Cadwell Lab Research
Our laboratory is interested in how host-pathogen interactions establish the course of the ensuing inflammatory response. The immune system is faced with the incredible responsibility of controlling infectious agents, but at the same time must limit the collateral damage to surrounding tissue that inevitably occurs during this process. Accumulating evidence suggests that many serious disorders are due to unresolved inflammation triggered by pathogens. Thus, it is critical that we define the factors and pathways that contribute to pathogen recognition and clearance.
One disease that exemplifies the above situation is the intestinal inflammatory disease Crohn’s disease. Crohn’s disease involves poorly defined environmental factors as well as many gene variants including a polymorphism in ATG16L1, an autophagy gene with known antimicrobial functions. We found that mice with mutations in ATG16L1 develop intestinal disease only in the presence of a norovirus infection. This virus-plus-susceptibility gene interaction depends on a combination of factors including inflammatory cytokines and commensal bacteria. Using this system, we hope to elucidate pathogenesis mechanisms at both the cellular and whole organism levels, and ultimately understand how complex inflammatory diseases are initiated and maintained.
The small intestinal crypt (yellow dashed line) contains several Paneth cells that package antimicrobial granules. Lysozyme (red) is not packaged properly into these granules in Crohn's disease patients with a polymorphism in ATG16L1 or virus-infected mice with mutations in ATG16L1. Blue = nucleus, scale bar = 10μm.