Vibrio cholerae: Attack!

Vibrio cholerae: Attack!

My sixth structure of Christmas is out to kill human gut cells, with help from a human protein. But has it simply shown up (drunk) at the wrong party?

Interactions between two living organisms nearly always involve proteins. All proteins fold into precise, beautiful shapes, tweaked and perfected by evolution over millions of years to perform very specific tasks. In a successful interaction, two of these shapes will fit together perfectly – like a plug and socket – to make things happen.

There are lots of ways organisms can interact, some of which are mutually beneficial.

Making a deal: When two organisms are about to interact, such as when bacteria that fix nitrogen are sweet-talked (quite literally – they are paid in sugar) into the roots of plants that need nitrogen, there is a careful ‘handshake’ between proteins in the plant and proteins in the bacterium.

Checking in: Friendly bacteria in our gut are engaged in constant molecular chit-chat with gut-wall cells about whether they are happy (or not).

Reproduction: And of course, every organism that reproduces sexually (and that’s quite a few) has to engage in some sort of molecular dance during the exchange of gametes, whether it’s ‘sperm meets egg’, ‘pollen meets ovary’, or whatever crazy sex mushrooms have (don’t ask).

The perfect fit… unfortunately

Each of those mutually beneficial molecular exchanges involves two proteins whose shapes fit exactly, so they know when they’ve met the right partner.

The two complementary surfaces fit together at just the right strength. In fact, too strong an interaction is sometimes a bad idea – sometimes you just need a quick handshake and let go! Everything has to be tuned just right.

But of course not every interaction is mutually beneficial. Every parasite that aims to invade or usurp another living cell needs to get an unwilling partner to do its dirty work somehow.

The parasitic Vibrio cholerae bacterium, which kills human gut cells, does this very well. Its henchman is the so-called ‘CTA1 subunit’ of the cholera toxin, (which originates from a bacteriophage, but more on that later), and its dupe is the human signalling protein ARF6. The two fit together almost perfectly, as you can see.

Breaking in

The fit of human ARF6 and Vibrio cholera CTA1 is so precise that it triggers part of the cholera toxin to wake up, reveal itself and get to work inside the host cell. But it has to get in the gut cell first.

The toxin is a two-part bacterial complex, actually part of a bacteriophage (a bacterial virus), so it is essentially a parasite on a parasite. It tricks the gut cell into ‘swallowing’ it and delivering it to a precise location.

Once the toxin is united with ARF6, the pairing prompts part of the toxin to go into ‘active mode’ and gum up the signalling pathway of parts of the cell.

Change the locks?

There are many, many molecular steps required to get the cholera toxin into active mode. Given such a huge number of moves in this molecular ballet, one could be forgiven for thinking it would be pretty easy for the host (i.e. human) to shut it down. Just change the shape of one of the interaction sites and, hey presto! the toxin can’t work.

That does make sense, as it happens all the time during evolution: host proteins change every time a parasite works out how use them, in a kind of never-ending arms race. Every parasite wants a way into a cell, and nearly every cellular receptor (proteins sticking out of the cell) is a potential entry point. Because of this, most cellular receptors evolve far more quickly than their intra-cellular compatriots.

However, there is a huge asymmetry here between host and parasite. It may be a good thing for a host to be resistant to a particular disease, but it is not always essential for survival. Most parasites don’t kill the host anyway, and it’s a bit pointless if you’re never going to be infected in the first place.

But for the parasite, this is a life-and-death game for them. Every successful parasite must have been successful at invading or subverting its host. Winning the arms race is far more important to the parasite than it is to you.

Don’t kill the host

In the bound cholera structure, the bacterial complex finds its perfect fit on a surface at the ‘business end’ of ARF6, which is a signalling molecule. ARF6 is thought to bind to many different proteins in its day-to-day signalling business, so changing even one of its amino acids to evade the complex could potentially interfere with its normal functions.

So what’s going on here? Why would it be in the cholera complex’s interest to mess up the signalling in its host? It’s not a tremendously winning strategy for a parasite to kill its hosts. If all your hosts die, it’s really bad for the long-term survival of your species.

Quite often the ‘best’ parasites are the ones that hang around for a long time, happily reproducing but not causing life-threatening harm to their hosts (just making their lives really unpleasant).

Right time, wrong party

Our worst, most lethal diseases are often caused by poorly adapted parasites that are in the wrong place at the wrong time. In effect, they have infected the ‘wrong’ host. For example, the Ebola virus is endemic in bats in West Africa – a sort of ‘common cold’ in the bat world. But when it finds its way into humans, Ebola causes excruciating internal bleeding and death. The match is a bad one for both for humans and the parasite.

Humans are odd hosts. We have exploded over the planet so quickly – and changed the environment around us in so many ways – that all sorts of viruses and bacteria get churned up and moved around to weird places. They can be quite successful even when they have pretty bad strategies, like killing a large number of human hosts.

The strategy of Vibrio cholera is a real puzzle. The cholera toxin, remember, is a parasite on the parasite. It’s not quite clear whether the bacterium or the virus it carries benefits from the relentless diarrhoea it causes.

One thing is for sure: it might be a perfect fit, but it is a very bad match.

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