Blood Cell Mutations Raise Risk of Dangerous Bacterial Infections, Giant Study Finds

Some of the most consequential genetic changes in the human body are not inherited from our parents but acquired over a lifetime, accumulating silently in the stem cells that replenish our blood. A sweeping new study published in Nature Communications has now linked these acquired mutations, a phenomenon known as clonal haematopoiesis, to a dramatically elevated risk of serious bacterial infection, one of the leading causes of death in older adults worldwide. The findings suggest that the same somatic mutations long associated with leukaemia and cardiovascular disease also weaken the immune system’s frontline defences, and that the degree of risk depends on precisely which gene is mutated and how large the mutant clone has grown.

Clonal haematopoiesis occurs when a haematopoietic stem cell acquires a somatic mutation that gives it a survival or proliferation advantage, allowing it to outcompete normal stem cells and produce an expanding fraction of the body’s blood cells. The phenomenon becomes increasingly common with age, and its presence in blood DNA can be detected through sequencing long before any disease develops. Researchers have previously tied clonal haematopoiesis to heightened risks of blood cancers, heart attacks and strokes, but its role in infectious disease has remained far less clear. The new study, led by Eleanor Fewings of the Illumina Artificial Intelligence Laboratory together with collaborators at the Broad Institute, Massachusetts General Hospital, Vanderbilt University Medical Center and Memorial Sloan Kettering Cancer Center, set out to answer that question at unprecedented scale.

The team assembled genetic and clinical data from three population cohorts totalling 590,537 individuals, applying a multi-parameter somatic variant calling and filtering pipeline designed to detect even low-frequency mutations in blood-derived DNA with high confidence. Across 43 genes implicated in clonal haematopoiesis, they identified 19,822 mutations in 40,560 people, corresponding to a prevalence of 6.87 percent. To guard against spurious findings, the researchers then validated their results in a combined analysis encompassing 889,215 individuals, one of the largest somatic genetics investigations ever conducted. The sheer scale of the resource allowed them to dissect risk not just for clonal haematopoiesis as a whole, but for individual mutated genes, specific recurrent mutations and expanding clones defined by variant allele fraction, a measure of the proportion of blood cells carrying the mutation.

The central result was unambiguous: people with clonal haematopoiesis were significantly more likely to develop serious bacterial infection, with a hazard ratio of 1.22 and a p-value of 4.66 × 10⁻²⁹, an association so statistically strong that chance can be essentially excluded. The effect was independent of haematological malignancy, meaning it was not simply a case of undiagnosed cancer causing infections, and it remained robust after adjustment for inflammatory comorbidities and genetic ancestry. Perhaps most strikingly, clonal haematopoiesis was also associated with a 1.84-fold increase in mortality within 28 days of infection, indicating that the mutations do not merely raise the likelihood of becoming infected but also compromise the body’s ability to survive the encounter.

The study’s most clinically consequential contribution, however, lies in its demonstration that risk is strongly dose-dependent and mutation-specific. Among individuals carrying recurrent mutations in five particular genes, SRSF2, DNMT3A, SF3B1, IDH2 and NRAS, a group numbering 2,143 people, the absolute risks were substantial. For those with expanded SRSF2 P95 clones, a specific recurrent mutation in a splicing factor gene, between 22 and 25 percent developed a serious bacterial infection within ten years. That figure rivals the predictive power of well-established clinical risk factors and suggests that a single detectable point mutation in a blood sample can flag a person as being at markedly elevated infectious risk years in advance.

The mechanistic logic behind these associations is rooted in what the mutated genes actually do. DNMT3A encodes a DNA methyltransferase essential for normal stem cell differentiation, while SRSF2 and SF3B1 are splicing factors that govern how RNA transcripts are processed, and IDH2 and NRAS participate in metabolic and signalling pathways respectively. When these genes are disrupted, the resulting blood cells can behave abnormally in ways that impair innate and adaptive immunity, including altered production of inflammatory cytokines and compromised function of neutrophils and macrophages, the cellular workhorses of bacterial defence. The new epidemiological findings align with this biology, showing that the immune consequences of clonal haematopoiesis are not confined to cancer predisposition but extend to everyday host defence against bacteria.

