Research points to key gene responsible for innate immune activation

UMass Medical School scientists help explain yersinia pestis virulence

By Jim Fessenden

UMass Medical School Communications

July 31, 2012
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   Egil Lien, PhD
   

Scientists at UMass Medical School are studying an old-world disease to gather new insights into the human innate immune system. Using the bubonic plague as a model system, researchers have pinpointed a gene critical to detecting and responding to the bacteria. The work, described in the journal Immunity, suggests that activation of the NLRP12 gene could be a therapeutic target to stimulate the innate immune system against other pathogens.

 

Efficient evasion of the innate immune system is a key evolutionary component of the virulence of Yersinia pestis, the bacterium that causes plague. Those same factors that contribute to Y. pestis’s deadly history, though, make it a unique model for understanding how the innate immune system protects us from bacterial infection.

“The plague bacteria has developed several different ways to minimize activation of the immune system, preventing the host from mounting a robust defense to its presence,” said Egil Lien, PhD, associate professor of medicine and microbiology & physiological systems. “Because Y. pestis is so incredibly efficient at turning off the innate immune system, it provides an excellent means for evaluating the relative importance of those components and the protection they provide against bacterial infection when we turn them back on.”

In the study, Dr. Lien, Graduate School of Biomedical Sciences doctoral student Greg Vladimer and colleagues pinpointed a gene, NLRP12, responsible for detecting and responding to plague bacteria. This is the first clear role described for NLRP12 in infection resistance. The NLR family, of which NLRP12 is part, has more than 20 members that function as part of a multi-protein complex called inflammasomes that are responsible for creating some key mature inflammatory cytokines. It is these inflammatory cytokines—in the case of Y. pestis it’s interleukin-18—that the innate immune system uses to fight off bacteria. Until now, the function NLRP12 plays in this process waspoorly understood and its role in promoting resistance to infection unclear.

“We know that interleukin-18 (IL-18) is an essential part of a host’s defense against this pathogen and that its absence is correlated to mortality rates for some attenuated plague strains,” said Lien. “What was unclear was how IL-18 was being turned off.”

The Immunity study shows that NLRP12 deficient hosts had higher mortality rates and bacterial loads after being infected with Y. pestis strains. These hosts also showed lower amounts of interleukin-18, which is essential for fighting off the bacteria.

“This suggests that NLRP12 plays an important role in sensing and responding to the Y. pestis bacteria,” said Lien. “The inability of the NLRP12 to detect the pathogen appears to create a downstream cascade that results in less inflammosome complexes and fewer mature IL-18 proteins being made to fight off the bacteria, which ultimately contributes to Y. pestis’s virulence.”

Though NLRP12 plays a key role in detecting Y. pestis bacteria, its role in recognizing other bacterial pathogens is less clear. NLRP12-deficient hosts infected with the Salmonella bacteria, for instance, were still able to fight off infection, unlike their Y. pestis-infected counterparts. It’s likely that other NLRs work in collaboration to recognize and respond to pathogens.

Still, the emerging role of infammasomes as key players in host defenses during infection makes them desirable targets for therapeutic intervention and drug development, said Lien, while mutations to several NLRs genes has been linked to inflammatory diseases.

“Given the importance of NLRP12, it is possible that it also plays an important role in resisting infections caused by other human pathogens,” said Lien. “While more research needs to be done to further explore the NLR role in host defense, this study points to them as an exciting and important potential therapeutic target.”