Studying human inflammasome signaling in an in vivo context using humanized mice

Inflammasomes are protein complexes that mount potent pro-inflammatory responses upon sensing microbial or host-derived stress signals. Patient and in vitro human cell line observations as well as mouse model experiments have implicated inflammasome signaling in numerous diseases including sepsis and human immunodeficiency virus (HIV) infection. This raised a considerable interest in exploring the possibilities for therapeutic targeting of individual inflammasome activation mechanisms in these diseases. However, the lipopolysaccharide (LPS)-induced inflammasome activation pathway that is thought to contribute to bacterial sepsis acts differently in humans when compared to mice, and modelling HIV infection in mice is not possible due to the restricted species tropism of HIV. Therefore, in this project I will investigate the role of inflammasome signaling in LPS-induced toxicity as well as in HIV infection by using immune deficient mice that were humanized by reconstitution with human stem cells from umbilical cord blood. This way, by prior genome-editing of the human stem cells using Crispr/Cas9 technology, I will create humanized mice carrying either wild-type or inflammasome-deficient human immune systems. By challenging these humanized mice with LPS or an HIV infection I will experimentally address how inflammasome signaling impacts on these responses in the context of an in vivo human immune system, which will improve predictions for future translational success.