Anti-infective therapeutics and predictive modelling to tackle Staphylococcus aureus disease
Lead Research Organisation:
University of Bath
Department Name: Biology and Biochemistry
Abstract
Staphylococcus aureus is a major human pathogen that causes a broad range of infections resulting in significant morbidity and
mortality globally. Due to the constant threat of antimicrobial resistance, the WHO has placed S aureus on the list of priority
pathogens for which the development of antibiotics and novel immunotherapeutics is urgently required. All successful pathogens
have evolved mechanisms to resist host immunity which are intimately aligned with their pathogenicity. Importantly, the primary
host response to S aureus occurs via complement. Complement is an elegant evolutionarily conserved system, playing essential roles
in early defences by working in concert with immune cells to survey, label and destroy microbial intruders and coordinate
inflammation. To tackle S aureus infection we have designed this project with two major goals: 1) Construct novel anti-infective
immunotherapeutic fusion proteins which will bind to the surface of S aureus and disrupt essential virulence mechanisms while
simultaneously activate the complement system, facilitating enhanced complement fixation and subsequent clearance by immune
cells. 2) Develop a machine learning framework to predict the severity of S aureus infection. By combining genotype and virulence
phenotype generated in this proposal, this aim will first identify and functionally confirm virulence signatures associated with
immune evasion. Secondly, this data together with previously obtained clinical patient data, will be incorporated into mathematical
and statistical models designed to predict determinants associated with poor infection outcome. Combined, these goals will address
central issues regarding the treatment and disease management of multi-drug resistant S aureus infections.
mortality globally. Due to the constant threat of antimicrobial resistance, the WHO has placed S aureus on the list of priority
pathogens for which the development of antibiotics and novel immunotherapeutics is urgently required. All successful pathogens
have evolved mechanisms to resist host immunity which are intimately aligned with their pathogenicity. Importantly, the primary
host response to S aureus occurs via complement. Complement is an elegant evolutionarily conserved system, playing essential roles
in early defences by working in concert with immune cells to survey, label and destroy microbial intruders and coordinate
inflammation. To tackle S aureus infection we have designed this project with two major goals: 1) Construct novel anti-infective
immunotherapeutic fusion proteins which will bind to the surface of S aureus and disrupt essential virulence mechanisms while
simultaneously activate the complement system, facilitating enhanced complement fixation and subsequent clearance by immune
cells. 2) Develop a machine learning framework to predict the severity of S aureus infection. By combining genotype and virulence
phenotype generated in this proposal, this aim will first identify and functionally confirm virulence signatures associated with
immune evasion. Secondly, this data together with previously obtained clinical patient data, will be incorporated into mathematical
and statistical models designed to predict determinants associated with poor infection outcome. Combined, these goals will address
central issues regarding the treatment and disease management of multi-drug resistant S aureus infections.
Organisations
Publications
Bettoni S
(2024)
C4b-Binding Protein and Factor H Attenuate NLRP3 Inflammasome-Mediated Signalling Response during Group A Streptococci Infection in Human Cells.
in Journal of innate immunity
Related Projects
| Project Reference | Relationship | Related To | Start | End | Award Value |
|---|---|---|---|---|---|
| EP/X022935/1 | 02/04/2023 | 31/03/2024 | £190,380 | ||
| EP/X022935/2 | Transfer | EP/X022935/1 | 14/06/2024 | 03/06/2025 | £93,198 |
| Description | Staphylococcus aureus is a major human pathogen and leading cause of bacteraemia and infective endocarditis as well as bone, skin and soft-tissue, pleuropulmonary and implant-related infections. S. aureus disease is further complicated by strains that are resistant to multiple, clinically relevant antibiotics. In this proposal we aimed to develop novel anti-infective, resistance-proof fusion proteins that target and disrupt essential surface expressed S. aureus virulence factors while activating the immune system to promote pathogen clearance by host immune cells. This was based on 1) previous data by our group that showed success in developing complement activating fusion proteins against other important bacterial pathogens and 2) data in the literature that identified appropriate surface proteins to target, namely a cell wall anchored staphylococcal protein named SdrE. Data from the scientific community indicated that SdrE mediated the recruitment of both C4b-binding protein (C4BP) and Factor H, two soluble complement inhibitors, and were deemed by us in our proposal as appropriate virulence factors to target. However our novel analysis showed that the recruitment of C4BP is not an immune evasion strategy employed by S. aureus (PMID: 37668351). We turned our attention to SdrE recruitment of Factor H, where in our unpublished data we observed no involvement of SdrE in recruiting Factor H, again contrary to published data. We then focused on understanding what surface expressed staphylococcal proteins are important in resisting complement deposition. We are currently conducting experiments to answer these questions and have a manuscript in preparation. To sum, we have identified novel roles for the fibronectin binding proteins (FnBPA and B) and clumping factors (ClfA and B) in mediating the restriction of complement deposition. In addition we analysed how FH is bound to the staphylococcal surface and provide information on the requirements of active C3b to be deposited and the expression of key staphylococcal complement evasins. Finally we provide a comprehensive picture of staphylococcal avoidance of complement using whole cell bacteria and flow cytometry which we believe is vastly superior to investigating recombinant proteins in understanding bacteria-complement interactions. Due to the issues with developing anti-infective proteins stated above, we also turned our attention towards how another human pathogen, Streptococcus pyogenes evades the host immune response. We discovered that both Factor H and C4BP attenuate inflammasome-mediated immune responses during infection of human immune cells. Furthermore, we showed for the first time that C4BP is engulfed by cells together with S. pyogenes and that C4BP limited the cleavage of gasdermin D which interfered with cascade-1 enzymatic activity and subsequence IL-1B secretion. Our paper (PMID: 39496236) addresses a novel S. pyogenes immune evasion strategy linking complement evasion to reduce intracellular sensing of GAS by host cells. |
| Exploitation Route | S. aureus resistance to complement research: Confirming the precise role of staphylococcal surface proteins in mediating complement resistance is essential for understanding the fundamental bases of host-pathogen interactions and for developing accurate and effective immunotherapeutics. To date decades of intensive research and funding across the US, UK and Europe there is still no vaccine against S. aureus. We hope that our work will provide clarity into how this versatile pathogen escapes complement detection. S. pyogenes research: We explored a novel evasion strategy by S. pyogenes that links the recruitment of FH and C4BP to reduce intracellular sensing and inflammasome activation by primary immune cells. Several different bacteria can both recruit FH and C4BP and become internalised; our data is the first to show internalised C4BP with bacteria; therefore our observations may lead to other elucidation of other evasion strategies employed by major microbial pathogens. Moreover interfering with this interaction constitutes a novel therapeutic intervention strategy and should be explored in detail. |
| Sectors | Healthcare |