Ubiquitin in host defense against pathogenic Mycobacteria
- Author(s): Collins, Cathleen Ann
- Advisor(s): Lowell, Clifford A
- Brown, Eric J
- et al.
M. tuberculosisone of the world's most prevalent pathogens, infecting one third of humans and contributing to 2 million deaths each year. M. marinum (Mm) has been increasingly studied as a model of M. tuberculosis due to its relative safety and its shared mechanisms of pathogenesis; for example, previous studies have highlighted the importance of the secretion system ESX-1 in pathogenesis of both M. tuberculosis and Mm. In this thesis we show that the host's ubiquitin system, best known for tagging host proteins for degradation, also recognizes Mm that have escaped their original phagosomes via an ESX-1-dependent mechanism and entered into the cytosol. Ubiquitinated bacteria have two distinct fates; ubiquitin tagged Mm can be sequestered into lysosome-like compartments, but they also can shed cell wall, which may allow them to evade sequestration. Lysosomal sequestration is independent of autophagy, a response to starvation or infection that leads to degradation of organelles and certain other intracytosolic pathogens. These experiments reveal ubiquitination as a mechanism of host cell recognition of Mycobacteria and the existence of a new interface between the host and invading microbe that may be amenable to therapeutic intervention.