Molecular pathogenesis

Tuberculosis (TB) is the deadliest human pathogen, even to this day. Although antituberculars (antibiotics used to treat TB) are available, TB therapy is long and complex. The culprit is a subpopulation of Mycobacterium tuberculosis (Mtb) that resists killing by the host immune system or antibiotics. Better known as an intracellular pathogen, Mtb is also found extracellularly in necrotic lesions (granulomas). This subpopulation is notoriously difficult to eradicate during treatment and their physiology is the big unknown. We hypothesize that zinc ion (Zn2+) limitation is a “secret ingredient”- a simple environmental cue that leads to complex physiological changes in the elusive extracellular Mtb. While intracellular Mtb must cope with a Zn2+ overload, extracellular Mtb released from lysed macrophages into necrotic granulomas has a limited access to this nutrient. Zn2+ sequestration is a part of the host’s nutritional immunity, which is achieved by accumulation of neutrophil derived protein calprotectin. In contrast to many other pathogens, Mtb can overcome this severe Zn2+ depletion. In addition, Mtb can use Zn2+ depletion to signal the release into the extracellular environment and employ various protective mechanisms, including ribosome restructuring (see below). In order to understand how bacterial respond to Zn2+ limitations and their interaction with the host, Dr. Prisic’s group uses classic microbiological techniques, genetic manipulation, microscopy, in vivo and in vitro infection models, and multi-omics analysis of Mtb and other mycobacteria.

Mycobacterial alternative ribosomes

Mtb and many other bacteria, replace Zn2+-dependent ribosomal proteins with Zn2+-independent paralogs to form alternative ribosome when zinc is limited. Therefore, bacteria may use changes in zinc availability as a signal to adjust their physiology to specific environments. In particular, morphogenic programs, including cell wall remodeling triggered by zinc depletion may allow bacteria to survive stresses imposed by their host or shifting environments, as seen in pathogenic and non-pathogenic bacteria, respectively. Dr. Prisic uses a range of methods to study those regulatory mechanisms, including proteomics, microscopy, flow cytometry, and various in vitro and in vivo phenotypic assays.

Selected Publications

  1. Dow A^, Burger A, Marcantonio E^, and Prisic S* (2022) Multi-Omics Profiling Specifies Involvement of Alternative Ribosomal Proteins in Response to Zinc Limitation in Mycobacterium smegmatis Front. Microbiol., 13:811774, Feb 10, 2022

  2. Dow A^, Sule P, O'Donnell T, Burger A, Mattila JT, Antonio B^, Vergara K, Marcantonio E^, Adams LG, James N, Williams PG, Cirillo JD, Prišić S* Zinc limitation triggers anticipatory adaptations in Mycobacterium tuberculosis PLoS Pathog 17(5): e1009570, May 14, 2021

  3. Tobiasson V#, Dow A#^, Prišić S*, Amunts A* Zinc depletion does not intrinsically induce ribosome hibernation in mycobacteria Proc Natl Acad Sci USA. 116(7):2395-2397, Feb 12, 2019

  4. Dow A^ and Prišić S* Alternative ribosomal proteins are required for growth and morphogenesis of Mycobacterium smegmatis under zinc limiting conditions PLoS One.13(4):e0196300, Apr 23, 2018

  5. Prišić S*, Hwang H, Dow A^, Barnaby O, Pan TS^, Lonzanida JA^, Chazin WJ, Steen H, Husson RN Zinc Regulates a Switch between Primary and Alternative S18 Ribosomal Proteins in Mycobacterium tuberculosis Mol Microbiol 97(2):263-80 Jul 2015

*corresponding author, ^undergraduate or graduate student mentee, # equal contribution

Full list of publications and other information can be found here.