Innate immunity

Oral

Neutrophil maturation and their response to infectious pathogens are regulated by microbiota

Co-Author(s)

• AP

  Anastasia Petenkova, PhD

  Postdoctoral Fellow
  Brigham and Women's Hospital
• AK

  Abirami Kugadas, PhD

  Postdoctoral Fellow
  Brigham and Women's Hospital
• JG

  Jennifer Geddes-McAlister, PhD

  University of Guelph
• MM

  Michael Mansour, MD, PhD

  Assistant Professor
  Massachusetts General Hospital
• DS

  David Sykes, MD, PhD

  Instructor in Medicine
  Massachusetts General Hospital

Presenting Author(s)

• MG

  Mihaela Gadjeva, PhD

  Assistant Professor
  Brigham and Women's Hospital

It has long been considered that a neutrophil’s response to various infectious challenges is innately pre-determined. Here, we provide data that demonstrates that neutrophil proteomes are modulated by the microbiota. We found that the proteomic signatures of mature neutrophils derived from germ free (GF) and specific pathogen free (SPF) mice were significantly different. In the absence of microbiota, mature neutrophils lacked GM-CSF-driven priming.

GF-serum exposed neutrophil progenitors did not mature efficiently and had compromised bactericidal properties when compared to progenitors matured in SPF-derived serum. To identify molecular pathways, we set-up an in vitro system where neutrophil progenitors were transduced with lenti-guides to knock-down key microbiota-driven gene targets. To identify which of the microbiota-regulated proteins directly impacted bactericidal functions of neutrophils, we knocked out 19 candidates and tested their killing of P. aeruginosa. Excitingly, one of the targets demonstrated a superior inhibition of neutrophil bactericidal capacities. This protein had no previously identified function. Namely, the knock down of prenylcysteine oxidase-like 1 (pcyox 1l) protein reduced killing of  P. aeruginosa in vitro due to diminished ROS release. It is likely that pcyox-1l generates ROS, independent of the NADPH oxidase. Hence, we identified a novel mechanism for microbiota-driven control of innate immunity.

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. In conclusion, neutrophil responses, although innately determined, are adapted and molded by the commensal presence.