Discovery of human single nucleotide polymorphisms affecting staphylococcal diseases

• Applicant: Professor Dr. Volker Winstel
• Subject Area: Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 449712894

Sequence analyses of human genomes and their diversity led to the discovery of genetic polymorphisms impacting infectious diseases. Specifically, genome-wide association studies (GWASs) discovered striking associations between common or rare genetic polymorphisms that contribute to resistance or enhanced susceptibility to clinically-important pathogens such as human immunodeficiency virus (HIV) or Mycobacterium tuberculosis. In addition, epidemiological studies have revealed variable susceptibilities of distinct human populations toward the same pathogenic agent, underlying the importance of human diversity and host genetics. Overall, these studies provided novel insights into a complex process of host-microbe interaction and confirmed a crucial role of the human genetic architecture in the susceptibility to many pathogens. Nonetheless, the susceptibility or resistance loci for a great majority of infectious diseases remain to be identified. In particular, human single nucleotide polymorphisms (SNPs) and underpinning genetic determinants that affect infections by high priority pathogens such as Staphylococcus aureus, a deadly Gram-positive bacterium causing fatal diseases in humans, are largely unknown. To decipher the impact of human genetic variation on human health and staphylococcal infections, this research project seeks to discover unique host genetic determinants and associated polymorphisms that impair S. aureus disease pathogenesis. Initial work will focus on the genes and take advantage of CRISPR/Cas9 mutagenesis in human immune cells to dissect the pathogen’s strategy of disrupting host multicellular assemblies. Once identified, a comprehensive analysis of host SNPs in candidate genes will examine the functional importance of human genetic diversity on S. aureus infections. Predictive models can be derived from these results and will be tested in a mouse model with cell type-specific defects in candidate genes under pathogen challenge in the presence or absence of the contributing bacterial pathway. The clinical significance of this work is the simultaneous identification of host determinants required for S. aureus pathogenesis along with the analysis of genetic polymorphisms affecting human susceptibility to staphylococcal diseases. Understanding host genetic features that influence staphylococcal disease pathogenesis may lead to the development of new immunomodulatory therapeutic strategies to combat drug-resistant S. aureus, including methicillin-resistant S. aureus (MRSA).

• DFG Programme: Research Grants