Groundbreaking study discovers how the human body mounts a bewildering defense against invading pathogens

A radical discovery has provided new insight into the function of the immune system. Led by researchers from the Lawrence Berkeley National Laboratory and University of California, Berkeley, a team of scientists has identified a ring-shaped protein cluster utilized by the immune system. Called the “NAIP5-NLRC4 inflammasome”, this ring of proteins has been observed neutralizing pathogens and calling for support.

“This was very surprising. The immune system protein uses many protein parts, including some of previously unknown function,” said lead researcher and UC Berkeley structural biologist Eva Nogales.

For the study, the researchers utilized cryo-electron microscopy (cryo-EM) to construct a detailed, three-dimensional visualization of a NAIP5-NLRC4 inflammasome as it bound a flagellin, a hollow cylinder that forms the filament of bacterial flagellum. The primary function of this whip-like appendage is to propel bacteria forward.

According to NERSC.gov, this is how NAIP5-NLRC4 inflammasomes are formed. Specifically, an NAIP5 protein must first latch onto a flagellin molecule. Following this, copies of an NLRC4 protein coalesce to create the ring-like structure.

“Looking at our structure, we can directly visualize the molecular interface between flagellin and NAIP5, revealing how the bacterial protein is recognized. We found that flagellin is in contact with six different parts, called domains, of NAIP5, some of which had not previously been thought to be important for recognizing flagellin — and one of which had no known function at all,” remarked Nogales.

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In addition to attaching themselves to bacterial flagella, the researchers found that NAIP5 proteins inspect portions of these structures. Russell Vance, an investigator from the Howard Hughes Medical Institute has called this a “very effective immune response.”

By first analyzing potential threats, the immune system is able to determine the best course of action. In the case of the NAIP5-NLRC4 inflammasome, the NLRC4 protein signals a chemical alarm that induces pyroptosis. This process is defined as a highly dramatic type of programmed cell death that most often occurs as part of an antimicrobial response. Immune system cells swell up, burst open, and unleash cytokines that summon help from other immune system cells.

Speaking of their findings, co-lead author Nicole Haloupek remarked: “Bacteria evolve quickly, duplicating themselves orders of magnitude faster than we can reproduce them and making multitudes of new mutant strains. If just one bacterium had a mutation in flagellin that allowed it to sneak past NAIP5, it would have a massive advantage and multiply.

“We hypothesized that the fact that so many domains of NAIP5 connect to flagellin meant that major mutations would be needed for a bacterium to go unnoticed.”

To verify this, Haloupek and her colleagues created mutant strains of Legionella pneumophila, the bacteria responsible for Legionnaire’s disease. In spite of the minor changes to their flagella, the Legionella bacteria were unable to escape detection by NAIP5 proteins. Furthermore, any significant flagella mutations did indeed allow bacteria to bypass NAIP5 proteins. However, doing this impeded flagella motion and made it difficult for bacteria to move around.

“It helps us understand why the pathogen can’t escape just by mutating,” said Vance.

The researchers further noted that their findings could pave the way for more studies revolving around immune system proteins. In particular, they believe that future studies could one day help scientists figure out why certain parts of the immune system work so well, and what would happen if and when the immune response veers off course. Moreover, the researchers hope to determine if other Nod-like receptor (NLR) proteins act in an identical fashion.

“We are especially interested to know whether the multi-surface recognition of flagellin employed by NAIP5 is used by other immune sensors,” explained Vance.

See more reports on medical research breakthroughs at Research.news.

Sources include:

NERSC.gov

HMMI.org