One of the well-known strategies employed by our immune system to destroy microbes consists in depriving them of essential nutrients such as heavy metals, particularly iron. For the first time, an international study headed by researchers from the Institut de Pharmacologie et de Biologie Structurale (CNRS/Université Paul Sabatier – Toulouse III), the Centre d'Immunologie de Marseille Luminy (CNRS/Inserm/Université de la Méditerranée) and the Institut Pasteur has shown that the reverse is also true: the immune cells are capable of mobilizing reserves of heavy metals, especially zinc, to poison microbes. This phenomenon has been demonstrated for Mycobacterium tuberculosis
, the agent responsible for tuberculosis in humans, which accounts for nearly 2 million deaths worldwide each year, and for Escherichia coli
, of which certain strains can cause serious infections of the digestive and urinary systems. In immune system cells (macrophages(2)) that have ingested M. tuberculosis
or E. coli
, the researchers observed a rapid and persistent accumulation of zinc. They also observed the production, on the surface of the microbes, of numerous proteins whose role is to “pump out”, in other words eliminate, heavy metals. In macrophages, the microbes are thus exposed to potentially toxic quantities of zinc and they try to protect themselves against intoxication by synthesizing these pumps. Inhibiting the pumps through genetic engineering provides proof of evidence: M. tuberculosis
and E. coli
become even more sensitive to destruction by macrophages.
Zinc, although toxic when ingested in too high quantities, is therefore beneficial for the immune system, particularly because it is used by macrophages to poison microbes. Equivalent mechanisms could exist for other heavy metals such as copper. These results have very concrete clinical implications. In particular, they re-open the debate on dietary supplementation (e.g. with zinc) and they may also lead to new antibiotics that would block the action of microbial pumps on metals or to new attenuated vaccine strains, which have already been tested as vaccine candidates.
© Chantal de Chastellier
This figure shows a tuberculosis bacillus (M. tuberculosis) in a macrophage. The compartment in which the bacillus resides (a vacuole known as a phagosome) is rich in zinc, which can be seen in the form of small black deposits (zinc sulfate) by electron microscopy after specific treatment.
(1) These researchers work at the Institut de Pharmacologie et de Biologie Structurale (CNRS/Université Paul Sabatier – Toulouse III), the Centre d'Immunologie de Marseille Luminy (CNRS/Inserm/Université de la Méditerranée) and the Unité de Génétique Mycobactérienne of the Institut Pasteur.
(2) A macrophage is a cell of the immune system. It is found in tissues that can be subject to infections or to an accumulation of debris that needs to be eliminated (liver, lungs, lymph glands, spleen, etc.) and has a phagocytosis function, i.e. the ability to ingest bacteria, yeasts, cell debris, etc. (the intracellular vesicle that is formed during phagocytosis is known as a phagosome and will be directed to the lysosome for its complete degradation).
P1-type ATPases mediate microbial resistance to zinc poisoning in human macrophages. Botella H, Peyron P, Levillain F, Poincloux R, Poquet Y, Brandli I, Wang C, Tailleux L, Tilleul S, Charrière G, Waddell SJ, Foti M, Lugo-Villarino G, Gao Q, Maridoneau Parini I, Butcher PD, Ricciardi Castagnoli P, Gicquel B, de Chastellier C & O Neyrolles, Cell Host & Microbe, 14 September 2011