Abstract
Purpose :
Our goal is to identify pathways amenable for targeting to improve bactericidal functions of neutrophils and thereby provide antibiotic-independent means to strengthen host protection.
Methods :
Using quantitative LC-MS/MS we defined neutrophil proteomes under different conditions such as presence or absence of microbiota or infection. To interrogate functions of state-specific protein signatures neutrophil cell lines were developed using immature progenitors were selected 19 targets were CRISPERed out. The knock-out neutrophils were tested for killing of P. aeruginosa.
Results :
We found that the proteomic signatures of mature neutrophils derived from germ free (GF) and specific pathogen free (SPF) mice were significantly different at baseline and during infection, demonstrating plasticity. We identified that microbiota-induced mTOR-dependent pathways strengthen bactericidal potential of neutrophils via altering neutrophil metabolism. We have also identified, previously unrecognized function for the protein pcyox1L in controlling Rheb levels in neutrophils and, hence, affecting neutrophil bactericidal potential.
Conclusions :
Cumulatively, our data support the concept that microbiota affects neutrophil maturation by defining not only the quantity, but also the quality of mature neutrophils. We predict that neutrophil responses can be specifically tailored to pathogens and, although innately determined, are adapted and molded by the challenge.
This is a 2020 ARVO Annual Meeting abstract.