From bad to worse: Does zinc limitation make M. tuberculosis more virulent?
1:University of Hawaii at Manoa
Mycobacterium tuberculosis (Mtb) residing within the core of necrotic granulomas are difficult to eradicate. These persisters are not well-characterized, thus hindering discovery of new TB treatments. As a part of the nutritional immunity, zinc ion (Zn²⁺) is sequestered in necrotic granulomas. We hypothesize that Zn²⁺ limitation in necrotic granulomas leads to formation of a distinct Mtb subpopulation, which alters their interaction with the host and allows survival. We previously demonstrated that Zn²⁺ limitation causes physiological changes in Mtb that go well beyond Zn²⁺ conservation, but likely prepare Mtb for impending phagocytosis. Compared to Zn²⁺-replete bacteria, Zn²⁺-limited Mtb have altered cell wall, higher tolerance to oxidative stress, different susceptibility to certain antibiotics, and increased virulence in the mouse infection model. Our current study aims to understand how this adaptation influences Mtb’s interactions with the host. Therefore, we investigated how macrophages respond to these two different Mtb subpopulations using transcriptomics, cell viability assays, reactive oxygen species (ROS) production, and bacterial uptake and survival analysis. The results of this study indicate that macrophages are able to distinguish between the two bacterial subpopulations, i.e., Zn²⁺-replete and Zn²⁺-limited Mtb, and the latter results in increased bacterial uptake, more macrophage death, decreased pro-inflammatory response, and higher ROS production. Therefore, by attempting to limit Mtb growth, the host defense creates even more adversarial enemy. Considering that most studies have been conducted with Zn²⁺-replete Mtb, the newly discovered unique characteristics of the Zn²⁺-limited Mtb and their distinct interactions with macrophages may be the key for improving TB therapy.