| First Author | López-Yglesias AH | Year | 2019 |
| Journal | PLoS Pathog | Volume | 15 |
| Issue | 6 | Pages | e1007872 |
| PubMed ID | 31194844 | Mgi Jnum | J:290806 |
| Mgi Id | MGI:6435505 | Doi | 10.1371/journal.ppat.1007872 |
| Citation | Lopez-Yglesias AH, et al. (2019) TLR11-independent inflammasome activation is critical for CD4+ T cell-derived IFN-gamma production and host resistance to Toxoplasma gondii. PLoS Pathog 15(6):e1007872 |
| abstractText | Innate recognition of invading intracellular pathogens is essential for regulating robust and rapid CD4+ T cell effector function, which is critical for host-mediated immunity. The intracellular apicomplexan parasite, Toxoplasma gondii, is capable of infecting almost any nucleated cell of warm-blooded animals, including humans, and establishing tissue cysts that persist throughout the lifetime of the host. Recognition of T. gondii by TLRs is essential for robust IL-12 and IFN-gamma production, two major cytokines involved in host resistance to the parasite. In the murine model of infection, robust IL-12 and IFN-gamma production have been largely attributed to T. gondii profilin recognition by the TLR11 and TLR12 heterodimer complex, resulting in Myd88-dependent IL-12 production. However, TLR11 or TLR12 deficiency failed to recapitulate the acute susceptibility to T. gondii infection seen in Myd88-/- mice. T. gondii triggers inflammasome activation in a caspase-1-dependent manner resulting in cytokine release; however, it remains undetermined if parasite-mediated inflammasome activation impacts IFN-gamma production and host resistance to the parasite. Using mice which lack different inflammasome components, we observed that the inflammasome played a limited role in host resistance when TLR11 remained functional. Strikingly, in the absence of TLR11, caspase-1 and -11 played a significant role for robust CD4+ TH1-derived IFN-gamma responses and host survival. Moreover, we demonstrated that in the absence of TLR11, production of the caspase-1-dependent cytokine IL-18 was sufficient and necessary for CD4+ T cell-derived IFN-gamma responses. Mechanistically, we established that T. gondii-mediated activation of the inflammasome and IL-18 were critical to maintain robust CD4+ TH1 IFN-gamma responses during parasite infection in the absence of TLR11. |
