Bacteria can directly trigger the nerves that sense pain, suggesting that the body's own immune reaction is not always to blame for the extra tenderness of an infected wound. In fact, mice with staph-infected paws showed signs of pain even before immune cells had time to arrive at the site, researchers report online August 21 in Nature.
"Most people think that when they get pain during infection it's due to the immune system," says coauthor Isaac Chiu of Boston Children's Hospital and Harvard Medical School. Indeed, immune cells do release pain-causing molecules while fighting off invading microbes. But in recent years scientists have started uncovering evidence that bacteria can also cause pain.
Chiu and his colleagues stumbled on this idea when they grew immune cells and pain-sensing cells together in a dish. The researchers were trying to activate the immune cells by adding bacteria to the mix but were surprised to see an immediate response in the nerve cells instead. This made them suspect that nerve cells were sensing the bacteria directly.
To take a closer look at a real infection, the team injected the back paws of mice with Staphylococcus aureus, a bacterium that causes painful sores in humans. The researchers measured how tender the infected area was by poking it with flexible filaments of plastic. If the mouse didn't like being prodded, it would lift its paw, giving a sensitive measure of each infection's ouch factor.
The mice's paws were most sensitive when bacterial cell numbers were at their peak, six hours after infection. By the time the immune response caught up, at 48 hours after infection, the pain had largely ebbed away. The researchers identified two protein factors released by S. aureus that could trigger nerve cells in dishes and that were also painful when injected into the mice.
These factors seemed to be more important than the immune system in making mouse paws achy, since mice with faulty immune responses were at least as tender as normal mice, the researchers report. However, pain from immune reactions might play a more significant role in other kinds of infections, Chiu cautions, since not all bacterial species are as good as S. aureus at evading the immune system.
The team guessed that the nerves were helping to alert the immune system to the presence of bacteria, but when they tested this idea, they got a surprise. "We saw the opposite of what we expected," Chiu says. When the researchers infected mice that lacked pain-sensing nerve cells, even more immune cells rushed to the site of infection than in normal mice. This implies that the nerve cells normally suppress the immune system, Chiu says.
Chiu doesn't know why pain should dampen the body's defenses against pathogens but speculates that when tissue is damaged by injury, an overenthusiastic immune system may need to be held back. Bacteria like S. aureus might take advantage of pain's anti-immune effects to avoid detection, he suggests, "but it's an open question."
Kevin Tracey, an immunologist and president of the Feinstein Institute for Medical Research in Manhasset, N.Y., says the results fit with his own studies that show nerve signals can put the brakes on immune responses. "It's a beautiful study," Tracey says. "It's important because it shows that in order to understand the immune system, you really have to understand the nervous system."