The impact of macrophage iron export during mycobacterium tuberculosis infection
Abreu, Rodrigo Bessa
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Mycobacterium tuberculosis (Mtb) is still one of the major infectious diseases in the world with over 9 million cases and 1.5 million deaths in 2014. Iron is a crucial micronutrient for both mammals and bacteria, and upon infection, Mtb must fight the host for the same iron pool. Iron dysregulation in the host strongly associates with poor outcomes with several infectious diseases, including tuberculosis, AIDS and malaria, while inefficient iron scavenging by pathogens severely affects their virulence. Hepcidin is the major regulator of iron serum levels in mammals, and promotes intracellular iron sequestration in hepatocytes and macrophages. In this dissertation, we first assessed the impact of Tool-Like Receptor (TLR) activation in iron homeostasis of human macrophages and elucidated the mechanisms of iron dysregulation in macrophages during infection. Here we show that TLR signaling induces hepcidin and downregulates ferroportin, promoting intracellular iron sequestration in human macrophages. Furthermore, here we reported that Hepc is highly expressed in human macrophages after TLR activation. This dissertation hypothesizes a novel mechanism by which Mtb circumvents the innate immune system, increasing intracellular iron bioavailability through induction of Hepc and downregulation of ferroportin expression in macrophages. TB incidence has been declining worldwide, but is still a major public health concern in African and Asian countries. Furthermore, the increase in drug resistance cases calls for new therapeutic strategies to replace or complement currently available therapies. Recently, host-directed therapies showed promising results against Mtb, enhancing the effect of currently available anti-mycobacterial drugs, or directly decreasing bacterial replication. In this dissertation we show that IFNγ, which is associated with a protective immune response during tuberculosis infection, significantly inhibits pathogen-associated intracellular iron sequestration in macrophages and decreases iron availability to intracellular bacterial pathogens exposing iron dysregulation as an important factor during both innate and adaptive immunity against these pathogens. Thus, in the final chapters of this dissertation, I hypothesized that hepcidin inhibitors such as heparin or specific blocking antibodies significantly decrease intracellular bacterial replication during Mtb infection in human macrophages. Altogether, this dissertation uncovers macrophage iron export as an important host-directed therapeutic target during M. tuberculosis infection.