So-called sleeper cells are never entirely at rest, reported scientists based at Imperial College London (ICL). These cells, which are more properly known as persister cells, not only go (mostly) dormant to escape antibiotic treatments, they also stay sufficiently alert to manipulate our immune cells. They’re a nightmare when they get inside macrophages, lurk for extended periods, and patiently weaken their hosts’ inflammatory abilities.
The findings uncovered by the ICL team may help explain why some people suffer from repeated bouts of an illness, despite taking antibiotics. “Persisters are often the culprit for repeat or hard-to-treat infections,” noted Sophie Helaine, Ph.D., a senior lecturer at ICL. “The classic scenario is a person suffers some type of illness—such as a urinary tract infection or ear infection—and takes antibiotics that stop the symptoms, only for the infection to return a few weeks later.”
In addition to leading the ICL research team, Dr. Helaine is the senior author of a study (“Salmonella persisters undermine host immune defenses during antibiotic treatment”) that appeared December 7 in the journal Science. The study emphasized that during an infection, a proportion of Salmonella cells can enter a reversible state of growth arrest without becoming fully dormant. While dialing back their activities, these cells can tolerate environmental stresses such as antibiotics. At the same time, they can actively modulate their environment.
“Persisters reprogram macrophages by means of effectors secreted by the Salmonella pathogenicity island 2 type 3 secretion system,” the study’s authors detailed. “These effectors dampened proinflammatory innate immune responses and induced anti-inflammatory macrophage polarization.”
Whenever bacteria such as Salmonella invade the body, many of the bugs enter a type of standby mode in response to attack by the body immune system, which means they are not killed by antibiotics. These bacterial persister cells stop replicating and can remain in this dormant, sleeper-cell state for days, weeks, or even months. When antibiotic treatment has been stopped, if some of these bacterial cells spring back to life, they can trigger another infection.
When persisters were discovered in 1944, they were thought to be dormant inactive bacteria lying low in the body, acting as a time bomb for relapse. In the latest research, the scientists reveal that the persisters, while hiding in the body’s immune cells, are actually able to weaken the killing ability of the macrophages. The work was conducted in collaboration with the Vogel lab at the Helmholtz Institute for RNA-based Infection Research in Germany, a site of the Helmholtz Centre for Infection Research.
“Previously, it was thought the persisters are completely dormant. However, the reality we revealed here is much scarier,” explained Peter Hill, an ICL researcher and co-author of the current research. “They chip away at the defenses from the inside, weakening the power of the macrophages. This means that once antibiotic treatment stops, they might have created a much more favorable environment for another bout of infection, or even a completely new infection from another bacteria or virus.”
Although scientists studied Salmonella infection of mouse macrophages in this research, many types of bacteria that commonly cause illness are known to form persisters in humans, including E. coli and the bacillus responsible for tuberculosis and Salmonella itself. The scientists are now investigating whether there is any way of turning the tables against the bacteria, and if they can target the mechanism by which the persisters weaken our immune cells.
“Although these findings suggest the persisters have a more profound effect on our immune defenses than previously thought, they also reveal a potential bacterial weakness,” noted Dr. Helaine. “Persisters are hard to treat as they are invisible to antibiotics, but it may be this mechanism of weakening our immune cells could be a vulnerability of these persisters. We could potentially target this mechanism, and more efficiently clear hard-to-treat infections.”
