Abstract
Mycobacterium tuberculosis (Mtb), a major global health threat, replicates in macrophages until IFN-γ activates the macrophages to traffic Mtb to the lysosome. How IFN-γ elicits this effect is unknown, but many studies suggest a role for autophagy, a process by which cytoplasmic contents are targeted for lysosomal degradation. The involvement of autophagy has been defined based on studies in cultured cells where Mtb colocalizes with autophagy (ATG) factors, stimulation of autophagy increases bacterial killing, and inhibition of autophagy allows for increased bacterial survival. Notably, these studies reveal modest (1.5- to 3-fold change) effects on Mtb replication. In contrast, mice lacking ATG5 in LysM+ cells succumb to Mtb within 30 days, an extremely severe phenotype similar to mice entirely lacking IFN-γ signaling. Importantly, ATG5 is the only ATG factor that has been studied during Mtb infection in vivo and autophagy-independent functions of ATG5 in immunity have been described. We used a genetic approach to elucidate the role for multiple ATG genes and the requirement for autophagy in resistance to Mtb infection in vivo. We discovered that, contrary to expectation, autophagic capacity does not correlate with the outcome of Mtb infection. Instead, ATG5 plays a unique role in protection against Mtb by preventing PMN-mediated immunopathology. Furthermore, while ATG5 is dispensable in alveolar MΦ during Mtb infection, loss of ATG5 in PMN can sensitize mice to Mtb. These findings shift the our understanding of the dominant role of ATG5 in the immune response to Mtb in vivo, reveal a new outcome of ATG5 activity in immunity, and shed light on early events in innate immunity that are required to regulate both tuberculosis disease pathology and Mtb replication.
Committee Chair
Christina L. Stallings
Committee Members
Brian T. Edelson, Shabaana Khader, Deborah J. Lenschow, Audrey Odom, L. David Sibley, Herbert W. Virgin, IV
Degree
Doctor of Philosophy (PhD)
Author's Department
Biology & Biomedical Sciences (Molecular Microbiology & Microbial Pathogenesis)
Document Type
Dissertation
Date of Award
Summer 8-15-2016
Language
English (en)
DOI
https://doi.org/10.7936/K7XK8CZM
Author's ORCID
https://orcid.org/0000-0003-1330-8525
Recommended Citation
Kimmey, Jacqueline M., "Characterization of autophagy-dependent and independent roles of ATG5 in controlling Mycobacterium tuberculosis infection" (2016). Arts & Sciences Theses and Dissertations. 861.
The definitive version is available at https://doi.org/10.7936/K7XK8CZM
Comments
Permanent URL: https://doi.org/doi:10.7936/K7XK8CZM