Research Project: Are Low Zinc Levels Fueling TB Infection?
basic biologic mechanisms
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.
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.