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Researchers from the University of Cologne, the German Center for Infection Research (DZIF), and the Broad Institute of Harvard and MIT present a remarkable clinical case in the New England Journal of Medicine. The case provides new insights into the evolution of bacterial pathogens and presents the concept of heterovirulence, i.e., the simultaneous presence of subpopulations with different levels of virulence within a single infection.
The case began with a chronic urinary tract infection caused by Klebsiella pneumoniae, a common pathogen responsible for nosocomial infections. However, the patient subsequently developed a brain abscess. Analysis revealed that, in addition to a “classic” bacterial population, a second, significantly more virulent subpopulation existed in the patient’s urine and was also present in the brain abscess.
Using whole-genome sequencing, the research team demonstrated that both populations had a common origin. Subsequent mechanistic investigations, including targeted genome modifications, functional analyses, and infection models, enabled the researchers to reconstruct the evolutionary steps that led to the emergence of the increasingly virulent subpopulation. These experiments revealed that just a few point mutations were sufficient to form an enlarged bacterial capsule which protected the bacteria from being taken up by immune cells and increased their virulence in infection models.
Previous work by the research group had already shown that common Klebsiella pneumoniae bacteria can become more virulent through simple mutations that lead to a larger capsule. These capsule mutants were associated with bloodstream infections, providing initial evidence of capsule subpopulations in a limited number of patient urine samples.
“In this case, we were able to directly link clinical observations and molecular mechanisms for the first time,” explains Prof. Christoph Ernst, the study’s first and co-senior author. Ernst, a DZIF scientist at the Institute of Medical Microbiology, Immunology, and Hygiene at the University Hospital of Cologne, adds: “Our results show that highly virulent subpopulations can develop in a seemingly harmless reservoirs, such as urinary tract infections, and contribute to the spread of the infection within the same patient.”
The case described thus demonstrates that such processes occur within individual patients and can have clinically relevant consequences. The researchers assume that the severity of an infection depends on the nature of the underlying mutations as well as the patient’s condition. Aside from increasingly virulent infections, hetervirulence may also promote chronic infections.
Another important aspect highlighted by this case is that uncontrolled acute and latent infections enable the emergence of heterovirulent populations. This could be particularly relevant in the case of multidrug-resistant pathogens.
“We therefore suspect that the prevalence of heterovirulent populations is particularly pronounced in multidrug-resistant infections. To this end, we are conducting DZIF-funded studies at the University Hospital of Cologne and developing new drugs to treat multidrug-resistant infections,” explains Ernst, who works in the DZIF research area Healthcare-Associated Infections.
The researchers see parallels to so-called heteroresistance, in which antibiotic-resistant subpopulations within an infection can complicate antibiotic treatment and are difficult to detect. However, virulent subpopulations are even more difficult to detect because bacterial virulence traits are not yet part of standard diagnostics.
The study underscores the importance of a better understanding of bacterial evolution in patients and highlights new avenues for diagnosing and treating complex infections.
Prof. Dr. Christoph M. Ernst
University of Cologne
christoph.ernst@uni-koeln.de
Ernst CM, Fischer LKS, Manson AL, Li L, Ma P, Anahtar MN, Bhattacharyya RP, Earl AM, Clatworthy AE, Hung DT. Klebsiella Brain Abscess and Evolution of Heterovirulence in the Urinary Tract. N Engl J Med. 2026 Jul 23;395(4):408-410. https://www.nejm.org/doi/full/10.1056/NEJMc2108952
https://www.dzif.de/en/urinary-tract-infection-brain-abscess-how-bacterial-subpo... Press release of the German Center for Infection Research (DZIF)
https://www.dzif.de/en/healthcare-associated-infections Research area "Healthcare-Associated Infections" of the German Center for Infection Research (DZIF)
Transmission electron micrograph of a cell from an increasingly virulent subpopulation of Klebsiella ...
Copyright: Christoph Ernst
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