legionella – an intracellular pathogen

I know I’ve said it before, but you really do learn something new every day 🙂 I was browsing through my collection of Science alerts & an item about Legionella caught my eye. Legionella pneumophila is the bacterium that causes Legionnaires’ disease, so named because it was first identified when several people attending a 1976 meeting of the American Legion came down with a serious form of pneumonia. But what I didn’t know was that this bacterium is able to grow inside the cells of those affected with it – it’s what’s known as a ‘facultative’ intracellular pathogen (where ‘facultative’ means that it doesn’t have to live this way & can also live outside of the host’s cells). This raises a couple of interesting questions – how does it manage to avoid being digested by the cells it infects, and how does it get the various bits & pieces that it needs in order to survive & reproduce?

In the wild, Legionella is a free-living bacterium, although it must replicate within species of Amoeba. As a human pathogen L.pneumophila is picky about which cells it lives in, going for the immune cells that go around cleaning up both the detritus of dead host cells & also any pathogens that they detect (Diez et al. 2010). In the normal way of things, anything swept up by a macrophage is taken into the cell by a process called phagocytosis: the item is engulfed by the cell and enclosed in a membranous ‘bubble’ that pinches off from the macrophage’s cell membrane. This bubble, called a phagosome, then fuses with little membrane-bound sacs full of digestive enzymes & its contents are promptly digested.

But if a macrophage – or an amoeba – gobbles up a Legionella bacterium that sequence of events is never completed. The phagosomes containing L.pneumophila never fuse with lysosomes (those bags of digestive enzymes) and instead, the bacteria happily grow & reproduce inside their host cells. This is no accident – the Legionella cells produce enzymes that inhibit the fusion of lysosome & phagosome. What’s more, Diez et al. comment that the phagosomes containing these bacteria are closely associated with the host cell’s endoplasmic reticulum & in addition the phagosome membranes contain ribosomes – this is interesting because it suggests that a) the ‘bacterial’ phagosomes may be obtaining materials via the endoplasmic reticulum, & b) that there is protein synthesis happening on the phagosome’s membrane.

This stands to reason as the metabolic demands of a replicating intracellular bacterium will be quite specific and the only way they can be met is by hijackng normal processes in the host cell. Often this movement involves little membrane-bound sacs (vesicles) that bud off the endoplasmic reticulum.  One way that  L.pneumophila manages this is by ‘recruiting’ a specific enzyme, a ‘small GTPase’, to the outer surface of the phagosome membrane (Muller et al, 2010). . Small GTPases regulate a whole range of cellular functions – the relevant one here is vesicle transport, although they’re also involved in things like cell division & formation of a nucleus. By regulating vesicle transport the bacterium gains access to the nutrients it needs for its own growth and cell division. In fact, Legionella produces around 60 different proteins that either alter various regulatory pathways in the host cell – including preventing digestion of the bacterial interloper – or are secreted into that host (Cazaket et al. 2004).

Of course, it’s all well & good growing inside a host cell, where you are to some degree protected from the rest of the animal host’s immune system. But eventually the Legionella must escape & spread, & to do this the host cell needs to die. Diez & his colleagues note that in the test-tube Legionella can induce apoptosis in macrophages, & suggest this is done by blocking the actiion of a protein that nromally inhibits cell death. Lose enough macrophages in this way, & you’ll come down with the symptoms of legionellosis.

C.Cazalet, C.Rusnick, H.Bruggemann, N.Zidane, A.Magnier, L.Mz, M.Tichit, S.Jarraud, C.Bouchier, F.Vandenesch, F.Kunst, J.Etienne, P.Glaser & C.Buchrieser (2004) Evience in the Legionella pneumophila genome for exploitation of host cell functions and high genome plasticity. Nature Genetics 36: 1165-1173. doi: 10.1038/ng1447

E.Diez, Z.Yaraghi, A.MacKenzie & P.Gros (2000) The neuronal apoptosis inhibitory protein (Naip) is expressed in macrophages and is modulated after phagocytosis and during intracellular infection with Legionella pneumophilaJournal of Immunology 164: 1470-1477   

M.P.Muller, H.Peters, J.Blumer, W.Blankenfeldt, R.S.Goody & A.Itzen (2010) The Legionella effector protein DrrA AMPylates the membrane traffic regulator Rab1b. Science 329 (5994): 946-949. doi: 10.1126/science.1192276

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