Researchers at Newcastle University, UK and the University of Illinois, USA are investigating how infectious microbes can survive attacks by the body’s immune system. By better understanding the bacteria’s defence mechanism, new strategies can be developed to cure infections that are currently resistant to treatments.

The study, which is published in PLoS Pathogens, focused on Staphylococcus aureus - renowned as the so-called ‘superbug’ methicillin resistant S. aureus, or MRSA - a common bacterium found in or on approximately half of the population.  While S. aureus usually safely coexists with healthy individuals, it has the ability to infect nearly the entire body.

Subverting the immune response

The human body uses a diverse array of weapons to fight off bacteria. “Our immune system is very effective and prevents the majority of microbes we encounter from causing infections,” said Dr Thomas Kehl-Fie, a microbiologist at the University of Illinois. “But pathogens such as S. aureus have developed ways to subvert the immune response.”

S. aureus can overcome one of the body’s key defences known as “nutritional immunity”. Other less pathogenic relatives are stopped by this defence, which prevents bacteria from obtaining critical nutrients. It starves S. aureus of manganese, a metal needed by the bacterial enzyme superoxide dismutase (SOD). This enzyme functions as a shield, minimizing the damage from another weapon in our body’s arsenal, the oxidative burst. Together, the two host weapons usually function as a one-two punch, with nutritional immunity weakening the bacteria’s shields, enabling the oxidative burst to kill the bacterium.

S. aureus is particularly adept at causing devastating infections. Differing from other closely related species, S. aureus possesses two superoxide dismutases. The team discovered that the second superoxide dismutase enhances the ability of S. aureus to resist nutritional immunity and cause disease.

“This realisation was both exciting and perplexing, as both superoxide dismutases were thought to utilise manganese and therefore should be inactivated by manganese starvation,” said Dr Kehl-Fie.

Adaptability

The most prevalent family of SODs, to which both of the S. aureus SOD enzymes belong, has long been thought to come in two flavours: those that are dependent on manganese for function and those that utilise iron.

In light of their findings, the team evaluated if the second staphylococcal SOD was dependent on iron. Surprisingly, they discovered that the second SOD was capable of using either metal. While the existence of these “cambialistic” SODs, capable of using both iron and manganese, was proposed decades ago, the existence of this type of enzyme was largely dismissed as a quirk of chemistry, unimportant in real biological systems. The team’s findings dispel this notion, demonstrating that cambialistic SODs critically contribute to infection.

The team found that, when starved of manganese by the body, S. aureus activated the cambialistic SOD with iron instead of manganese, ensuring its critical bacterial defensive barrier was maintained.

“The cambialistic superoxide dismutase plays a key role in this bacterium’s ability to evade the immune defence,” said Dr Kevin Waldron in the Institute for Cell and Molecular Biosciences at Newcastle University. “Importantly, we suspect similar enzymes may be present in other pathogenic bacteria. Therefore it could be possible to target this system with drugs for future antibacterial therapies.”

Due to the emergence and spread of antibiotic resistant bacteria, such as MRSA, staphylococcal and other infections are becoming increasingly difficult, if not impossible, to treat.

This has led leading health organizations, such as the Centers for Disease Control and Prevention and the World Health Organization, to issue an urgent call for new approaches to combat the threat of antibiotic resistance. 

Reference: A superoxide dismutase capable of functioning with iron or manganese promotes the resistance of Staphylococcus aureus to calprotectin and nutritional immunity. PLoS Pathogens.