Researchers at Boston Children’s Hospital discuss new potential avenues for controlling sepsis and the runaway bacterial infections that provoke it in an article for Nature. Scientists in Boston Children’s Program in Cellular and Molecular Medicine (PCMM) reveal the final cellular events necessary for both sepsis and stemming the bacterial attack in a series of experiments. Research has shown that at any sign of bacterial invasion, protein complexes called inflammasomes are activated, reports Science Daily. The activation triggers a process called pyroptosis in which infected cells explode open and release bacteria and chemical signals that sound an “immune alarm.”
The Science Daily news report notes that too strong an alarm can trigger sepsis and cause deadly 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,” explains Judy 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.”
Once activated, inflammasomes activate enzymes called caspases that cut a molecule called gasdermin D in two, and this cleave unleashes gasdermin D’s active fragment, known as gasdermin-D-NT, as indicated on the Science Daily news report. However, how this causes pyroptosis has not been known. The researchers showed that gasdermin-D-NT both perforates the membranes of the bacteria that are infecting cells and kills them and also punches holes in the membrane of the host cell, which causes pyroptosis. The research team found that nearby infected cells are left unscathed.
In addition, the researchers discovered that gasdermin-D-NT directly kills bacteria outside of cells, including Listeria, S. aureus, and E. coli.
According to Science Daily, the results need to be replicated in animal models of infection and sepsis; however, Lieberman believes that understanding how gasdermin-D-NT works could be harnessed to help treat dangerous bacterial infections. For sepsis, Lieberman wonders about ways of inhibiting or blocking gasdermin-D-NT, such as with strategies targeting caspase enzymes or antibodies.
Lieberman says, “Because of widespread antibiotic resistance, we have to think about other strategies. 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.”
Photo Credit:Xing Liu, PhD, Boston Children’s Hospital and Youdong Pan, PhD, Brigham & Women’s Hospital
Source: Science Daily