Imperial researchers reveal how Strep A disarms immune defences

Researchers have uncovered how a major bacterial pathogen disables one of the body’s first lines of immune defence, revealing a potential new target for future vaccines and anti-virulence therapies.

The study, published in Proceedings of the National Academy of Sciences (PNAS), reveals how Streptococcus pyogenes, (Strep A), uses a bacterial protein called SpyCEP to interfere with the immune system’s response to infection. 

Strep A is responsible for a wide range of illnesses, from mild throat infections to severe and sometimes life-threatening invasive disease. A key reason the bacterium can cause serious infections is its ability to evade the immune system. 

One of the body’s earliest responses to bacterial infection is the recruitment of neutrophils, specialised white blood cells that rapidly move towards sites of infection to attack invading microbes. These cells are guided by chemical signals called chemokines, including CXCL8, which acts like a distress signal calling neutrophils into infected tissues. 

The Imperial-led study has revealed how SpyCEP disables this signal through a previously unknown mechanism. 

Rather than acting like a conventional enzyme that recognises its target through a rigid ‘lock-and-key’ interaction, SpyCEP uses a flexible region called the cleaved autocatalytic maturation loop (CAML) to capture and reshape CXCL8, making it vulnerable to being cut and neutralised. 

By disrupting CXCL8, SpyCEP prevents neutrophils from being effectively recruited to the site of infection, helping Strep A evade immune attack and spread. 

Professor Steve Matthews said: ‘The most striking part of this work is that despite SpyCEP being a highly ordered enzyme that we can visualise by cryo-EM, its unique power comes from its dynamic and flexible mode of substrate recognition. By also using NMR spectroscopy, we could capture a mechanism that would be impossible to understand from a single static structure alone. This gives us a more complete picture of how SpyCEP works and opens up new ways to think about how to stop Group A Strep from disarming the immune system.’ 

Revealing a hidden mechanism 

The researchers combined several advanced techniques, including cryo-electron microscopy, nuclear magnetic resonance (NMR) spectroscopy, native mass spectrometry and glycan microarray analysis, to build a detailed picture of how SpyCEP interacts with CXCL8. 

Their findings show that the CAML region of SpyCEP plays several important roles. It helps the bacterial protein recognise its target, alters the structure of CXCL8, and allows SpyCEP to interact with glycosaminoglycans, molecules that help organise chemokines within tissues. 

This suggests that SpyCEP is adapted to find and disable CXCL8 precisely where immune cells would normally be recruited during infection. 

The discovery challenges the traditional view of proteases as enzymes that rely on fixed structures to recognise their targets, highlighting how flexibility and molecular disorder can give bacterial proteins new ways to manipulate host biology. 

Supporting future vaccine strategies 

The findings could help guide future approaches to preventing Strep A infections. Because SpyCEP is already being explored as a vaccine target, understanding which parts of the protein are essential for its activity could help researchers design vaccines that generate antibodies capable of blocking its function. 

Professor Shiranee Sriskandan, Co-Director, CBRB, said: ‘Strep A is one of the most under-recognised bacterial killers globally. SpyCEP is one of the reasons that Strep A is so virulent, as it prevents neutrophils from approaching the site of infection by cleaving all nearby neutrophil chemokines. Understanding the structural biology of SpyCEP – and how it recognises, then cleaves chemokines – is of crucial importance, because it allows scientists to understand where those antibodies need to bind, and therefore allows us to develop more effective and focused vaccines in the future.’ 

The work also highlights the potential of anti-virulence therapies – treatments designed not to kill bacteria directly, but instead to block the mechanisms they use to cause disease. 

Such approaches are of growing interest as antimicrobial resistance continues to threaten the effectiveness of existing antibiotics. By disabling bacterial weapons such as SpyCEP, future therapies could help the immune system clear infections while potentially placing less pressure on bacteria to develop resistance. 

A collaborative effort 

The research brought together expertise from across Imperial, involving multiple departments, centres and faculties, alongside industrial collaborators. 

Professor James Pease, National Heart and Lung Institute, said: ‘As a chemokine biologist, I have found this project immensely satisfying, learning how a clinically important pathogen undermines the chemokine system to great effect. In addition to aiding vaccine design, our study might also suggest other ways of neutralising chemokine function in inflammatory settings, where neutrophil recruitment may be problematic. It has been great fun working with so many researchers with differing expertise, and a good example of what we can achieve when we work collaboratively.’ 

The team’s next steps will explore whether other bacterial proteases use similar mechanisms to remodel their targets, while continuing to investigate how these insights could support future SpyCEP-based vaccine strategies. 

The researchers say the findings provide a new understanding of how bacterial pathogens exploit molecular flexibility to overcome human immune defences and offer new opportunities to develop ways of stopping them.