Dr. Prišić received her B.Sc. degree and then Ph.D. in Biochemistry from the University of Belgrade and Iowa State University, respectively. As a graduate student, she studied plant terpene cyclases, including structure-function relationship and enzymatic mechanisms of these enzymes under guidance of Dr. Reuben Peters. Toward the end of her Ph.D. study, she came across a terpene cyclase from Mycobacterium tuberculosis (Mtb) and started learning more about this pathogen. Stunned, but inspired by the fact that this causative agent of tuberculosis still represents a major threat to human health, Dr. Prišić joined Dr. Robert Husson’s laboratory at Boston Children’s Hospital/Harvard Medical School to gain experience in microbiology and specifically to work on Mtb. For her postdoctoral training (2007-2012), she worked on Mtb Ser/Thr protein kinases and their selected targets. As a Research Associate (2012-2014) at Boston Children’s Hospital, Dr. Prišić worked on ribosome regulation in Mtb. Although mostly focused on Mtb, her research findings and interests might be applicable to other bacteria and therefore be relevant for other infectious diseases (e.g. diseases caused by Clostridium difficile, Streptococcus pneumoniae, Pseudomonas aeruginosa, or Staphylococcus aureus). In addition to being a devoted scientist, Dr. Prišić is passionate about teaching and mentoring, with special emphasis on supporting underserved and underrepresented students. Dr. Prisic joined Microbiology Department of University of Hawaiʻi at Mānoa in August 2014.
Hypothesis: Regulation of Mycobacterium tuberculosis (Mtb) translation via ribosomal protein modification (phosphorylation, acetylation), expression of alternative ribosomal proteins, and binding of metal ions has an important role in the transition of Mtb between active growth and a non-growing persistent state, in phenotypic drug tolerance, and transmission.
Following infection of the human host, Mtb encounters diverse environments and goes through remarkable adaptations in order to evade elimination by the immune system. Depending on the host-pathogen interactions, TB can present as latent or active disease, with the potential to switch between these two forms. Although these transitions are essential for the success of Mtb as a pathogen and make TB treatment complex, the bacterial mechanisms that lead to a formation of different Mtb populations in vivo are poorly understood. It is assumed, however, that change from active growth to non-growing persistence would require a significant decrease in metabolic activity, including essential processes such as translation.
Transcriptional control is a common way of adjusting to decreased demand for ribosomal proteins in bacteria that are less metabolically active, but bacteria cannot afford to waste already synthesized ribosomes. For example, E. coli has several strategies to decrease translation in stationary phase or starvation while preserving ribosomes: ribosome dimerization, ribosomal protein L12 acetylation, and translation elongation factor EF-Tu phosphorylation. In addition to regulation of global ribosomal activity, other mechanisms may alter ribosome specificity, such as translation of leaderless mRNAs in response to certain stresses.
Although poorly understood in prokaryotes in general, mechanisms of ribosome regulation are particularly intriguing and obscure in mycobacteria. For example, in addition to a full set of conserved ribosomal proteins, Mtb has five alternative ribosomal proteins (AltRPs), whose expression is repressed by zinc. In addition to alternative ribosomal proteins, Mtb appears to use post-translational modification of ribosomal proteins for translation regulation. In our previous study, we identified several ribosomal proteins that are phosphorylated under various in vivo-relevant stress conditions (Prišić et al, PNAS 2010). Mtb also has at least two putative ribosomal protein acetyl-transferases. Even if the extensive modifications of rRNAs and regulation of ribosome biogenesis is not taken in account, a combination of the abovementioned layers of ribosome regulation may give a numerous possibilities for stress response and fine tuning of protein synthesis. Dr. Prišić uses a range of methods to study those regulatory mechanisms, including genetic manipulation of Mtb, in vitro and in vivo phenotypic analysis, proteomics, protein-ligand interactions, and ribosome activity/specificity assays.
While the goal of Dr. Prišić’s study is to understand translation regulation by Mtb, her research may also have implications for new approaches to treatment. Translation has been a target of numerous successful antibiotics such as aminoglycosides and tetracyclines, but targeting the regulation of this essential process may provide additional benefits. Such drugs would also be active against drug-resistant strains of Mtb and might also enhance the efficacy of existing antibiotics against phenotypically tolerant bacteria. Further, considering the conserved nature of protein translation, this study may have a broad impact on our understanding of similar mechanisms in other bacteria and could eventually lead to treatment improvements against a wide range of bacterial infections.