Loss of function Dnmt3a mutation leads to aberrant neutrophil migration

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.