Research reveals how fungal infection activates inflammation

Scientists at St. Jude Children’s Research Hospital have identified the mechanisms of inflammasome activation induced by infection with the fungal pathogen Aspergillus fumigatus. Fungal infection, particularly with A. fumigatus, is one of the leading causes of infection-related death in people with weakened immune systems. The work provides clues to a potential therapeutic approach to treat infectious and inflammatory disorders. The results were published online today in Nature.

“Inflammasomes are important sentinels of an organism’s innate immune defense system,” said corresponding author and founding member of the inflammasome field Thirumala-Devi Kanneganti, Ph.D., of the Department of Immunology at St. Jude. “Our previous work showed that fungal pathogens activate the inflammasome, but the exact mechanism of action of inflammasome engagement was unknown.”

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.

Research has identified galactosaminogalactan (GAG), a new molecular model associated with fungal pathogens. GAG is essential for the activation of the NLRP3 inflammasome induced by A. fumigatus. Scientists have shown that A. fumigatus deficient in GAG fails to induce activation of the inflammasome. Conversely, the overproduction of GAG by A. fumigatus increases the activation of the inflammasome.

In addition, activation of the inflammasome is essential for eliminating A. fumigatus infections in animals. The fungal strain A. fumigatus which failed to produce GAG ​​was more virulent in mice, while the strain which overproduced GAG was less virulent.

Likewise, 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 GAG to induce activation of the inflammasome,” said lead author Benoit Briard, Ph.D., formerly of St. Jude Immunology. “These findings demonstrate the mechanism for the therapeutic potential of GAG in inflammatory diseases.”