Human restricted pathogens such as Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella catarrhalis and Haemophilus influenzae, as well as bacteria that are responsible for human specific disease, such as adherent-invasive and diffusely adhering E. coli, have evolved unique mechanisms to target and exploit host cellular CEACAM receptors during the course of infection. To gain further insight into how pathogens interact with CEACAMs, my studies have focused on understanding the molecular basis of bacterial attachment to CEACAMs by M. catarrhalis and N. gonorrhoeae. It is now evident M. catarrhalis and Neisseria sp. use two structurally and phylogenetically unrelated adhesins to bind CEACAMs on host cells; UspA1 and Opa proteins, respectively.
In this thesis, I identify the sequence determinants for CEACAM binding in both Neisseria sp. Opa proteins and M. catarrhalis UspA1 proteins and show these sequences exist in distinct structural architectures within each adhesin, with the CEACAM binding regions in UspA1 existing in the context of an α-helical coiled coil structure while Opa sequences are localized to surface exposed loops that are presumably flexible in nature.
I also highlight the functional diversity that exists with respect to CEACAM binding, within both the Opa and UspA protein families, a finding important in furthering our understanding of the role of CEACAM in bacterial infections. Finally, these studies show that sequences within Opa are sufficient for adherence to CEACAM, providing important insight into the development of CEACAM-specific therapeutics that have potential applications for a variety of distinct conditions ranging from autoimmunity to cancer.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/17735 |
| Date | 23 September 2009 |
| Creators | Brooks, Michael |
| Contributors | Gray-Owen, Scott |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
Page generated in 0.0022 seconds