From urinary tract infection to brain abscess: Bacterial subpopulations can spread to distant body sites

Researchers present a clinical case in the New England Journal of Medicine that provides new insights into the evolution of bacterial pathogens and presents the concept of hetero-virulence, or 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 hospital-acquired 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 produce 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.
The case demonstrates that such processes occur within individual patients and can have clinically relevant consequences. The researchers think 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, heterovirulence 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.

A chronic Klebsiella pneumoniae urinary tract infection contained coexisting subpopulations with distinct virulence (heterovirulence), one of which disseminated to cause a brain abscess. Whole-genome sequencing and functional analyses showed that a few point mutations enlarging the capsule increased immune evasion and virulence. Heterovirulence may drive both severe and chronic infections, especially in multidrug-resistant strains, yet remains largely undetected by current diagnostics.
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.

Christoph M. Ernst et al, Klebsiella Brain Abscess and Evolution of Heterovirulence in the Urinary Tract, New England Journal of Medicine (2026). DOI: 10.1056/nejmc2108952