ImMiGeNe - Zusammenspiel von Immunparametern, Mikrobiota und Genetik des Wirts während der Stammzelltransplantation im Kindesalter
Bioinformatik und Theoretische Biologie
Immunologie
Zusammenfassung der Projektergebnisse
The gut microbiota are thought to strongly influence human health and are regulated by innate (mediated, for example, by pattern recognition receptors (PRRs) via recognition of microbeassociated molecular patterns, MAMPs) and adaptive (mediated by antigens and soluble IgA) immune recognition and effector mechanisms. However, the interplay of microbiota, host immune system and host genetics have not always been studied systematically and longitudinally. Since microbiome studies in humans are usually non-interventional for ethical reasons, the relationships established so far have, for the major part, been based on observations in mouse models or purely correlative without establishing causalities. Stem cell transplantation (SCT) patients undergo significant interventions in terms of their microbiota, immune system, and host genetics, providing the unique opportunity to assess the impact of strong interventions on both the microbiota and the immune system in human subjects. But how donor immuno-genetics affect matching within a SCT recipient in terms of host factors beyond classical HLA (e.g. including so-called minor histocompatibility antigens, miHAs, e.g. coding SNPs, and non-typical HLAs) is not fully understood, and whether the donor immune system encounters ‘matching issues’ due to the recipient’s microbiota having been imprinted by the recipient immune system is unclear. Within the ImMiGeNe study (NCT02940093) longitudinal (nine time points) stool, urine, and blood samples as well as full clinical documentation had been acquired for 20 donor-recipient SCT pairs and fecal samples had already been subjected to metagenomics shotgun microbiome analysis. In order to correlate changes in the microbiome to changes in host genetics and immune system, we here proposed to conduct whole-exome sequencing (WES) and transcriptomics of SCT donor and recipients via the DFG-funded Tübingen NGS hub, NCCT. We sought to explore whether differences between donor and recipient in terms of PRRs affect MAMP abundance and mutations at the level of the microbiota. Additionally, we sought to perform microbiota shotgun metagenomics sequences for evidence of ‘imprinting’ by the recipient’s immune system, and whether changed immunogenicity of certain taxa leads to a change in microbiome composition post-SCT. Our joint aim was to discover host and microbial biomarkers for the prediction and subsequent reduction/prevention of SCT-associated adverse effects and to gain valuable insights into the interplay between microbiota and host via this unbiased multi-omics approach. Collectively, the study has only provided limited insights into the above questions due to 1) technical difficulties in the acquisition of e.g. the metagenomics data; 2) high inter-individual differences with simultaneous limited cohort size. Nevertheless, we provide here an insight into the obtained data which illustrate the complexity of both systems and the need for larger studies.
Projektbezogene Publikationen (Auswahl)
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Fish TLR5 develops a taste for viral RNA. EMBO reports, 23(8).
Weber, Alexander N. R.
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naRNA-LL37 composite DAMPs define sterile NETs as self-propagating drivers of inflammation. EMBO Reports, 25(7), 2914-2949.
Bork, Francesca; Greve, Carsten L.; Youn, Christine; Chen, Sirui; N., C. Leal Vinicius; Wang, Yu; Fischer, Berenice; Nasri, Masoud; Focken, Jule; Scheurer, Jasmin; Engels, Pujan; Dubbelaar, Marissa; Hipp, Katharina; Zalat, Baher; Szolek, Andras; Wu, Meng-Jen; Schittek, Birgit; Bugl, Stefanie; Kufer, Thomas A. ... & Weber, Alexander N. R.
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Bruton’s tyrosine kinase (BTK) and matrix metalloproteinase-9 (MMP-9) regulate NLRP3 inflammasome-dependent cytokine and neutrophil extracellular trap responses in primary neutrophils. Journal of Allergy and Clinical Immunology, 155(2), 569-582.
Leal, Vinicius N.C.; Bork, Francesca; Mateo, Tortola Maria; von Guilleaume, Juli-Christin; Greve, Carsten L.; Bugl, Stefanie; Danker, Bettina; Bittner, Zsofia A.; Grimbacher, Bodo; Pontillo, Alessandra & Weber, Alexander N.R.
