Human Innate Immunity to Toxoplasma gondii Is Mediated by Host Caspase-1 and ASC and Parasite GRA15

Interleukin-1 beta (IL-1 beta) functions as a key regulator of inflammation and innate immunity. The protozoan parasite Toxoplasma gondii actively infects human blood monocytes and induces the production of IL-1 beta; however, the host and parasite factors that mediate IL-1 beta production during T. gondii infection are poorly understood. We report that T. gondii induces IL-1 beta transcript, processing/cleavage, and release from infected primary human monocytes and THP-1 cells. Treating monocytes with the caspase-1 inhibitor Ac-YVAD-CMK reduced IL-1 beta release, suggesting a role for the inflammasome in T. gondii-induced IL-1 beta production. This was confirmed by performing short hairpin RNA (shRNA) knockdown of caspase-1 and of the inflammasome adaptor protein ASC. IL-1 beta induction required active parasite invasion of monocytes, since heat-killed or mycalolide B-treated parasites did not induce IL-1 beta. Among the type I, II, and III strains of T. gondii, the type II strain induced substantially more IL-1 beta mRNA and protein release than did the type I and III strains. Since IL-1 beta transcript is known to be induced downstream of NF-kappa B signaling, we investigated a role for the GRA15 protein, which induces sustained NF-kappa B signaling in a parasite strain-specific manner. By infecting human monocytes with a GRA15-knockout type II strain and a type I strain stably expressing type II GRA15, we determined that GRA15 is responsible for IL-1 beta induction during T. gondii infection of human monocytes. This research defines a pathway driving human innate immunity by describing a role for the classical inflammasome components caspase-1 and ASC and the parasite GRA15 protein in T. gondii-induced IL-1 beta production. IMPORTANCE Monocytes are immune cells that protect against infection by increasing inflammation and antimicrobial activities in the body. Upon infection with the parasitic pathogen Toxoplasma gondii, human monocytes release interleukin-1 beta (IL-1 beta), a "master regulator" of inflammation, which amplifies immune responses. Although inflammatory responses are critical for host defense against infection, excessive inflammation can result in tissue damage and pathology. This delicate balance underscores the importance of understanding the mechanisms that regulate IL-1 beta during infection. We have investigated the molecular pathway by which T. gondii induces the synthesis and release of IL-1 beta in human monocytes. We found that specific proteins in the parasite and the host cell coordinate to induce IL-1 beta production. This research is significant because it contributes to a greater understanding of human innate immunity to infection and IL-1 beta regulation, thereby enhancing our potential to modulate inflammation in the body.