Transcriptome Profiling Reveals CD73 and Age-Driven Changes in Neutrophil Responses against Streptococcus pneumoniae

Area of Science:

• Immunology
• Molecular Biology
• Genomics

Background:

• Neutrophils are crucial for fighting Streptococcus pneumoniae infections.
• Neutrophil function, including antimicrobial activity, diminishes with advanced age.
• CD73, an enzyme vital for neutrophil antimicrobial function, is downregulated in aged neutrophils.

Purpose of the Study:

• To investigate the transcriptional changes in neutrophils upon Streptococcus pneumoniae infection.
• To identify signaling pathways regulated by CD73 and affected by aging.
• To understand how CD73 influences neutrophil adaptability to bacterial challenges.

Main Methods:

• Isolation of bone marrow-derived neutrophils from wild-type (WT) young and old mice, and CD73 knockout (CD73KO) young mice.
• Ex vivo infection of neutrophils with Streptococcus pneumoniae.
• RNA sequencing (RNA-Seq) to identify differentially expressed genes (DEGs) and long noncoding RNAs (lncRNAs).
• Analysis of the c-Jun N-terminal kinase (JNK)-mitogen-activated protein kinase (MAPK) pathway and AP-1 transcription factor activity.

Main Results:

• Infection induced significant transcriptional changes, most pronounced in CD73KO neutrophils, with more downregulated than upregulated genes.
• Aging and CD73 deficiency led to dampened immune responses, evidenced by downregulated DEGs.
• CD73KO neutrophils showed increased lncRNA expression, potentially regulating signaling pathways.
• The JNK/MAPK pathway and AP-1 activation were upregulated in infected CD73KO and old WT neutrophils.
• Inhibition of JNK/AP-1 restored the phagocytic capacity of these neutrophils.

Conclusions:

• Neutrophil gene expression modulation for bacterial infection adaptation is partly controlled by CD73.
• This adaptive capacity declines with age, impacting host defense.
• Targeting the CD73-regulated JNK/AP-1 pathway may restore neutrophil function in aged individuals and CD73-deficient states.