Scientists identify the mechanisms underlying the activation of inflammasomes by fungal pathogens

Scientists at St. Jude Children’s Research Hospital have identified the mechanisms behind infection-driven inflammasome activation with the fungal pathogen Aspergillus fumigatus. Fungal infection, especially with A. fumigatus, is a leading cause of infection-associated deaths in people with compromised immune systems. The work provides clues to a potential therapeutic approach for treating infectious and inflammatory disorders. The findings were published online today inNature.

Inflammasomes are important sentinels of an organism’s innate immune system. Our previous work showed that fungal pathogens activate the inflammasome, but the exact mechanism of action for inflammasome involvement was unknown. “

Thirumala-Devi Kanneganti, Ph.D., of the St. Jude Department of Immunology, corresponding author and founding member of the inflammasome field

To understand these mechanisms for A. fumigatus, Scientists looked for molecular models associated with pathogens, which can stimulate the innate immune response by activating the inflammasome. Scientists focused on NLRP3, the most studied inflammasome sensor.

The research identified galactosaminogalactan (GAG), a new molecular model associated with fungal pathogens. GAG is essential for A. fumigatus– NLRP3-induced inflammasome activation. Scientists have proved it A. fumigatus deficient in GAG fail to induce activation of the inflammasome. Conversely, the overproduction of GAG by A. fumigatus increases the activation of the inflammasome.

Furthermore, activation of the inflammasome is critical for cancellation A. fumigatus infections in animals. The A. fumigatus The fungal strain that failed to produce GAG ​​was more virulent in mice, while the strain that produced excess GAG was less virulent.

Similarly, activation of the inflammasome is protective during intestinal inflammation in a mouse model of colitis, an inflammatory disease. Treatment with purified GAG provided protection against colitis.

“We have shown that protection against this inflammatory disease depends on the ability of the GAG ​​to induce activation of the inflammasome,” said first author Benoit Briard, Ph.D., formerly of St. Jude Immunology. “These results demonstrate the mechanism for the therapeutic potential of GAG in inflammatory diseases.”