Macrophages are effective weapons used by our immune system to absorb and digest pathogenic intruders. Some bacteria, however, can subvert this defence mechanism and even multiply within the macrophages. Cell biologists at the University of Bonn have revealed such a strategy in a recently publication in the journal 'Traffic' (Vol. 6, No. 8, August 2005, pp.635-653). Their findings reveal that the pathogens escape the 'stomach' of the macrophages which might otherwise digest them.
Action stations in the horse's lung! A bacterium has just been inhaled into a horse's bronchial tubes, and immune cells are quickly recruited to the spot to neutralise the intruder. Macrophages, cells whose job is to devour such intruders, are attracted by substances typical of bacteria, which surround the microbe like a cloud. As soon as the immune cells have detected the intruder, they cover the bacterium with part of their own cell membrane like a hood, creating a membrane sac in which the intruder is trapped. This 'phagosome' (from Greek phagein = to eat) cuts itself off into the inside of the macrophage and is now the point on which all the macrophage's offensive weaponry is concentrated: the phagosome is flooded with oxygen radicals and acid. Another kind of membrane bags, the lysosomes, merge with the phagosome and confront the microbe with highly reactive digestive enzymes. A few hours after the first alarm bells have rung there is nothing left of the bacterium, and the potential danger has been eliminated.
Multiplication inside the killer
This is what normally happens. However, a whole range of pathogens have become specialised in tricking this very part of the defence mechanism and survive or even multiply in these macrophages which are actually supposed to kill them.
One of these pathogens is Rhodococcus equi. This bacterium can cause a lung disease in young foals which is very similar to tuberculosis in humans. Hence, it is not too surprising that Rhodococcus equi is closely related to the tubercle bacillus (Mycobacterium tuberculosis). Since macrophages are the main target of Rhodococcus in the horse's lung, a lot of rhodococci are found there during an infection.
In the Bonn Institute of Cell Biology Eugenia Fernandez and Marco Polidori in Professor Albert Haas's team have been examining why Rhodococcus equi is not killed and digested in macrophages, and is even able to multiply there. In the course of this study the group was able to demonstrate that the rhodococci are able to put prevent the phagosome development inside the macrophage, preventing acidification and merging with the lysosomes. As a result the bacteria are not exposed to the large array of lysosomal digestive enzymes and acid.
Killing the killer
'Basically what this means is that the rhodococci manipulate their host cell, they make it themselves comfartable in an environment free of acid and digestive enzymes and multiply there,' Professor Haas comments. Within a few days after the onset of the infection, the macrophages die of the infection, they disintegrate and release the multiplied pathogens.
The Bonn cell biologists have demonstrated in the past that this cell death is 'necrotic'. This means that cell components escape, attract other immune cells and activating them. Ultimately the result is inflammation and tissue damage. 'It is quite possible that rhodococci do not really mind this,' Professor Haas says, 'since they can then grab a passing macrophage and colonise fresh material.'
The next aim of the Bonn researchers is to investigate which bacterial features are important for preventing the merger of phagosomes and lysosomes, and how the immune system normally successfully eradicates an infection despite all the tricks the bacteria use.
Rhodococci, incidentally, can also cause diseases resembling TB in AIDS patients which may be fatal. 'This is an additional important aspect for our work,' Prof. Haas stresses. 'We assume that our research can contribute to understanding TB in humans.' Unlike foals, however, the vast majority of humans do not need to be afraid of this pathogen. 'In every spadeful of soil from an affected farm there are millions upon millions of rhodococci, yet it practically never happens that healthy humans are successfully infected by them.'