Caspase-11 Modulates Inflammation and AttenuatesToxoplasma gondiiPathogenesis

Abstract

Toxoplasma gondii is an obligate intracellular parasite that is the etiologic agent responsible for toxoplasmosis. Infection with T. gondii results in activation of nucleotide binding domain and leucine rich repeat containing receptors (NLRs). NLR activation leads to inflammasome formation, the activation of caspase-1, and the subsequent cleavage of IL-1β and IL-18. Recently, a noncanonical inflammasome has been characterized which functions through caspase-11 and appears to augment many biological functions previously considered to be dependent upon the canonical inflammasome. To better elucidate the function of this noncanonical inflammasome in toxoplasmosis, we utilized Asc −/− and Casp11 −/− mice and infected these animals with T. gondii. Our data indicates that caspase-11 modulates the innate immune response to T. gondii through a mechanism which is distinct from that currently described for the canonical inflammasome. Asc −/− mice demonstrated increased disease pathogenesis during the acute phase of T. gondii infection, whereas Casp11 −/− mice demonstrated significantly attenuated disease pathogenesis and reduced inflammation. This attenuated host response was associated with reduced local and systemic cytokine production, including diminished IL-1β. During the chronic phase of infection, caspase-11 deficiency resulted in increased neuroinflammation and tissue cyst burden in the brain. Together, our data suggest that caspase-11 functions to protect the host by enhancing inflammation during the early phase of infection in an effort to minimize disease pathogenesis during later stages of toxoplasmosis.

Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases

“…Casp1 −/− Casp11 −/− mice are also susceptible to infection by the protozoa Toxoplasma gondii and Trypanosoma cruzi, a phenotype associated with reduced IL-1β or IL-18 production [161][162][163]. A further study demonstrates that in response to infection with T. gondii, mice lacking caspase-11 alone have reduced levels of local and systemic cytokines during the acute phase, whereas inflammation is elevated in the brain during the chronic phase of infection 164. Further investigations are required to unveil individual functions of inflammatory caspases in protozoan infections.MouseProtozoan Phenotype compared to wildtype mice Casp1 −/− Casp11 −/− Leishmania amazonensis…”

“…A further study demonstrates that in response to infection with T. gondii , mice lacking caspase-11 alone have reduced levels of local and systemic cytokines during the acute phase, whereas inflammation is elevated in the brain during the chronic phase of infection (164). Further investigations are required to unveil individual functions of inflammatory caspases in protozoan infections.…”

The Goldilocks Conundrum: NLR Inflammasome Modulation of Gastrointestinal Inflammation during Inflammatory Bowel Disease

“…Specifically, our research has recently revealed that caspase-11 modulates Inflammation during Toxoplasma gondii infection. 78 Using Casp11 -/- mice, our results revealed that noncanonical Inflammasome signaling significantly impacts neuro-Inflammation and cyst burden during the chronic phases of disease. 78 While the mechanism underlying these findings remains unclear, these data suggest a role of caspase-11 in the sensing and response to a currently unidentified molecular pattern associated with this eukaryotic parasite or imply that noncanonical Inflammasome signaling is functioning in response to intracellular changes driven by the parasite.…”

“…78 While the mechanism underlying these findings remains unclear, these data suggest a role of caspase-11 in the sensing and response to a currently unidentified molecular pattern associated with this eukaryotic parasite or imply that noncanonical Inflammasome signaling is functioning in response to intracellular changes driven by the parasite. 78 Thus, it is highly likely that future studies will continue to expand the role of noncanonical Inflammasome function and signaling.…”

Gasdermin-D-dependent IL-1αrelease from microglia promotes protective immunity during chronicToxoplasma gondiiinfection

“…In sum, these studies suggest roles for IL-1 β , IL18, IL-1R, NLRP1 and/or NLPR3 inflammasome sensors, the inflammasome adaptor protein ASC, and inflammatory caspases-1 and −11. 25–28 However, the role of IL-1 signaling in the brain during chronic infection has not been addressed.…”