When antibiotics fail: A potential new angle on severe bacterial infection and sepsis
Bacterial infections that don't respond to antibiotics are of rising concern. And so is sepsis - the immune system's last-ditch, failed attack on infection that ends up being lethal itself. Sepsis is the largest killer of newborns and children worldwide and, in the U.S. alone, kills a quarter of a million people each year. Like antibiotic-resistant infections, it has no good treatment.
Reporting this week in Nature, scientists in Boston Children's Hospital's Program in Cellular and Molecular Medicine (PCMM) describe new potential avenues for controlling both sepsis and the runaway bacterial infections that provoke it.
It was already known that bacterial invasion causes protein complexes called inflammasomes to become activated, triggering a "death pathway" known as pyroptosis: the infected cells explode open, releasing bacteria as well as chemical signals that sound an immune alarm.
An activated inflammasome (Wu laboratory/Liman Zhang)
But there needs to be a balance: too strong an alarm can trigger sepsis, causing fatal blood-vessel and organ damage.
"The immune system is trying like hell to control the infection, but if the bacteria win out, the immune response can kill the patient," explainsJudy Lieberman, MD, PhD, senior investigator on the study together with Hao Wu, PhD, also in the PCMM. "Most attempts to quiet the immune response haven't worked in treating sepsis in the clinic, because the parts that trigger it haven't been well understood."
Lieberman, Wu and colleagues set out to fill in these details, revealing the final cellular events necessary for both sepsis and stemming the bacterial attack.
A deep dive on bacterial sepsis
Activated inflammasomes were already known to activate enzymes called caspases that cut a molecule called gasdermin D in two. This cleavage unleashes gasdermin D's active fragment, known as gasdermin-D-NT. But how this gets cells to the end game - the killing of bacteria - was a mystery.
Now, careful experiments by Lieberman, Wu and colleagues show that gasdermin-D-NT has a multi-pronged action. On the one hand, it perforates the membranes of the bacteria that are infecting cells and kills them. It also punches holes in the membrane of the host cell, causing pyroptosis - killing the cell and releasing bacteria and immune alarm signals. (Nearby uninfected cells are left unscathed.)
Finally, once outside the cell, gasdermin-D-NT directly kills bacteria, including E. coli, S. aureus andListeria. In a dish, this happened quickly - within five minutes.
Inflammasomes, activated by bacterial infection, in turn activate caspase enzymes. The enzymes cleave gasdermin D in two, releasing active fragments known as gasdermin-D-NT (red ovals). The fragments group together to form pores that punch holes in the membrane of the infected cell, causing pyroptosis - expelling the bacteria together with cytokines that sound an immune alarm. In addition, the gasdermin-D-NT fragments perforate the membranes of bacteria (in green), killing them directly. (Credit: Xing Liu, PhD, Boston Children's Hospital and Youdong Pan, PhD, Brigham & Women's Hospital)
The results now need to be replicated in animal models of infection and sepsis, but Lieberman believes that understanding how gasdermin-D-NT works could be harnessed to help treat highly dangerous bacterial infections, while also helping to curb the runaway immune response that leads to sepsis.
"Because of widespread antibiotic resistance, we have to think about other strategies," Lieberman says. "Since the fragment kills bacteria but not uninfected host cells, one can imagine injecting the fragment directly, especially to treat a localized infection involving antibiotic-resistant bacteria."
For sepsis, Lieberman speculates about ways of inhibiting or blocking gasdermin-D-NT, such as with antibodies or strategies targeting caspase enzymes.
Gasdermin-D-NT's dual action is double-edged to be sure: It sounds the alarms - sometimes too loudly - but also helps put out the fire. So safely controlling this protein fragment would be tricky. Interventions to manipulate gasdermin-D-NT have not yet been tried in animals, a necessary next step. But since antibiotic resistance is increasing and cytokine inhibitors haven't worked well in controlling sepsis, this new knowledge could provide important new leads.
The study was funded by the National Institutes of Health (grant R01AI123265). Xing Liu, PhD, Zhibin Zhang, PhD and Jianbin Ruan, PhD are co-first authors on the paper.