Saturday, April 20, 2024
4/20/2024
PROJECT SUMMARY The human complement system is a collection of ~30 membrane-bound or serum proteins which form a tightly regulated proteolytic cascade with antimicrobial and homeostatic effector functions. Complement dysregulation contributes significantly to a wide array of human diseases including arthritis, age-related macular degeneration, and transplant rejection. Although only two complement-directed drugs are currently FDA approved, therapeutic intervention of complement has gained traction with the advent of several new drugs in the preclinical and clinical pipeline. Nature has provided an unexpected source of novel complement inhibitory mechanisms in the form of microbial immune evasion proteins, and strides have recently been made in translating these evolutionarily-optimized inhibitory templates into novel therapeutics. However, relatively few examples of classical pathway specific immune evasion strategies have been described. Given the causal link of the classical pathway in neurodegenerative conditions such as Alzheimer’s disease and schizophrenia, this represents a critical deficit in our knowledge which stands to be addressed by the scientific community. The etiological agent of Lyme disease, Borrelia burgdorferi, is transmitted to humans by the bite of infected Ixodes ticks where it disseminates and colonizes remote tissues. Untreated B. burgdorferi infection causes disease in immune competent hosts, in part, by evading innate immune systems such as complement. Recently we reported that the lipoprotein B. burgdorferi BBK32 specifically prevents activation of the complement classical pathway by acting as a nanomolar inhibitor of the first component of complement, C1. We hypothesize that in addition to BBK32, B. burgdorferi expresses additional factors which also recognize and interfere with C1, and that one of these immunomodulators is the lipoprotein CspA. The overarching goal of this project is to shed light on the interaction of B. burgdorferi with the classical pathway of complement as outlined by three Specific Aims. In the first Aim, we will investigate the structural and molecular basis for C1 inhibition by BBK32 and follow-up on interesting preliminary data which suggests that other Lyme disease associated Borrelia BBK32’s have differential activity. In the second aim, we will use a multi-platform approach to quantitatively measure the novel interaction between CspA and the pattern recognition protein of the classical pathway, C1q. In Aim 3, we will use in vivo imaging in mouse models of Lyme borreliosis to explore the hypothesis that the presence of multiple overlapping classical pathway evasion proteins in B. burgdorferi contributes significantly to its ability to cause infection. By completing this research plan, we will greatly improve our understanding of how an important human pathogen causes disease while simultaneously laying the groundwork for the development of novel classical pathway complement-directed therapeutics for the treatment of devastating human autoimmune, inflammatory, and neurodegenerative diseases.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
