The bacterial fugitives behind hospital-acquired pneumonia
A new study shows how hospital-acquired ‘A. baumannii’ microbes can prolong infection by hiding from antibiotics inside immune cells
When bacteria infect our bodies, a fierce battle unfolds. Microbes fight for resources to grow and spread, and in response, get bombarded by medications and our immune response. If successful, these defense mechanisms clear out the invaders and prevent infection from spreading. Some pathogens, however, have evolved elaborate ways to avoid detection. In a recent study, researchers at Washington University in St. Louis (WUSTL) uncovered how one bacterial species, Acinetobacter baumannii, hijacks immune cells to hide from the body’s anti-bacterial mechanisms. Once the immune system eliminates the microbes outside the cells, these fugitives re-emerge from their hideout and start the infection all over again.
A. baumannii is challenging to fend off due to its own defense mechanisms, known as antibiotic resistance genes, that counter most drugs at clinicians’ disposal. This hardiness has made treating A. baumannii so difficult that the World Health Organization has classified it as a critical priority pathogen. The pathogen’s preferred targets don’t make treatment any easier — A. baumannii commonly infects the critically ill, often in a hospital’s intensive care unit (ICU), causing up to 3% of pneumonia cases acquired in hospitals. Patients with such infections stay in the hospital for an extra month on average, with mortality rates around the world ranging from 24% to 83%.
With this rising threat, scientists are racing against the clock to better understand A. baumannii and develop more effective medicines. In their study, WUSTL researchers found that A. baumannii has an unusual way of prolonging infection.
“The bacteria can go inside the immune cells that are supposed to kill it, survive there, replicate, divide, get out of there, and start a new infection,” study lead and WUSTL Professor of Molecular Microbiology Mario Feldman explained. “This is a big problem for antibiotics.” Not only do the bacteria have antibiotic resistance genes to fight back against the drugs, but also have alternative countermeasures if the pathogen encounters a new drug for which it has no resistance.
Unarmed but resilient
Before this study, scientists knew that A. baumannii could infiltrate immune cells in test tubes. The immediate next question for Manon Janet-Maitre, a postdoctoral researcher in Feldman’s lab, was whether these sneaky bacteria could reignite infections in the lungs.
First, she infected immunocompromised mice with A. baumannii to mimic what happens during hospital outbreaks. She waited one day for the microbes to infect the lung cells, including macrophages — the very immune cells responsible for destroying pathogens. She then washed fluid and extra cells out of the bacteria-ridden mouse lungs, leaving only the macrophages, some of which harbored fugitive A. baumannii. These macrophages were inhaled by another group of mice. If the fugitive bacteria were inactive, these mice would remain healthy. Instead, the bacteria multiplied and caused new infections.
“Those intracellular [bacteria] can serve as reservoirs for seeding infection,” Janet-Maitre explained.
While the experiment showed that the hidden bacteria could be reactivated in other hosts, this didn’t explain why patients were spending more time in the ICU. In a hospital setting, it was unlikely that a patient would hardly inhale lung macrophages of another patient if confined to a negative pressure room. Instead, Janet-Maitre proposed that the fugitive bacteria might keep the infection going within a patient even after the extracellular, non-fugitive bacteria have been destroyed. This could explain why pneumonia caused by A. baumannii leads to lengthy hospital stays.
The researchers then shifted their focus to the tools A. baumannii uses to survive inside macrophages. “[We] wanted to know what the bacterium is doing there, because if we found how they do it, we may stop it,” Feldman said. A. baumannii is known as a minimalist in terms of its molecular arsenal. “We were super surprised,” Janet-Maitre recalled. “It’s [surviving inside macrophages] so well, but it doesn’t have all the weapons that are known to other bacteria.”
Instead, A. baumannii uses multiple strategies to “persist and resist” despite lacking weaponry. The bacteria change their energy source, activate a stress response, produce proteins for scavenging nutrients, and even change their surface to adapt to the new environment. “The combination of all those factors [lets the bacteria] thrive and survive inside of the macrophage," Janet-Maitre explained.
Exposing the fugitives
This study is part of a larger effort of Feldman’s lab and others to unravel how A. baumannii are so successful at infecting immunocompromised patients and evading treatments.
“It changes the way that we think about [A. baumannii] infections,” said Northeastern University Associate Professor of Biology Edward Geisinger, who studies A. baumannii and was not involved in the WUSTL study. Considering how A. baumannii was mistakenly labeled by the scientific community as living exclusively outside host cells, this study underscores the need to “be flexible about the way we think about the pathogenic strategy of this bacterium,” according to Geisinger.
Feldman views this work as a paradigm shift: the ability of A. baumannii to hide inside host immune cells could explain why many antibiotics work in test tubes but fail in clinical trials.
“This has to be taken into account for development of new drugs,” Janet-Maitre said.
In the future, Feldman and his colleagues hope to prevent bacteria from seeking refuge in immune cells. If the findings of fugitive pathogens discovered in the mouse model are confirmed in humans, a new approach to treating A. baumannii infections could be possible; trapping the bacteria outside of host cells, for example, may make existing drugs more effective. In that case, last-resort antibiotics — the rare few that A. baumannii is not resistant to — could eliminate the microbes for good, leaving no fugitives behind.