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Infection, Immunity and Inflammation Track
B.S. 2011, Rochester Institute of Technology, Rochester, NY
Thesis Advisor: Marcela Rodriguez, PhD
Public Health Research Institute
Monday, August 7, 2017
11:00 A.M., International Center for Public Health (ICPH), 1st Floor Auditorium
The capacity of M. tuberculosis (Mtb) to persist in an infected host causing a latent TB infection (LTBI) is a major obstacle to TB control. A better understanding of the mechanisms by which Mtb persist in the host, the physiology of non-replicating bacilli and the conditions that trigger non-replicative persistence is needed to identify targets for effective therapies, against LTBI.
Like most living organisms, Mtb needs iron (Fe) for growth. Fe is the preferred redox cofactor used by proteins that participate in critical functions, from respiration to DNA replication. The requirement of high affinity Fe-acquisition systems for Mtb virulence and the exacerbation of TB in Fe-supplemented hosts indicate that Fe-restriction is an effective host strategy to control Mtb proliferation. However, Fe-supplementation, to treat anemia in humans, is a well-known risk factor for reactivation of LTBI, suggesting that Fe-restriction is also a factor in the maintenance of latency. To test the hypothesis that Fe deprivation triggers non-replicative persistence, we studied Mtb under Fe-starvation in vitro. We found that although Fe-starving Mtb are able to persist for long time, refractive to antibiotics and capable of resuming normal growth when Fe becomes available. This raises the possibility that a robust nutritional immunity, that effectively restricts Mtb access to Fe, might also contribute to the onset of LTBI. Using genetic, transcriptomic and metabolomic analyses we investigated the strategies used by Mtb to persist under Fe-starvation. We showed that persistence of Mtb under iron starvation is dependent on strict control of endogenous Fe-utilization and is associated with upregulation of pathogenicity and intrinsic antibiotic resistance determinants. Mtb mutants compromised in their ability to survive Fe-starvation were identified. The findings are relevant to the design of new host and pathogen directed therapeutic strategies to eliminate persisting Mtb. In addition, the Fe-starvation conditions that we established represent a valuable model system for testing the activity of new drugs against non-replicating Mtb.