Sladjana Prisic, PhD

Tuberculosis (TB) claims over 1 million lives every year. TB was the deadliest infectious disease until 2020, when it was dethroned by COVID-19. The ongoing pandemic has a detrimental effect on global efforts to control TB. Alternative approaches are needed for treating TB, as the current treatment regimens are long and complex, and will not be sufficient to eradicate TB. In addition, the increase in drug resistance is making the discovery of new TB treatments even more pressing. We will study whether the low zinc environment found in infected tissues triggers adaptive changes in the bacterium that causes TB. These changes allow bacteria to be more efficiently engulfed by immune cells called macrophages and to interfere with the immune response to the infection. Identification of the responses triggered by the bacteria found in the low-zinc environment will allow for discovery of new drug targets to improve TB therapy.

Update:
Macrophages are host cell that Mycobacterium tuberculosis bacteria (Mtb) take over and use to replicate. We identified a large number of genes that are expressed at different levels in macrophages infected with low-zinc vs. standard-zinc Mtb. We used this information to focus on a protein called Lipocalin-2 and its role in macrophage response to Mtb infection. By deciphering if/how the host uses Lipocalin-2 and how macrophages respond to the infection with zinc limited Mtb, we will be able to identify new targets of host-directed therapy against TB. This approach targets proteins Mtb need to live and multiply, rather than fighting the bacteria themselves.

Final Project Update: 
Despite the availability of antibiotics, tuberculosis (TB) causes over a million deaths each year. Current treatment is lengthy and complex, and drug resistance is making it urgent to find new therapies. This study suggests that the low zinc levels in dead lung tissues may trigger changes in Mycobacterium tuberculosis (Mtb), the bacteria responsible for TB. These zinc-deficient areas can harbor persistent Mtb that are hard for the immune system and antibiotics to clear, contributing to the need for complicated treatment regimens. 

We found that zinc-limited Mtb are more effectively engulfed by macrophages, the immune cells that kill bacteria. However, instead of being eliminated, these bacteria lead to the death of the macrophages they infect and stimulate them to produce harmful reactive oxygen species. The genes expressed by macrophages infected with zinc-limited Mtb indicate that this strain may disrupt the immune response, affecting the overall disease outcome. 

This study suggests that zinc plays a crucial role in the interactions between host and pathogen in TB. Most previous experiments have used Mtb grown in zinc-rich media, so future research should focus on zinc-limited Mtb to discover new drug targets that could shorten TB treatment. Additionally, live vaccines like BCG should also be tested with zinc-limited Mtb to see if they provide better protection. By considering zinc-deficient Mtb, the field of TB research may move closer to developing more effective prevention and treatment strategies for this serious disease.