Loss of Function Dnmt3a Mutation Leads to Aberrant Neutrophil Migration

Area of Science:

• Immunology
• Hematology
• Virology

Background:

• Clonal hematopoiesis (CH) is linked to increased infection risk, but mechanisms are unclear.
• Dnmt3a mutations are common in CH and associated with immune dysfunction.
• Influenza A virus (IAV) pneumonia serves as a model to study CH-related immune deficits.

Purpose of the Study:

• To investigate the impact of Dnmt3a deficiency on innate immune defense during IAV pneumonia.
• To elucidate the cellular and molecular mechanisms underlying impaired immune responses in Dnmt3a-deficient mice.
• To explore the translational relevance of these findings in human conditions associated with DNMT3A mutations.

Main Methods:

• Utilized a murine model of IAV pneumonia with Dnmt3a-deficient mice.
• Assessed pulmonary viral burden, neutrophil accumulation, and function (chemotaxis, maturation, antimicrobial capacity, metabolism).
• Performed transcriptomic profiling of lung neutrophils and proteomic analysis of plasma from individuals with germline DNMT3A mutations.

Main Results:

• Dnmt3a-deficient mice showed increased viral load and reduced neutrophil lung infiltration despite normal circulating neutrophil counts.
• Neutrophils from Dnmt3a-deficient mice exhibited impaired chemotactic migration in vitro.
• Transcriptomic analysis revealed downregulated chemotaxis and cytokine signaling pathways, including reduced Cxcr1 expression. Plasma proteomic data showed altered cell migration and cytoskeletal dynamics in individuals with germline DNMT3A mutations.

Conclusions:

• Dnmt3a loss impairs innate immune defense through cell-intrinsic defects in neutrophil migration.
• This compromised leukocyte trafficking leads to ineffective pathogen clearance.
• Findings provide mechanistic insight into CH-associated infection susceptibility and suggest targeting leukocyte trafficking for therapeutic interventions in aging populations with CH.