Date of Degree
PhD (Doctor of Philosophy)
Molecular and Cell Biology
Fayyaz S. Sutterwala
The innate immune response to pathogens by the host is dependent upon the interplay of both pathogen and host intrinsic factors. Nucleotide-binding domain leucine-rich repeat containing (NLR) and pyrin and HIN200 domain containing (PYHIN) proteins are intracellular sensors of damage-associated and pathogen-associated molecular patterns. The studies presented here focus on the PYHIN molecule, AIM2, and the NLR, NLRP12, and the importance of bacteria- and host-associated proteins in the coordination of the innate immune response to the Gram-negative pathogen Fracisella tularensis. We have found that several genes expressed by F. tularensis encode for proteins that, when disrupted, cause the bacteria to trigger hyper- or hypoactivation of the AIM2 inflammasome. Bacteria with a mutation in FTL_0724, which hyperactivates the AIM2 inflammasome, are highly attenuated in a mouse model of infection, and induce robust caspase-1 processing and secretion of IL-1β by bone marrow derived macrophages (BMDMs). In contrast the hypoactivating mutant of F. tularensis, FTL0699, reduces IL-1β secretion by BMDMs and remains virulent in in vivo models of infection.
We have also investigated the role of host-expressed NLRs in F. tularensis infection models. We have found that NLRP12 is important in the coordination of the innate immune response to F. tularensis through the modulation of CXCL1 production. We hypothesized that decreased CXCL1 production by Nlrp12-deficient mice was in turn responsible for the diminished recruitment of neutrophils in to the lungs of Nlrp12-deficient mice following intranasal challenge with F. tularensis. Nlrp12-deficient mice were found to be highly susceptible to infection with F. tularensis, and succumbed to infection at a much higher rate than wild-type mice. Taken together these data demonstrate that a number of pathogen and host factors can play critical roles in the outcome F. tularensis infections.
AIM2, Francisella tularensis, NLRP12
xii, 112 pages
Includes bibliographical references (pages 104-112).
Copyright © 2014 Tyler Kent Ulland