The attack of the ‘epidemic clones’: How harmless bacteria came to cause half a million deaths a year

It took 200 years — just a microsecond in the timeline of humanity — for the bacteria Pseudomonas aeruginosa to go from being harmless microbes that inhabited ponds, streams and plants, to being one of the great threats of infection on the planet. Causing more than 500,000 deaths a year, these bacilli are today on the World Health Organization’s blacklist as a “high priority” pathogen due to their resistance to antibiotics and widespread expansion across the globe. Research published on July 5 in the journal Science has mapped the genomic journey of this bacterial species and discovered that P. aeruginosa takes advantage of an immunological defect in patients with cystic fibrosis to survive and spread.

“Over the last 200 years or so, certain individual bacteria, which we call clones, managed to absorb new genes and become more capable of infecting humans. These clones then expanded and spread throughout the world. The most probable expansion date for the first clone is around 1890, although the confidence interval is wide,” explains scientist Andrés Floto, professor of Respiratory Biology at the University of Cambridge and author of the study. The researchers call the family branches of the P. aeruginosa family tree that spread around the world “epidemic clones.” The study found 21 clones are responsible for more than 50% of all P. aeruginosa infections on the planet. “They are likely to be the main drivers of antibiotic resistance and deaths,” says Floto in an email.

The harmful impact of the P. aeruginosa is relatively new. After exploring the family tree of this species, the authors cautiously conjecture that the entire phenomenon began at the end of the 18th century. “It is unlikely that before that date they would have posed a significant threat to human health,” says Floto.

Since the beginning of the 19th century, the researcher points out, “there has been an increasingly frequent appearance of these epidemic clones.” The researchers believe that each clone experienced at least one significant population expansion between 1850 and 2000. “They have emerged randomly around the world, but they seem to expand with increasing frequency. For example: from 1900 to 1950, six epidemic clones emerged; and between 1950 and 2000, 12 appeared,” explains Floto.

According to the scientist, the bacteria’s global expansion among humans continue to happen more and more regularly: “We are seeing more and more epidemic clones emerging and spreading throughout the world, which we believe may be due to air pollution and housing density.” The authors of the study suggest that the spread of these more aggressive bacterial families was accelerated by overpopulation in cities, a product of migratory movements to large cities during industrialization. This created a breeding ground with densely populated areas, while a spike in pollution led to greater susceptibility to infections and made it easier for these infectious diseases to spread.

Today, the P. aeruginosa have become opportunistic pathogens. This means that they do not harm healthy people, but they do cause lung and systemic infections in individuals who have a compromised immune system. For example, people with chronic obstructive pulmonary disease (COPD) or cystic fibrosis. Infections due to P. aeruginosa have been reported among patients admitted to hospitals (nosocomial infections), as well as in community settings. It is on the watch list of all health authorities, explains Bruno González-Zorn, director of the Antimicrobial Resistance Unit at the Complutense University of Madrid and World Health Organization (WHO) advisor on this topic. “It is very important. It has an extraordinary capacity to adapt to many ecosystems, and what worries us so much is its level of resistance to antibiotics and the number of patients it kills each year,” says González-Zorn.

After analyzing nearly 10,000 human, animal and environmental samples of this microorganism, the Cambridge researchers were able to trace the family history of P. aeruginosa, and they also identified a bacterial tolerance mechanism that may be key to understanding its resistance. In samples from patients with cystic fibrosis, scientists discovered that macrophages — which are immune cells responsible for engulfing and killing harmful microorganisms — were not able to eliminate P. aeruginosa: these clones managed to survive within macrophages and cause a persistent infection.

Scientists believe that the ability to survive macrophages is due to a combination of the bacteria’s genetics — they identified a gene involved in this process — and a failure in the cystic fibrosis patients’ line of defense. “The bacteria takes advantage of this immunological defect to infect this group of patients,” says Floto.

More virulent and effective

In this transition to infecting humans, these bacteria have been evolving, adapting through DNA mutations, and have become more effective in infecting the lung and more virulent in resisting the scourge of antibiotics. The study also found that these multiple rounds of adaptation to the lung and subsequent transmission to another person occurred differently for the bacteria that infect patients with cystic fibrosis compared to the bacilli that attack people who do not have this disease. “The bacteria become increasingly specialized and certain clones continue to be transmitted between patients with cystic fibrosis, while other clones are transmitted between patients without this disease. But these specialized bacterial clones lose the ability to be transmitted from patients with cystic fibrosis to patients without it, and vice versa,” he explains.

María del Mar Tomás, microbiologist at the University Hospital Complex of A Coruña in Spain and spokesperson for the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC), highlights the importance of this research, in which she has not participated, arguing it deepens the knowledge of the mechanisms of bacterial tolerance and resistance. These molecular systems help the bacillus survive stress. “This is very important because they are global mechanisms, which are activated in any stress situation for the bacteria, such as hunger or an antibiotic. And this can be a therapeutic target for the design of new therapies,” she says.

González-Zorn agrees: “It is an important study because it allows us to know the evolutionary trajectory of the bacteria and how it manages to establish strategies to produce disease. If we know these mechanisms, we will be able to design strategies to contain the bacteria.”

The researcher, for their part, say that the findings highlight “the importance of global surveillance and cross-infection prevention in averting the emergence of future epidemic clones.” “We have indications that epidemic clones will become increasingly adapted to the human lung and will be increasingly resistant to antibiotics if they are allowed to continue this cycle of infection, adaptation and transmission,” warns Floto.

Given the speed at which epidemic clones appear, the researcher says these clones need to be actively tracked down to prevent them from spreading. He adds that it is also key to quickly detect the bacteria in the lung and eradicate it as soon as possible. Although there are control measures to prevent P. aeruginosa infections in cystic fibrosis, Floto points out that the study’s results show that transmission between humans “also occurs very frequently in people without cystic fibrosis,” meaning there needs to be further debate on how to protect these other at-risk groups.

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