Angle of Attack

Protein fragment offers new way to try battling bacterial infections and sepsis

Image: jarun011/iStock

Bacterial infections that don’t respond to antibiotics are of rising concern, as is sepsis: the immune system’s last-ditch, failed attack on infection that ends up being lethal itself.

Reporting online in Nature on July 6, Harvard Medical School researchers at Boston Children’s Hospital describe new potential avenues for controlling sepsis and the runaway bacterial infections that provoke it.

Sepsis kills a quarter of a million people each year in the United States and is the largest killer of newborns and children worldwide. Like antibiotic-resistant infections, it has no good treatment.

Through meticulous experiments in the lab, scientists in the Program in Cellular and Molecular Medicine (PCMM) at Boston Children’s have revealed the final cellular events necessary for sepsis and for stemming the bacterial attack.

 Protein components come together in the inflammasome to form a “wheel of death” against bacteria. Image: Wu lab

Recent research has shown that at any sign of bacterial invasion, protein complexes called inflammasomes are activated. This activation triggers a process called pyroptosis. The infected cells explode, releasing bacteria as well as chemical signals that sound an immune alarm.

But there’s 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,” explained Judy Lieberman, HMS professor of pediatrics at Boston Children’s.

Leiberman and Hao Wu, the Asa and Patricia Springer Professor of Structural Biology and professor of biological chemistry and molecular pharmacology at HMS and a member of the PCMM at Boston Children’s, are co-senior investigators on the study.

“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 said.

Once activated, inflammasomes 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 causes pyroptosis hasn’t been known.

Lieberman, Wu and their colleagues now show that gasdermin-D-NT packs a one-two punch.

First, 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, the team found.

Second, the team discovered that gasdermin-D-NT directly kills bacteria outside of cells, including Escherichia coli, Staphylococcus aureus and Listeria. In a dish, this happened within five minutes.

Graphic representation of the cascade from inflammasome activation through pyroptosis and bacterial death. Image: Xing Liu and Youdong Pan

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.

“Because of widespread antibiotic resistance, we have to think about other strategies,” Lieberman said. “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.

The study was funded by the National Institutes of Health (grant R01AI123265).

Adapted from a Boston Children's news release.