When it comes to fighting infections, it might seem like the more immune system firepower, the better. But in reality, the body’s response to bacteria and other invaders is a delicate balancing act. If the response is too little or too late, an infection can become unbeatable. But if the immune system comes on too strong, it may end up doing more harm than good.
New research suggests a genetic variation that arose in the first inhabitants of Europe may have helped them and their descendants hit the immune response sweet spot. These results, published online this week in Proceedings of the National Academy of Sciences, may also help scientists better understand sepsis, a state of whole-body inflammation in response to infection that is the tenth leading cause of death in the United States, with an annual cost of nearly $17 billion.
Studies have shown that people who have one copy of a T at in the TIRAP gene are less susceptible to infection with malaria, tuberculosis, bacteremia and pneumococcal disease. Scientists know that the TIRAP gene encodes a protein involved in helping the body recognize and destroy a broad range of pathogenic bacteria. But what they haven’t known until now is how might affect this process.
To investigate, Bart Ferwerda of the Nijmegen Institute for Infectious Inflammation and Immunity in the Netherlands and an international team of collaborators infused volunteers with LPS, a toxin found in the outer membranes of some bacteria. They found that the variant was associated with the release of more pro-inflammatory signaling molecules into the bloodstream in response. The variant occurs at much higher frequencies in people with European ancestry than either Africans or Asians. According to the authors, this suggests that the mutation didn’t arise until after the ancestors of East Asians and Europeans had split apart — sometime after the out-of-Africa migration but before the first people moved into Europe about 40,000 years ago.
Traditional thinking is that a person who ends up with high levels of pro-inflammatory signaling molecules in response to an infection is in trouble, because over-inflammation can lead to shock and death. But the authors suggest this may be true only in people who are already suffering from sepsis. In the initial stages of infection, high levels of pro-inflammatory molecules could actually be very beneficial.
Their theory is that in the harsh environment the ancestors of modern Europeans encountered, those with the variant were more resistant to infections. But if an infection did set in, their immune responses weren’t so overzealous that they were at risk for septic shock.
