Disease tolerance research points to treatments that limit infection damage instead of killing microbes

Scientists have discovered that disease tolerance, rather than just killing microbes, can be a key factor in survival during infections. Two identical mice infected with the same deadly pathogen can have vastly different outcomes. One may survive while the other dies. Traditionally, scientists believed that the pathogen burden was the determining factor, assuming that the immune system would eventually overwhelm the body.

However, HHMI Investigator Janelle Ayres found that this assumption was incorrect. Ayres documented disease tolerance in fruit flies as a graduate student and has spent the past two decades studying it in mammals. Disease tolerance refers to the body's ability to limit the physiological damage caused by a pathogen, rather than eliminating it altogether.

Ayres' research focused on Citrobacter rodentium, a gut-dwelling pathogen. She found that half of the mice died and half survived when exposed to the same pathogen load. When the surviving mice were given an iron supplement alongside the infection, 100% survived, even when exposed to 10, 100, or 1,000 times the lethal dose of bacteria.

The iron did not kill the bacteria, but rather initiated metabolic changes in the mice that increased glucose availability for the bacteria, prompting them to dial down their virulence over time. Ayres then explored the role of age in sepsis responses. She applied two strains of bacteria that commonly cause sepsis to both young and old mice, with the same pathogen burden and dose.

The results showed that young mice that died had enlarged hearts, while old mice that died had shrunken, atrophied hearts. Young mice that survived never showed signs of illness, while older mice that survived experienced a day or two of sickness. Gene activity in the hearts of young mice protected them from cardiac growth and organ damage, while the same genes drove illness and death in older mice.

This suggests that beneficial traits can become detrimental with aging, a concept known as antagonistic pleiotropy. Ayres' findings indicate that targeting these genes with drugs could potentially save young sepsis patients but may have lethal effects on elderly patients experiencing the same infection. This research suggests that understanding commonalities in disease tolerance strategies across different infectious diseases could lead to the development of treatments that are effective across multiple diseases and do not contribute to drug resistance.