Regulatory functions of oxidative/antioxidative processes during host–pathogen interactions in tuberculosis

• Applicant: Professor Dr. Ulrich E. Schaible
• Subject Area: Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology ; Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 447447740

Tuberculosis (TB) remains the most common cause of death from a single infectious agent, Mycobacterium tuberculosis (Mtb). Emerging multi and extensively drug resistant Mtb infections and related treatment failures represent a global health crisis. As hallmark of active TB pathogenesis, neutrophils accumulate in lesions and, in pulmonary samples, represent the predominantly infected cell population. We recently found that Mtb induce necrotic cell death in neutrophils. Subsequent uptake of Mtb together with necrotic neutrophils by macrophages promotes mycobacterial growth and macrophage necrotic cell death. Reactive oxygen species (ROS) are mediators of neutrophil necrosis and likely, determinants of active TB pathogenesis such as exacerbated inflammation, necrotizing granulomas, tissue damage and, ultimately, Mtb aerosol transmission. However, it is unclear how ROS contribute to Mtb-induced necrotic cell death. It is widely recognized that ROS and reactive nitrogen species (RNS) as well as protective antioxidant systems are essential players in innate host defense - pathogen interactions. However, oxidant/antioxidant systems play a much broader role than just promoting death or survival of cells but are also involved in cell signaling functions. To understand the molecular interactions and regulatory functions of host cell oxidative/antioxidant pathways linked to apoptotic vs. necrotic cell death pathways triggered by Mtb, we propose global characterization of thiol oxidation/nitrosylation in Mtb-infected macrophages and neutrophils by the Ox-RAC method combined with focused studies on key redox pathways. Preliminary data suggest that, distinct sets of proteins become oxidized/reduced in macrophages vs. neutrophils upon Mtb infection as decision point for apoptosis vs. necrosis but may also affect distinct pathways. Our long-term goal is to have a mechanistic understanding of redox-based regulation and detailed structure-function analyses of key proteins to pinpoint their function in host cell responses. Combining biochemistry and cell biology expertise between our groups will integrate proteomics and cellular functional analyses to get physiologically relevant insights into phagocyte-Mtb interaction by revealing new mechanisms that govern the switch to either regulated cell death or necrosis and downstream responses and inflammation relevant to understand phagocyte redox systems in host-pathogen interactions beyond TB.

• DFG Programme: Research Grants
• International Connection: Israel
• International Co-Applicant: Professor Moran Benhar, Ph.D.