Language

English

Publication Date

9-1-2026

Journal

Experimental Hermatology

DOI

10.1016/j.exphem.2026.105486

PMID

42497960

PMCID

PMC13474270

PubMedCentral® Posted Date

8-15-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Clonal hematopoiesis (CH), an age-related expansion of somatically mutated hematopoietic clones, is associated with increased risk of severe infections including coronavirus disease (COVID)-19, yet the underlying mechanisms remain unclear. Here, we investigated the impact of Dnmt3a deficiency in a murine model of influenza A virus (IAV) pneumonia. Dnmt3a-deficient mice exhibited increased pulmonary viral burden and reduced neutrophil accumulation in IAV-infected lungs despite comparable circulating neutrophil numbers. Functional analyses of neutrophils showed impaired chemotactic migration in vitro, whereas maturation, antimicrobial enzyme content, and metabolic capacity were unchanged. Transcriptomic profiling revealed downregulation of pathways involved in chemotaxis, cytokine signaling, and cellular activation, including reduced expression of Cxcr1. Supporting the translational relevance of these findings, proteomic analysis of plasma from individuals with germline DNMT3A mutations (Tatton-Brown-Rahman syndrome) revealed alterations in proteins associated with cell migration and cytoskeletal dynamics. Collectively, our findings demonstrate that Dnmt3a loss compromises innate immune defense by impairing neutrophil migration in a cell-intrinsic manner, leading to ineffective pathogen clearance. This work provides mechanistic insight into how CH-associated mutations contribute to age-associated susceptibility to infection and highlights altered leukocyte trafficking as a potential therapeutic target in aging populations with CH.

Keywords

Animals, DNA Methyltransferase 3A, Neutrophils, Mice, Humans, Loss of Function Mutation, Mice, Knockout, DNA (Cytosine-5-)-Methyltransferases, Female, COVID-19, Chemotaxis, Leukocyte, Orthomyxoviridae Infections, Clonal hematopoiesis, Dnmt3a, Neutrophil migration, Influenza, Tatton-Brown-Rahman Syndrome

Published Open-Access

yes

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