Researchers figure out how the immune system sparks cell death

By Samantha Black, PhD, The Science Advisory Board editor in chief

September 2, 2021 -- Immunologists have discovered how the innate immune system launches a multifaceted attack against invaders through the use of multiple immune sensors. The work was published in Nature on September 1.

Inflammasomes are protein complexes that form in infected cells or cells that sense damage. The complexes include sensors that recognize different viruses, bacteria, and other pathogens or danger signals.

Inflammasomes drive inflammatory signaling, which activate inflammatory cell death pathways and eliminate the infection, but they can also contribute to pathological inflammation.

Thirumala-Devi Kanneganti, PhD, of the St. Jude department of immunology is a pioneer in the field of inflammasomes and was one of the first to identify inflammasome sensors.

In the past, research focused on how individual inflammasome sensors detect pathogens. It was believed that inflammasomes respond to pathogens by activating a single inflammatory cell death pathway. However, there is a growing body of evidence which suggests that multiple inflammasome sensors can be activated in response to an infection.

Kanneganti and her team were interested in understanding the regulation of inflammasomes and redundancies in cell death pathways. In 2016, the team reported that influenza infections activate molecules in multiple cell death pathways, a phenomenon they termed PANoptosis.

PANoptosis includes three types of programmed cell death: pyroptosis (lytic and rapid clearance), apoptosis (highly regulated and controlled), and necroptosis (associated with cell damage or pathogen infiltration), which is regulated by PANoptosomes.

In the current work, the St. Jude team infected wild-type bone marrow-derived macrophages (BMDMs) and BMDMs deficient in several major inflammasome sensors with herpes simplex virus 1 (HSV1) and Francisella novicida to determine if infection was AIM2 dependent.

They identified regulatory and molecular interactions among three inflammasome sensors that along with cell death proteins, drove formation of a PANoptosome (mega cell death complex).

"This new work builds on our quest to identify inflammasome regulation," Kanneganti said, in a statement. "Our study highlights how inflammasomes and multiple cell death components can and do work together in a mega protein complex called the PANoptosome to activate the innate immune response and unleash PANoptosis."

The researchers also identified the AIM2 inflammasome sensor as a "master regulator" of PANoptosome assembly in response to the experimental infections of herpes simplex virus 1 and the F. novicida bacterium. The AIM2 inflammasome can sense double-stranded DNA, and that sensing ability leads to pyroptosis. However, the full interactions of the inflammasome have been underappreciated to date.

Using immunoprecipitation, microscopy, and other techniques, researchers demonstrated that AIM2, other inflammasome sensors (Pyrin and Z-DNA binding protein 1), and cell death molecules were all part of this AIM2-PANoptosome. The PANoptosome drove inflammatory cell death, and the results were confirmed with in vivo models of HSV1 and F. novicida infection.

"This was critical evidence that the inflammasome sensors and molecules from multiple cell death pathways are in the same complex and highlighted the PANoptosome's role in protecting the host during live pathogenic infections," said SangJoon Lee, PhD, a postdoctoral fellow in the Kanneganti laboratory at St. Jude.

Pathogens broadcast their presence more widely to the immune system, which helps explain why the infections trigger PANoptosome assembly and a more robust immune response, according to the authors. They can also carry proteins that prevent the activation of specific cell death pathways. PANoptosis provides an immune system workaround to protect the host.

"The findings address a central question in the fields of innate immunity, cell death, and inflammasome biology," Kanneganti explained. "Our working hypothesis is that while the sensors involved may vary, most infections will induce formation of these unique innate immune complexes called PANoptosomes to unleash inflammatory cell death, PANoptosis."

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