Title: Pigments of after-life: a novel innate adaptation and persistence system in Mycobacterium tuberculosis
Funder: The Academy of Medical Sciences

Abstract: Mycobacterium tuberculosis (Mtb) is an intracellular pathogen that causes tuberculosis (TB). To multiply and establish infection, Mtb needs to acquire iron. Additionally, Mtb also needs to defend itself from toxic reactive oxygen and nitrogen species produced by immune cells. However, how Mtb evades our immune system and establishes infection is poorly understood. Recent studies have found that Mtb possesses a non-canonical haem oxygenase MhuD that catalyses haem degradation to acquire iron while producing an unusual purple pigment, mycobilin, as a by-product. This is different from the classical haem oxygenases in other bacteria that generate three products (iron, biliverdin, and carbon monoxide). Therefore, in addition to Mtb using siderophores to acquire iron, Mtb can access the largest iron pool in the human body by degrading haem. Why Mtb possesses the unique haem degradation system is not known. I hypothesise that the Mtb MhuD haem degradation plays a vital role in pathogenesis, enabling Mtb to adapt, persist, and thrive within the intracellular compartment of macrophages. In proof-of-concept studies to support my hypothesis, I discovered that MhuD is part of an uncharacterised Mtb mycobilin degradation pathway. Furthermore, Mhud mutation is associated with diminished haem storage capacity and increased hydrogen peroxide sensitivity, indicating a role in the defence against host immune response. This project will address how Mtb uses haem degradation to impact pathogenesis and, more specifically, long term persistence within the host. Such knowledge offers opportunities to develop new drug targets and use the pigment catabolites to offer new biomarkers for diagnosis.

Lay abstract: Tuberculosis (TB) is caused by the bacterium Mycobacterium tuberculosis (Mtb), which spreads through the air from person to person. In 2019, ~10 million fell ill from TB, causing over 1.4 million deaths. For Mtb to grow and successfully establish infection within a human host, it needs iron. However, the human body hides the majority of iron in the form of haem, the iron-caged molecule that makes our blood red. Recent studies have found that Mtb can break down haem to get to the iron while producing an unusual purple pigment as a by-product. This research aims to understand how and when Mtb uses its unique haem degrading enzyme to generate iron and the purple pigment. I postulate that Mtb uses its haem degrading enzyme to get the iron from the host to grow, and the purple pigment produced has a role in defending the bacteria against our immune system. To investigate the role of this enzyme, I will isolate the different components of the Mtb haem degradation system and work out how they are involved in Mtb iron utilisation for growth and defence against our immune system. The study will provide a clearer understanding of how Mtb uses haem, which will help us develop new anti-TB drugs in the longer term. Moreover, because almost all disease-causing bacteria need iron and can access this by degrading haem, I anticipate the study will provide a better understanding of the role of bacterial haem utilisation in other bacterial diseases.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;5.1 PHARMACEUTICALS
Health categories: INFECTION