A Novel Method To Understand Staphylococcus aureus Skin and Soft Tissue Infection

Through innovative techniques, we are uncovering how the immune system responds to Staphylococcus aureus skin infections. These insights could lead to breakthroughs in vaccine development and personalised treatments for antibiotic resistant infections.
A Novel Method To Understand Staphylococcus aureus Skin and Soft Tissue Infection
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Human skin and soft tissue infections (SSTIs) occur when our skin barrier is compromised, allowing pathogens (generally bacteria) to invade the deeper skin layers or soft tissue triggering inflammation and an immune response. SSTI encompasses a wide array of clinical conditions commonly seen in Primary Care, Emergency Departments or Hospital settings, including cellulitis, erysipelas, necrotising fasciitis, and lymphadenitis. While these conditions share a common route of infection, they vary greatly in how patient's present (their signs and symptoms) and in the potential severity and outcome. Among the many pathogens capable of causing SSTI, Staphylococcus aureus is by far the most common culprit.[1]

Staphylococcus aureus is a Gram positive, aerobic, coccus-shaped bacterium that often resides harmlessly on the skin surface as part of the normal flora of many people. People can be colonised with S. aureus persistently, intermittently or never at all. Little is understood about the factors leading to colonisation, however, it is well-established that colonisation significantly increases the likelihood of developing SSTIs. Although cases of cellulitis can typically be treated with antibiotics, SSTIs remain a leading cause of death worldwide. Recurrent infection is common, and a single episode of SSTI is in itself a major risk factor for future infections.[2]

The rise of multidrug resistant strains such as methicillin resistant Staphylococcus aureus (MRSA), have exacerbated the challenge for clinicians, especially given the limited treatment options available. Unfortunately, despite considerable research efforts, there is no effective vaccine against S. aureus. Many promising vaccine candidates have failed during the in-human stage of vaccine trials. This is partially because most of our understanding of the disease mechanisms and disease progression in SSTIs come from mouse and in-vitro models, which do not fully capture the complexity of human immune responses. Given the threat posed by multi-drug resistant strains and the lack of a viable vaccine against Staphylococcus aureus, there is an urgent need for innovative research methods to deepen our understanding of this disease.

A Novel Method to Understand SSTI

To address this knowledge gap, we have designed an observational cohort study to investigate the skin and immune response of people recovering from recent SSTI. The study will recruit 20 patients recovering from recent SSTIs (within the last six months), alongside 20 healthy control volunteers. These participants will undergo various procedures at the Sheffield Dermatology Research Skin Barrier Facility, where we will employ a mix of both traditional and novel research techniques.

One such technique is negative pressure suction blistering (NSPB), a method historically used in the treatment of conditions such as vitiligo, and more recently adopted in research assessing wound healing.[3], [4] In this procedure, a suction device is applied to the skin and negative pressure is used to separate the dermis from the epidermis, forming a blister. The blister fluid, which contains immune cells, is then extracted for analysis and the skin heals within a few days. This non-invasive technique is safe, typically well-tolerated and leaves the skin intact with minimal discomfort. It offers new potential to investigate immune cell behaviour within the skin, the primary site of immune response in SSTI, without causing significant disruption or long-term damage to the skin.

In addition to NPSB, we will assess the structural integrity of the skin and its ability to heal following SSTI. Using microneedles - commonly employed in dermatology to improve skin appearance, we will create superficial disruption to the skin. Optical coherence tomography (OCT) will then be used to capture detailed images of the skin structure before and after microneedling. This will help us better understand how the skin responds to physical damage and heals post-infection.

These novel techniques will be complemented by traditional methods such as venesection to analyse circulating immune cells, skin swabs to identify S. aureus colonisation status and 16s RNA sequencing to analyse the skin microbiome. By amalgamating data from these approaches, we aim to identify the hallmark features of disruption to the local and systemic immune response, skin architecture and local microenvironment following recent SSTI infection caused by S. aureus.

The Future of SSTI Research:

The results of this study may enable us to identify immune deficits associated with recent SSTI caused by S. aureus which could be used to develop potential testing strategies to identify patients at highest risk of recurrence. This, in turn, could lead to a more personalised approach to prevention of recurrent SSTI though, for example, prophylactic or standby antibiotics and vaccination.

Looking ahead, we hope to use this work as a stepping stone towards developing a model for a controlled human challenge study in Staphylococcus aureus, which currently does not exist. In human challenge studies, healthy volunteers are intentionally exposed to a pathogen in order to induce infection to which new treatments and vaccines can be tested. Controlling and monitoring the method of infection also allows researchers to observe early infection, which is often not possible in real-world settings. This type of study holds great promise for the development of early diagnostics, interventions and treatments. Human challenge studies have already delivered breakthroughs in diseases like COVID-19, pertussis, and malaria. However, the full potential of their use is yet to be tapped, particularly in the field of SSTI. By developing a controlled S. aureus human challenge model, we could gain unprecedented insights into early infection and immune responses, paving the way for new treatments, early diagnostics, and vaccine development.

References

[1] G. T. Ray, J. A. Suaya, and R. Baxter, ‘Microbiology of skin and soft tissue infections in the age of community-acquired methicillin-resistant Staphylococcus aureus’, Diagn. Microbiol. Infect. Dis., vol. 76, no. 1, pp. 24–30, May 2013, doi: 10.1016/j.diagmicrobio.2013.02.020.

[2] J. Cannon, J. Dyer, J. Carapetis, and L. Manning, ‘Epidemiology and risk factors for recurrent severe lower limb cellulitis: a longitudinal cohort study’, Clin. Microbiol. Infect., vol. 24, no. 10, pp. 1084–1088, Oct. 2018, doi: 10.1016/j.cmi.2018.01.023.

[3] A. F. Alexis, D. C. Wilson, J. A. Todhunter, and M. J. Stiller, ‘Reassessment of the suction blister model of wound healing: introduction of a new higher pressure device’, Int. J. Dermatol., vol. 38, no. 8, pp. 613–617, 1999, doi: 10.1046/j.1365-4362.1999.00800.x.

[4] X. Shi, F. Wang, Y. Sun, J. Du, and X. Ding, ‘Long-Term Effects and Prognosis Following Suction Blister Epidermal Grafting in Vitiligo Patients’, J. Cutan. Med. Surg., vol. 28, no. 3, pp. 264–268, May 2024, doi: 10.1177/12034754241238717.

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Biomedical Research
Life Sciences > Health Sciences > Biomedical Research
Immunological Surveillance
Life Sciences > Biological Sciences > Immunology > Adaptive Immunity > Cellular Immunity > Immunological Surveillance
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Life Sciences > Health Sciences > Clinical Medicine > Diseases > Infectious Diseases
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Life Sciences > Biological Sciences > Biological Techniques > Biological Models > Skin models
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