PhoP-regulated genes contribute to Mycobacteria tuberculosis-induced burst size necrosis in macrophages
Authors
Kativhu, Chido L.Faculty Advisor
Hardy KornfeldAcademic Program
Interdisciplinary Graduate ProgramUMass Chan Affiliations
MedicineDocument Type
Master's ThesisPublication Date
2021-02-01Keywords
tuberculosisTB
Mycobacterium tuberculosis
Mtb
PhoPR
necrosis
Bacterial Infections and Mycoses
Immunology of Infectious Disease
Pulmonology
Metadata
Show full item recordAbstract
Tuberculosis (TB) is primarily a pulmonary disease caused by Mycobacterium tuberculosis (Mtb). Mtb is highly infectious, but studies have shown that only 5–15% of Mtb-infected individuals develop TB disease. The Bacille Calmette-Gu.rin (BCG) vaccine is the only commercially available Mtb vaccine, but its efficacy varies based on the strain used. The Mtb PhoPR-mutant variant, MTBVAC, has been tested as a possible attenuated live vaccine against Mtb. Although it has successfully conferred durable CD4+ T-cell responses in infants, it has also resulted in adverse effects. Our goal is to identify PhoPR-regulated gene(s) that mediate Mtb-induced burst size necrosis in infected cells. PhoPR is a two-component system in mycobacteria. PhoR responds to environmental cues, such as changes in pH, and phosphorylates the PhoP transcription factor, which then activates or suppresses the expression of approximately 40 Mtb genes. The Mtb PhoPR-mutant strain is able to replicate in infected macrophages, but it does not induce the horizontal spread of Mtb to other immune cells. Our lab has previously shown that virulent, cytopathic strains of Mtb, such as H37Rv, suppress early apoptosis, have faster replication rates in macrophages, and trigger cell death at a lethal load threshold of approximately 25 bacteria. Cell death of infected macrophages primarily occurs via necrosis, which involves nuclear pyknosis without DNA fragmentation and general disruption of lipid bilayer membranes. Viable bacilli are released to infect other macrophages and neutrophils recruited to the developing TB lesion. Here, we show that PhoP contributes to burst size necrosis in macrophages and that the PhoP-regulated genes, fadD21 and pks3, are potential drivers of this necrosis. FadD21 and pks3 are involved in the generation of diacyl trehalose/penta-acyl trehalose (DAT/PAT) for cell wall synthesis, suggesting that Mtb cell wall composition may determine virulence. Therefore, we have uncovered potential targets for early intervention or vaccinations to avoid granuloma formation or tissue damage in response to Mtb-induced macrophage necrosis.DOI
10.13028/zbrv-4310Permanent Link to this Item
http://hdl.handle.net/20.500.14038/31349Notes
Committee members
- Chair: Stuart Levitz
- Member: Christopher Sassetti
- Member: Jennifer Wang
- Member: Kate Fitzgerald
Rights
Licensed under a Creative Commons licenseDistribution License
http://creativecommons.org/licenses/by/4.0/ae974a485f413a2113503eed53cd6c53
10.13028/zbrv-4310
Scopus Count
Collections
Except where otherwise noted, this item's license is described as Licensed under a Creative Commons license