In the classic children’s story Through the Looking-Glass, Alice is informed by Wonderland’s ruler, the Red Queen, that in her land “it takes all the running you can do to keep in the same place”.
This concept has been adopted by evolutionary biologists to illustrate how species pitted against each other both need to keep evolving in order to survive. Humans and Mycobacterium tuberculosis (Mtb), the infectious bacterium that causes tuberculosis, have been fighting it out for over 70,000 years, and Mtb has developed many strategies to avoid being killed off. When immune cells detect the presence of Mtb, they produce a molecule called interferon-gamma (IFN-g), which activates specialist cells called macrophages, allowing them to kill off any bacteria they encounter.
Thinking about the Red Queen, Dr Mohamed Ahmed, a recent SANTHE and Africa Health Research Institute PhD graduate based in the Leslie group, wondered if Mtb had evolved a way of sensing this crucial molecule. If so, it might help Mtb survive when the immune system became altered to its presence. Sure enough, working with other scientists at AHRI and collaborators from the University of Southampton, Mohamed showed, for the first time, that Mtb has developed a way of sensing IFN-g, through a protein embedded in its cell surface called MmpL10. Sensing IFN-g through MmpL10 causes Mtb to become more metabolically active and, if you like, ready to “run” in response to this new threat.
“I must admit my supervisor wasn’t convinced when I first put forward my idea,” said Mohamed. “But that is the beauty of science, you don’t have to stop at wondering, you actually get to test out your ideas in the lab and see if they are true or not.”
Work is currently on-going to try and understand how this mechanism helps Mtb and whether it can be used to help develop novel treatments. “We still need to unpick the details, but maybe it can give us a slight head-start in our ongoing race against this persistent and deadly disease,” said Dr Al Leslie, a faculty member at AHRI.
The findings are published as a paper ‘Mycobacterium tuberculosis senses host Interferon-γ via the membrane protein MmpL10’ in the journal Communications Biology, and can be accessed here.
Mohamed will soon be joining Prof Maziar Divangahi’s lab at McGill University in Montreal, Canada, for a postdoctoral fellowship where he will continue working on TB. His research will focus on BCG vaccination during the neonatal phase of life and how the resulting immune architecture in the lung and gut produces protection against TB.
Top image: Flow cytometry shows that recombinant human IFN-γ (a) but not recombinant human TNF-α (b) binds to Mtb in a dose-dependent manner at the indicated concentrations (ng/mL). Confocal microscopy confirmed binding of recombinant human IFN-γ to individual Mtb-GFP (c). Top panel shows control sample; bottom panel shows fully stained sample. In contrast to Mtb, BCG does not bind IFN-γ (d) nor increase respiration in response to IFN-γ at the indicated concentrations (ng/mL) (e). Data are shown as mean ± SEM of n = 3–5 technical replicates and represent at a minimum two independent experiments. Tukey’s correction multiple-comparison test was used for the statistical analysis.