Importantly, the associations held across diverse populations and were largely independent of the specific bacterial strain involved, suggesting a broad, generalised weakening of antibacterial immunity rather than vulnerability to any single pathogen. This universality strengthens the case that clonal haematopoiesis acts as a systemic modifier of immune competence. It also helps explain a long-standing clinical observation: older adults vary enormously in their susceptibility to sepsis and pneumonia, and much of that variation has remained unexplained by conventional risk factors such as diabetes, chronic kidney disease or immunosuppressive medication. Somatic mutations in the blood may account for a meaningful share of that unexplained risk.

The study was made possible by an extraordinary confluence of large-scale biobank resources, including the UK Biobank, Genomics England’s National Genomic Research Library and the BioVU biobank at Vanderbilt University Medical Center, with sequencing of 250,000 whole genomes funded by the Alliance for Genomic Discovery, a consortium of NashBio, Illumina and several pharmaceutical partners. This infrastructure reflects a broader shift in biomedical research toward population-scale sequencing, in which millions of routinely collected blood samples become windows into the somatic evolution occurring inside the body. What was once visible only through the lens of leukaemia genomes can now be quantified across entire populations, revealing subtle but consequential effects on common diseases.

The implications for clinical practice are potentially far-reaching. If clonal haematopoiesis screening were incorporated into routine care, individuals with high-risk clones, particularly expanded SRSF2 mutations, could be flagged for closer monitoring, earlier vaccination strategies, aggressive management of modifiable infection risks or a lower threshold for empirical antibiotic treatment when symptoms appear. The findings also raise the prospect of therapies that target the mutated clones themselves or their inflammatory downstream effects, an area of intense pharmaceutical interest given the established links between clonal haematopoiesis and cardiovascular disease. Several companies are already developing agents aimed at damping the inflammation driven by these clones, and infection risk may now join cardiovascular events and malignancy as an outcome worth tracking in such trials.

Caveats remain. The study is observational, and while the authors adjusted extensively for malignancy, comorbidities and ancestry, residual confounding cannot be fully excluded, and the precise molecular mechanisms connecting each mutation to impaired bacterial clearance will require experimental work in cellular and animal models. The published version is also an accepted manuscript shared early for rapid access and is subject to further editorial refinement. Nevertheless, the consistency of the dose-dependent signal across hundreds of thousands of people, multiple cohorts and diverse ancestries makes a compelling case that clonal haematopoiesis deserves recognition as a genuine risk factor for serious bacterial infection. For the millions of people who carry these silent mutations, the study transforms a hidden aspect of biological ageing into an actionable piece of medical information, and it signals that the era of somatic mutation screening for non-cancer diseases may be arriving faster than anyone anticipated.

Subject of Research: Association of clonal haematopoiesis mutations with risk of serious bacterial infection

Article Title: Clonal haematopoiesis subtypes confer dose-dependent risk of serious bacterial infection

Article References: Fewings, E., Yu, Z., Gutierrez, J. C., Truong, B., Fiziev, P. P., McRae, J., Schwartzentruber, J., Bick, A. G., Natarajan, P., Lareau, C. A., Ulirsch, J. C., & Farh, K. K.-H. (2026). Clonal haematopoiesis subtypes confer dose-dependent risk of serious bacterial infection. Nature Communications. https://doi.org/10.1038/s41467-026-77934-x

Image Credits: AI Generated

DOI: 10.1038/s41467-026-77934-x

Keywords: clonal haematopoiesis, somatic mutations, serious bacterial infection, SRSF2, DNMT3A, SF3B1, IDH2, NRAS, haematopoietic stem cells, sepsis, population genomics, immune ageing