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- W4313404557 abstract "Abstract Cutaneous leishmaniasis is a neglected tropical disease that results in severe, chronic lesions that are frequently resistant to parasite-directed therapy. Studies in patients and murine models indicate that NLRP-3 dependent IL-1β release is associated with more severe disease and treatment failure. One mechanism leading to IL-1β release as well as pyroptosis is the formation of pores by gasdermin D (GSDMD). To determine if GSDMD might contribute to IL-1β release and subsequent increased disease, we infected GSDMD knockout mice and wild-type C57BL/6 (WT) mice with Leishmania major and followed the course of infection. Contrary to our expectations, GSDMD KO mice infected mice developed more severe lesions compared with WT mice, but without a change in parasite burden. Because inflammasome activation without pyroptosis has been reported to lead to prolonged IL-1β release from hyperactivated dendritic cells, we tested whether blocking IL-1β signaling would prevent severe pathology in GSDMD KO mice. However, GSDMD KO mice treated with anti-IL-1β developed pathology similar to the untreated GSDMD KO mice, indicating that IL-1β was not mediating the increased pathology. Therefore, we next compared the immune responses in WT and GSDMD KO mice. The only significant difference found was an increase in the production of IFN-g, and our working hypothesis is that excess IFN-g may contribute to the disease severity. Why the absence of GSDMD leads to increased disease remains unclear, but previously it was found that the loss of GSDMD can have consequences beyond IL-1β release and pyroptosis. Current studies are focused on defining the mechanism(s) leading to increased disease in GSDMD KO mice. Supported by grants from NIH (5R01AI125265-05, 1R01AI150606-01, T32AR7465)." @default.
- W4313404557 created "2023-01-06" @default.
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- W4313404557 date "2022-05-01" @default.
- W4313404557 modified "2023-09-25" @default.
- W4313404557 title "GSDMD deficiency drives immunopathology in cutaneous leishmaniasis" @default.
- W4313404557 doi "https://doi.org/10.4049/jimmunol.208.supp.50.33" @default.
- W4313404557 hasPublicationYear "2022" @default.
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