Discovery of human single nucleotide polymorphisms affecting staphylococcal diseases
Final Report Abstract
Staphylococcus aureus is a notorious pathogen that uses sophisticated immune-evasion strategies to cause local and invasive infections. However, host factors and underpinning genetic determinants that affect staphylococcal infectious diseases are largely unknown. Thus, this research project aimed at identifying human factors and associated polymorphisms that impair S. aureus disease pathogenesis. Initial work focused on specific genes of the apoptotic signaling pathways and took advantage of CRISPR/Cas9 mutagenesis in human immune cells to dissect the pathogen’s strategy of disrupting host multicellular assemblies. Concurrently, a mouse model of bloodstream infection was used to demonstrate that the host apoptosis pathway plays a crucial role in rendering mammals susceptible toward S. aureus. Based on these findings, subsequent work along with genetic engineering was used to identify single nucleotide polymorphisms (SNPs) in key genetic elements of the host intrinsic pathway of apoptosis that alter the susceptibility of phagocytes toward staphylococci. In this manner, various candidate SNPs were discovered which shield host immune cells from the cytotoxic properties of S. aureus-derived effector-nucleosides that target mitochondria and the apoptosis-cell death axis. Overall, these studies uncovered a crucial signaling pathway that renders the host susceptible toward S. aureus thereby opening novel opportunities for the design of immunomodulatory therapeutic strategies.
Publications
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Methicillin-resistant Staphylococcus pseudintermedius synthesizes deoxyadenosine to cause persistent infection. Virulence, 12(1), 989-1002.
Bünsow, Dorothea; Tantawy, Eshraq; Ostermeier, Tjorven; Bähre, Heike; Garbe, Annette; Larsen, Jesper & Winstel, Volker
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Selective Host Cell Death by Staphylococcus aureus: A Strategy for Bacterial Persistence. Frontiers in Immunology, 11.
Missiakas, Dominique & Winstel, Volker
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Molecular Prerequisites for Neutrophil Extracellular Trap Formation and Evasion Mechanisms of Staphylococcus aureus. Frontiers in Immunology, 13.
von Köckritz-Blickwede, Maren & Winstel, Volker
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Staphylococcus aureus Multiplexes Death-Effector Deoxyribonucleosides to Neutralize Phagocytes. Frontiers in Immunology, 13.
Tantawy, Eshraq; Schwermann, Nicoletta; Ostermeier, Tjorven; Garbe, Annette; Bähre, Heike; Vital, Marius & Winstel, Volker
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Functional diversity of staphylococcal surface proteins at the host-microbe interface. Frontiers in Microbiology, 14.
Schwermann, Nicoletta & Winstel, Volker
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Pathogen-driven nucleotide overload triggers mitochondria-centered cell death in phagocytes. PLOS Pathogens, 19(12), e1011892.
Schwermann, Nicoletta; Haller, Rita; Koch, Sebastian; Grassl, Guntram A. & Winstel, Volker
