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Loss of function Dnmt3a mutation leads to aberrant neutrophil migration

ABSTRACT: Recent evidence links clonal hematopoiesis (CH), frequently driven by mutations in DNMT3A, to increased susceptibility to severe infections, including bacterial infections and COVID‑19. The primary goal of this study was to determine how loss of function Dnmt3a mutations alter the immune responses during acute viral infection. Using an acute influenza A (IAV) pneumonia model in Dnmt3a deficient (Dnmt3afl/fl;Vav-Cre or Dnmt3afl/fl;Mx1-Cre) and wild type mice, we found that loss of Dnmt3a in hematopoietic cells impairs antiviral defense by affecting the neutrophil’s ability to properly migrate towards the infected lung. For deeper mechanistical insight, we performed bulkRNA-seq on neutrophils (CD11b+ Ly6g+) sorted from lung and bone marrow of IAV infected and uninfected Dnmt3a-KO and Wild type mice. BulkRNA-seq revealed that Dnmt3a-deficient neutrophils exhibit transcriptional downregulation of Cxcr1 and other chemotaxis pathways, as well as altered expression of pathways associated with response to inflammatory stimuli. Together, these findings provide functional evidence that Dnmt3a-driven CH disrupts antiviral immunity and identify neutrophil chemotaxis defects as a central mechanistic link between DNMT3A loss of function and susceptibility to viral pneumonia.

ORGANISM(S): Mus musculus

PROVIDER: GSE328797 | GEO | 2026/08/19

REPOSITORIES: GEO

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Project description:Children are at high risk for influenza A virus (IAV) infections, which can develop into severe illnesses. However, little is known about interactions between the microbiome and respiratory tract metabolites and their impact on the development of IAV pneumonia in children. Using a combination of liquid chromatography tandem mass spectrometry (LC-MS/MS) and 16S rRNA gene sequencing, we analyzed the composition and metabolic profile of the oropharyngeal microbiota in 49 pediatric patients with IAV pneumonia and 42 age-matched healthy children. The results indicate that compared to healthy children, children with IAV pneumonia exhibited significant changes in the oropharyngeal macrobiotic structure (p = 0.001), and significantly lower microbial abundance and diversity (p < 0.05). These changes came with significant disturbances in the levels of oropharyngeal metabolites. Intergroup differences were observed in 204 metabolites mapped to 36 metabolic pathways. Significantly higher levels of sphingolipid (sphinganine and phytosphingosine) and propanoate (propionic acid and succinic acid) metabolism were observed in patients with IAV pneumonia than in healthy controls. Using Spearman's rank-correlation analysis, correlations between IAV pneumonia-associated discriminatory microbial genera and metabolites were evaluated. The results indicate significant correlations and consistency in variation trends between Streptococcus and three sphingolipid metabolites (phytosphingosine, sphinganine, and sphingosine). Besides these three sphingolipid metabolites, the sphinganine-to-sphingosine ratio and the joint analysis of the three metabolites indicated remarkable diagnostic efficacy in children with IAV pneumonia. This study confirmed significant changes in the characteristics and metabolic profile of the oropharyngeal microbiome in pediatric patients with IAV pneumonia, with high synergy between the two factors. Oropharyngeal sphingolipid metabolites may serve as potential diagnostic biomarkers of IAV pneumonia in children.

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Loss of function Dnmt3a mutation leads to aberrant neutrophil migration

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