Caspase-12 in regulation of immune responses during bacterial infection

01 January 2017 → 31 December 2019
Research Foundation - Flanders (FWO)
Research disciplines
  • Natural sciences
    • Other biological sciences
    • Other natural sciences
bacterial infections
Project description

Caspase(Casp)-12 is closely related to the inflammatory Casp-1 and -11 that are involved in inflammasome signaling, and mutations in human Casp-12 are associated with increased susceptibility to infection. Current understanding of the roles of Casp-12 in host defense is based on the analysis of available Casp-12 deficient mice. These mice are resistant to infection with bacterial, viral and fungal pathogens, and Casp-12 was proposed to negatively regulate inflammasome activation. We recently reported that existing Casp-12-/- mice also lack Casp-11, and we generated novel mice that specifically lack Casp-12 to show that - in contrast to current thinking - Casp-12 is dispensable for inflammasome regulation (Vande Walle et al. Nature, in press). My research also indicates that Casp-12-/- mice are highly susceptible to LPS-induced shock (Vande Walle et al., unpublished results). Casp-12 must therefore fulfill immune-regulatory functions that are uncoupled from inflammasome signaling. To investigate this, we will study the tissue-specific expression of Casp-12 in Aim 1 by analyzing Casp-12/LacZ reporter knock-in mice in which the Casp-12 gene is replaced by a ����galactosidase (LacZ) reporter. These results will be used in Aim 2, in which we will target Casp-12 in a cell- or tissue-specific way and subject these mice to LPS-induced shock as well as to bacterial infection models. Altogether these mice will be invaluable to define the (patho) physiological role of Casp-12.