From Urinary Tract Infection to Brain Abscess - How Bacterial Subpopulations Can Spread to Distant Sites in the Body

Their study "Klebsiella Brain Abscess and Evolution of Heterovirulence in the Urinary Tract" (https://www.nejm.org/doi/full/10.1056/NEJMc2108952) introduces the concept of heterovirulence - the coexistence of bacterial subpopulations with different levels of virulence within the same infection.

The investigation began with a patient suffering from a chronic urinary tract infection caused by Klebsiella pneumoniae, a common pathogen responsible for healthcare-associated infections. During the course of the illness, the patient unexpectedly developed a brain abscess. Detailed microbiological analyses revealed that, alongside a "classical" bacterial population in the urine, a second, considerably more virulent subpopulation was present. This highly virulent subpopulation was also identified in the brain abscess.

Using whole-genome sequencing, the researchers demonstrated that both bacterial populations originated from the same ancestral strain. Through a series of mechanistic studies - including targeted genome editing, functional analyses, and infection models - they reconstructed the evolutionary steps that led to the emergence of the more virulent subpopulation. Remarkably, only a few point mutations were sufficient to produce an enlarged bacterial capsule, which protected the bacteria from being engulfed by immune cells and significantly increased their virulence in experimental infection models.

Previous work by the research group had already suggested that otherwise typical Klebsiella pneumoniae strains can become more virulent through simple mutations that result in an enlarged capsule. These capsule variants had previously been associated with bloodstream infections and provided the first evidence of capsule-producing subpopulations in a limited number of urine samples from patients.

"In this case, we were able to directly connect clinical observations with the underlying molecular mechanisms for the first time," says Prof. Dr. Christoph Ernst, first author and co-senior author of the publication. Prof. Ernst, a DZIF scientist at the Institute of Medical Microbiology, Immunology and Hygiene at University Hospital Cologne and associated to the Center for Molecualr Medicine Cologne (CMMC), adds: "Our findings show that highly virulent subpopulations can evolve within an apparently harmless reservoir such as a urinary tract infection and subsequently contribute to the spread of infection within the same patient."

The case demonstrates that such evolutionary processes can occur within individual patients and may have clinically significant consequences. The researchers believe that the severity of an infection depends not only on the specific mutations acquired by the bacteria but also on the patient's overall condition. In addition to promoting more severe infections, these evolutionary changes may also contribute to the persistence of chronic infections.

Another important finding of the study is that uncontrolled acute and latent infections may provide the conditions necessary for heterovirulent populations to emerge. This could be particularly relevant in infections caused by multidrug-resistant pathogens. "We therefore suspect that heterovirulent populations are especially prevalent in multidrug-resistant infections," explains Prof. Ernst. "To investigate this hypothesis, we are conducting DZIF-funded studies at University Hospital Cologne while simultaneously developing novel therapeutic approaches to combat multidrug-resistant bacterial infections." Prof. Ernst conducts his research within the DZIF research area Healthcare-Associated Infections.

The researchers also draw parallels to the phenomenon of heteroresistance, in which antibiotic-resistant bacterial subpopulations within a single infection can complicate antimicrobial treatment while remaining difficult to detect. However, virulent subpopulations may be even more challenging to identify, as bacterial virulence traits are not yet routinely assessed in standard clinical diagnostics. The study highlights the importance of understanding bacterial evolution within individual patients and points to new opportunities for improving the diagnosis and treatment of complex bacterial infections.

Original Publication:
https://www.nejm.org/doi/full/10.1056/NEJMc2108952
Klebsiella Brain Abscess and Evolution of Heterovirulence in the Urinary Tract
Christoph M. Ernst, Lilly K.S. Fischer, Abigail L. Manson, Li Li, Peijun Ma, Melis N. Anahtar, Roby P. Bhattacharyya, Ashlee M. Earl, Anne E. Clatworthy, Deborah T. Hung
New England Journal of Medicine, 2026

This message has been translated and modified by the CMMC (K. Heber & D. Grosskopf-Kroiher) and is based on the text by the press and communications teams of the University Hospital Cologne (original German version here).