Maturation and resolution of Staphylococcus aureus skin abscess
Lead Research Organisation:
University of Cambridge
Department Name: Medicine
Abstract
Staphylococcus aureus (S. aureus) infections have been estimated to cause 1.1 million deaths worldwide annually. This makes it the bacterial pathogen causing the second largest number of deaths annually, after tuberculosis (1.6 million deaths). Given failures in effective vaccine development and the rising incidence of resistant strains (e.g. MRSA), S. aureus infection remains an aggressive challenge to human health.
One of the key features of S. aureus infection is the formation of abscesses; bacteria and pus-filled lesions with a fibrous capsule. These form in a broad range of tissues, from the superficial (e.g. skin) to the visceral (e.g. muscle, brain, lung, liver). S. aureus abscesses are very slow to resolve and often require surgical drainage and/or prolonged courses of intravenous antibiotics. In turn, this can lead to antibiotic resistance and additional risks (e.g. catheter-associated infection, drug toxicity and Clostridium difficile infection). The healthcare costs for adequately treating these infections can be prohibitive for health systems in developing economies. Additionally, in the developed world, these infections significantly impact marginalised communities (e.g. intravenous drug users) and frequently cause outbreaks in institutions (e.g. prisons).
Despite being a common and serious form of Staphylococcal infection, the biology of abscess has been remarkably unexplored, particularly from the perspective of how the immune system co-ordinates and resolves these infections. The aim of this project is to deliver a detailed characterisation of the key steps involved in how the body naturally resolves these infections in the skin. Insights we gain from this will allow us identify new treatment targets for these difficult to treat infections, helping them resolve faster. This work ultimately aims to improve outcomes for patients and reduce our reliance on prolonged antibiotics and surgery. This work may offer additional insights for other infections causing abscess and also offer insights into mechanisms of immune resolution in the skin generally, which may have implications for the treatment of a variety of dermatological conditions.
One of the key features of S. aureus infection is the formation of abscesses; bacteria and pus-filled lesions with a fibrous capsule. These form in a broad range of tissues, from the superficial (e.g. skin) to the visceral (e.g. muscle, brain, lung, liver). S. aureus abscesses are very slow to resolve and often require surgical drainage and/or prolonged courses of intravenous antibiotics. In turn, this can lead to antibiotic resistance and additional risks (e.g. catheter-associated infection, drug toxicity and Clostridium difficile infection). The healthcare costs for adequately treating these infections can be prohibitive for health systems in developing economies. Additionally, in the developed world, these infections significantly impact marginalised communities (e.g. intravenous drug users) and frequently cause outbreaks in institutions (e.g. prisons).
Despite being a common and serious form of Staphylococcal infection, the biology of abscess has been remarkably unexplored, particularly from the perspective of how the immune system co-ordinates and resolves these infections. The aim of this project is to deliver a detailed characterisation of the key steps involved in how the body naturally resolves these infections in the skin. Insights we gain from this will allow us identify new treatment targets for these difficult to treat infections, helping them resolve faster. This work ultimately aims to improve outcomes for patients and reduce our reliance on prolonged antibiotics and surgery. This work may offer additional insights for other infections causing abscess and also offer insights into mechanisms of immune resolution in the skin generally, which may have implications for the treatment of a variety of dermatological conditions.
Technical Summary
The aim of this project is to immunologically characterise the process of Staphylococcus aureus abscess resolution using a murine skin model and, more latterly, a human challenge model. In aim 1, we take an unbiased, multiomic approach to understanding this process utilising techniques such a bulk/single cell RNA sequencing, proteomics and high-dimensionality flow cytometry and confocal microscopy. This will allow us to build an immune cell atlas of the process of abscess resolution at unprecedented depth. The resulting data set will provide insights into the various stages of immune cell recruitment and key checkpoints in this process, in a physiologically relevant model. I aim to generate further hypotheses of how we can expedite the resolution process. I will then mechanistically validate or refute these in and ex vivo. This work will provide a publically available resource for other researchers in this field.
From the pilot data I have already collected during my Evelyn Trust Clinical Research Fellowship we have discovered that Neutrophil Extracellular Traps (NETs) are produced early in the formation of abscesses and these appear to interact closely with the forming fibrin and macrophage-rich capsule. In Aim 2, we'll further characterise the role that these NETs play and assess whether their presence is necessary to contain infection or whether they play a pathological role, delaying abscess resolution and causing tissue damage. We have gathered a number of tools to explore this, including a PADI4 KO mouse and pharmacological inhibitors of NETosis (e.g. GSK484 and Cl-amidine).
In Aim 3, we will explore the translatability of our findings from Aims 1 and 2, using a human challenge model of S. aureus skin infection by injecting killed S. aureus intradermally into healthy volunteers. This will be performed with the support and guidance of our external collaborators (Prof Akbar and Prof Gilroy - UCL), who have extensive experience utilising such models.
From the pilot data I have already collected during my Evelyn Trust Clinical Research Fellowship we have discovered that Neutrophil Extracellular Traps (NETs) are produced early in the formation of abscesses and these appear to interact closely with the forming fibrin and macrophage-rich capsule. In Aim 2, we'll further characterise the role that these NETs play and assess whether their presence is necessary to contain infection or whether they play a pathological role, delaying abscess resolution and causing tissue damage. We have gathered a number of tools to explore this, including a PADI4 KO mouse and pharmacological inhibitors of NETosis (e.g. GSK484 and Cl-amidine).
In Aim 3, we will explore the translatability of our findings from Aims 1 and 2, using a human challenge model of S. aureus skin infection by injecting killed S. aureus intradermally into healthy volunteers. This will be performed with the support and guidance of our external collaborators (Prof Akbar and Prof Gilroy - UCL), who have extensive experience utilising such models.
