A newly discovered protein is helping defeat a flesh-eating bacteria

The authors of the study describe NLRP3's ability to detect these toxins using the analogy of a home security system "that also doubles up as a fire detector."  

"This fire detector, like NLRP3, is very versatile and can protect the house, or in this case, our body," co-author Callum Kay, also from JCSMR, said. 

"But what if this fire detector was so sensitive that it interpreted smoke coming from a barbecue as a fire? Then the alarm would be constantly going off and cause chaos for the homeowner.  

"We found that NLRP3 acts in a similar way; the protein can become overactive and trigger a disproportionate response that causes more harm than good and can lead to sepsis, which can be life-threatening." 

When this occurs, the body's safety mechanisms that are designed to protect us fail. 

Using drugs to dampen the immune system's defensive response triggered by NLRP3 helped the scientists decipher the molecular mechanisms that cause the toxins to trigger the protein's alarm system. 

New understanding brings new treatments

The researchers now believe that by better understanding these mechanisms, they can develop new therapies to defeat the bacteria.   

"The death rate of muscle necrosis, which is caused by Clostridium perfringens, remains alarmingly high, exceeding 50 per cent," Dr. Mathur said. 

"By understanding the role NLRP3 plays in detecting these deadly toxins and the defensive mechanisms it activates to protect the body, we can start to develop new techniques that target the protein and 'dampen' its overactive response.  

"This would not only help prevent the body from triggering extreme and potentially deadly reactions to infection, but it could also help us find new ways to outsmart the bacteria and potentially develop new treatments," Mathur noted in the statement. 

The research is published in EMBO Reports. 

Study abstract:

Inflammasome signaling is a central pillar of innate immunity triggering inflammation and cell death in response to microbes and danger signals. Here, we show that two virulence factors from the human bacterial pathogen Clostridium perfringens are nonredundant activators of the NLRP3 inflammasome in mice and humans. C. perfringens lecithinase (also known as phospolipase C) and C. perfringens perfringolysin O induce distinct mechanisms of activation. Lecithinase enters LAMP1+ vesicular structures and induces lysosomal membrane destabilization. Furthermore, lecithinase induces the release of the inflammasome-dependent cytokines IL-1β and IL-18, and the induction of cell death independently of the pore-forming proteins gasdermin D, MLKL and the cell death effector protein ninjurin-1 or NINJ1. We also show that lecithinase triggers inflammation via the NLRP3 inflammasome in vivo and that pharmacological blockade of NLRP3 using MCC950 partially prevents lecithinase-induced lethality. Together, these findings reveal that lecithinase activates an alternative pathway to induce inflammation during C. perfringens infection and that this mode of action can be similarly exploited for sensing by a single inflammasome.