JNK/AP-1 signaling contributes to the impairment in S. pneumoniae killing by neutrophils in aged hosts

Lauren Heinzinger

Lab participants.

Participants from the Bou Ghanem laboratory.

Undergraduate Student Project

Introduction

Despite the widespread availability of antibiotics and vaccines, Streptococcus pneumoniae infections remain a significant problem in the elderly. My name is Lauren Heinzinger and I am a junior Biological Sciences major at UB. I have worked in the Bou Ghanem Lab for the past year, and we are interested in identifying the immune responses that decline with age. For example, we previously found that neutrophils or PMNs (a type of innate immune system cell) play an important role in the clearance of S. pneumoniae infections; however, neutrophil function declines with age. In this study, we took a transcriptomic approach in order to identify the genetic changes that lead to the neutrophil dysfunction seen in the elderly.

Abstract

Polymorphonuclear leukocytes (PMNs) or neutrophils are required to clear Streptococcus pneumoniae infections but PMN function declines in older individuals. CD73, an enzyme that produces extracellular adenosine, is required for PMN antibacterial function but is downregulated in PMNs from aged hosts. Our study aims to identify PMN transcriptome changes induced by S. pneumoniae infection to gain insight into the signaling pathways that are dysregulated in older individuals.  PMNs were isolated from young, old, and CD73 knockout (CD73-/-) mice and challenged with S. pneumoniae in-vitro. RNA-seq identified genes that were differentially regulated during infection and qPCR validated specific genetic targets. Upon infection, genes in the AP-1/JNK pathway were upregulated in PMNs from CD73-/- and old mice. Assays tested the bacterial killing efficiency of PMNs in the presence of AP-1/JNK inhibitors. AP-1 and JNK inhibition significantly boosted bacterial killing. These data suggest the AP-1/JNK pathway is controlled by CD73 and dysregulated with aging.

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