlands Metabolomics Centre. In another project we are investigating the effect of a few foods diets on the microbiota and behaviour of children showing ADHD symptoms.