Projects Pathogenesis of Bacterial Infections
S. aureus frequently causes invasive infections due to its ability to perturb host multicellular assemblies. During infection, S. aureus secretes a plethora of potent toxins and virulence factors that together manipulate human immune cell responses thereby affecting the clinical outcome of acute and recurrent infections. To dissect the pathogen’s strategy of disrupting host multicellular assemblies, current work seeks to explore the contribution of specific human genes toward staphylococcal pathogenesis and disease. Specifically, we investigate human signaling cascades and cellular pathways targeted by S. aureus-derived cytotoxins. By using organoid technologies and animal models of infectious disease, current projects also focus on the epidemiology and pathology of chronic staphylococcal infections of the respiratory tract. Ultimately, this research may help to develop new immunomodulatory therapeutic strategies against pathogenic staphylococci, including MRSA.
Sequence analyses of human genomes and their diversity led to the discovery of genetic polymorphisms impacting infectious diseases. However, human single nucleotide polymorphisms (SNPs) that influence staphylococcal infections are largely unknown. We investigate the hypothesis that SNPs in specific human genes are associated with the clinical outcome of infections caused by S. aureus and other staphylococci. In addition, we focus on chronic and recurrent infections that may have selected for specific traits in the human immune system. To achieve these goals, the laboratory takes advantage of CRISPR/Cas9 mutagenesis of host immune cells and mouse infection models. Predictions will also be validated by using computational approaches and unique biochemical techniques. Combined with genomic and molecular technologies, these studies are designed to answer the question why human populations exhibit variable susceptibility toward staphylococcal disease.
Staphylococcal manipulation of host immune cell assemblies
Tantawy E, Schwermann N, Ostermeier T, Garbe A, Bähre H, Vital M, Winstel V* (2022) Staphylococcus aureus Multiplexes Death-Effector Deoxyribonucleosides to Neutralize Phagocytes. Front Immunol. 10;13:847171. (*corresponding author)
Du X, Larsen J, Li M, Walter A, Slavetinsky C, Both A, Sanchez Carballo PM, Stegger M, Lehmann E, Liu Y, Liu J, Slavetinsky J, Duda KA, Krismer B, Heilbronner S, Weidenmaier C, Mayer C, Rohde H, Winstel V, Peschel A (2021) Staphylococcus epidermidis clones express Staphylococcus aureus-type wall teichoic acid to shift from a commensal to pathogen lifestyle. Nat Microbiol 6(6): 757–768.
Bünsow D, Tantawy E, Ostermeier T, Bähre H, Garbe A, Larsen J, Winstel V* (2021) Methicillin-resistant Staphylococcus pseudintermedius synthesizes deoxyadenosine to cause persistent infection. Virulence 12(1):989-1002 (*corresponding author)
Wanner S, Schade J, Keinhorster D, Weller N, George SE, Kull L, Bauer J, Grau T, Winstel V, Stoy H, Kretschmer D, Kolata J, Wolz C, Broker BM, Weidenmaier C (2017) Wall teichoic acids mediate increased virulence in Staphylococcus aureus. Nat Microbiol 2: 16257.
Funding: Else Kröner-Fresenius-Stiftung
Host susceptibility of staphylococcal infections
Schwermann N, Winstel V* (2023) Functional diversity of staphylococcal surface proteins at the host-microbe interface. Front Microbiol 18;14:1196957 (*corresponding author)
Missiakas D, Winstel V* (2021) Selective Host Cell Death by Staphylococcus aureus: A Strategy for Bacterial Persistence. Front Immunol 11:621733 (*corresponding author)
Winstel V*, Schneewind O, Missiakas D* (2019) Staphylococcus aureus exploits the host apoptotic pathway to persist during infection. mBio 10(6):e02270-19 (*corresponding author, shared)
Winstel V, Missiakas D, Schneewind O (2018) Staphylococcus aureus targets the purine salvage pathway to kill phagocytes. Proc Natl Acad Sci U S A 115(26): 6846-6851.