Solving the Mystery of the Plague That Decimated Ancient Athens

In 430 BC, during the Peloponnesian War, a plague ripped through Athens. We now know it was caused by typhoid fever. You’d think, when we’ve known about an infectious disease for a couple thousand years, we would know how it works. But we didn’t. Until now.

Plague, typhus, typhoid fever: some diseases sound so comfortably medieval. They make you picture scenes of “Bring out your dead!” (and of course the occasional “I’m not dead yet!”). But they're actually not as medieval as you'd think. It wasn't until this year that a group of researchers identified the toxin that causes the disease.

There are vaccines and antibiotics for typhoid fever, but where there is little access, typhoid still kills. It starts with fever, followed by little rose spots that appear on the chest and stomach. The stomach itself gets distended and makes a lot of noise (the awesomely scientific term is borborygmi). Then, intestinal hemorrhage, encephalitis, delirium, dehydration. Without immediate treatment, the final stage is death.

Typhoid fever is caused by the bacterium Salmonella enterica enterica, spread through fecal contamination — mostly in drinking water. But there’s a funny thing about the bacterium that causes typhoid fever: it’s a salmonella. All other salmonellas that we know of cause, well, salmonella. You know, food poisoning. Nasty, but in people who are pretty healthy, nothing remotely life threatening. But the salmonella bacterium that produces typhoid is a completely different animal. What’s the difference?

The difference is typhoid toxin. Made only once the bacterium is inside a cell, the typhoid toxin snakes outside the cell again once it is made. Though we've known about the existence of this toxin for a while now, scientists didn’t know whether it was really responsible for typhoid fever. At least, until Harvard medical researcher Jorge E. Galán and his colleagues injected the toxin into mice. The purified toxin produced many of the symptoms of typhoid fever (or at least, the mouse version), and the rodents died as quickly as if they’d been infected with typhoid fever itself.

It turns out that the typhoid toxin can cause severe DNA damage and prevent a cell from dividing, shutting down immune responses, and creating the symptoms of typhoid fever. And the typhoid toxin is flexible. It can bind to different receptor types on different cells, which means it can destroy a wide range of cells. It’s this flexibility of binding that makes it so dangerous.

The scientists who did these studies worked in relatively simple ways. They used binding studies, mutation of the various active sites of the toxin, crystallography to determine the structure of the toxin, and basic studies in mice and cells to discover if the toxin was the cause of typhoid fever. The end result is a very elegant study showing how the typhoid toxin works. But it makes me wonder: why didn’t anyone do this before?

Typhoid fever has been the cause of historical plagues (some believe the original Jamestown settlement died out of typhoid fever), and many personal tragedies (like the infamous Typhoid Mary). While there were vaccines developed and typhoid fever rates dropped with the advent of modern sanitation, people are obviously still dying of typhoid.

What took us so long to figure this toxin out? It’s hard to say for certain, but it looks like complacency played a role. Antibiotics can combat typhoid fever, and of course, the vaccine is fairly effective. But most importantly, modern sanitation (thank the chlorine in your water!) caused a huge drop in typhoid fever spread and deaths.

But it didn’t STOP it. There are still up to 33 million cases of typhoid fever per year (particularly in children), usually in Africa, Asia, and South America. But in the developed world, it’s out of sight, and out of mind.

Now that we have the structure of the typhoid toxin, and know where it binds and how it kills cells, we might have a better way to combat the toxin. Knowing how it's built gives us ideas about how to disrupt it. With some luck and a lot of work, maybe we’ll be able to comfortably put typhoid fever down as just another medieval disease that really doesn’t happen anymore.

Read the full scientific paper in Nature