Increased stability of class II MHC-peptide complexes in macrophages infected with mycobacterium avium and the examination of a novel role for cathepsin L in the innate immune response to Francisella Novicida infection

by 1977- Florence, William Clinton

Macrophages serve as a critical link between the innate and adaptive immune response to intracellular pathogens. The two primary goals of this thesis were to evaluate the stability of class II MHC-peptide complexes in macrophages infected with Mycobacterium avium and to examine the roles thatendocytic proteases may play in infection with Francisella novicida. We showed when class MHC class II peptides complexes are formed in the presence of Mycobacterium avium, they exhibit increased stability that is not a result of increased biosynthesis and is an endocytic event which is mediated by the ligation of innate immune receptors. The increase in stability of class II MHC-peptide complexes can be recapitulated using protease inhibitors, suggesting innate immune receptor ligation rescues class II complexes from premature degradation. Secondly, we uncovered a critical role for Cathepsin L in the innate immune response to the intracellular pathogen Francisella novicida. Mice lacking Cathepsin L are susceptible to sub-lethal infection with F. novicida, harbor increased bacterial numbers and produce increased amounts of IFN?. To date, this is first known role for Cathepsin L in the innate immune response to any pathogen. ii