TY - JOUR
T1 - Transcriptional diversity and niche-specific distribution of leukocyte populations during Staphylococcus aureus craniotomy-associated biofilm infection
AU - Aldrich, Amy L.
AU - Horn, Christopher M.
AU - Heim, Cortney E.
AU - Korshoj, Lee E.
AU - Kielian, Tammy
N1 - Funding Information:
This work was supported by the National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke R01 NS107369 (to T.K.). The University of Nebraska Medical Center (UNMC) Genomics Core receives partial support from the NIH/National Institute for General Medical Sciences (IDeA Networks of Biomedical Research Excellence - P20GM103427-14 and Centers of Biomedical Research Excellence - 1P30GM110768-01). Both the UNMC Genomics and Flow Cytometry Research Cores receive support from a Fred & Pamela Buffett Cancer Center Support Grant through the NIH/National Cancer Institute - P30CA036727.
Publisher Copyright:
Copyright © 2021 by The American Association of Immunologists, Inc.
PY - 2021/2/15
Y1 - 2021/2/15
N2 - Neurosurgery for brain tumor resection or epilepsy treatment requires a craniotomy to gain access to the brain. Despite prophylactic measures, infectious complications occur at a frequency of 1–3%, with approximately half caused by Staphylococcus aureus (S. aureus) that forms a biofilm on the bone flap and is recalcitrant to antibiotics. Using single-cell RNA sequencing in a mouse model of S. aureus craniotomy infection, this study revealed the complex transcriptional heterogeneity of resident microglia and infiltrating monocytes in the brain, in addition to transcriptionally diverse granulocyte subsets in the s.c. galea and bone flap. In the brain, trajectory analysis identified the transition of microglia from a homeostatic/anti-inflammatory to proinflammatory and proliferative populations, whereas granulocytes in the brain demonstrated a trajectory from a granulocyte myeloid-derived suppressor cell (MDSC)–like phenotype to a small population of mature polymorphonuclear neutrophils (PMNs). In the galea, trajectory analysis identified the progression from two distinct granulocyte-MDSC–like populations to PMN clusters enriched for IFN signaling and cell cycle genes. Based on their abundance in the galea and bone flap, PMNs and MDSCs were depleted using anti-Ly6G, which resulted in increased bacterial burden. This revealed a critical role for PMNs in S. aureus containment because MDSCs were found to attenuate PMN antibacterial activity, which may explain, in part, why craniotomy infection persists in the presence of PMN infiltrates. These results demonstrate the existence of a transcriptionally diverse leukocyte response that likely influences the chronicity of S. aureus craniotomy infection.
AB - Neurosurgery for brain tumor resection or epilepsy treatment requires a craniotomy to gain access to the brain. Despite prophylactic measures, infectious complications occur at a frequency of 1–3%, with approximately half caused by Staphylococcus aureus (S. aureus) that forms a biofilm on the bone flap and is recalcitrant to antibiotics. Using single-cell RNA sequencing in a mouse model of S. aureus craniotomy infection, this study revealed the complex transcriptional heterogeneity of resident microglia and infiltrating monocytes in the brain, in addition to transcriptionally diverse granulocyte subsets in the s.c. galea and bone flap. In the brain, trajectory analysis identified the transition of microglia from a homeostatic/anti-inflammatory to proinflammatory and proliferative populations, whereas granulocytes in the brain demonstrated a trajectory from a granulocyte myeloid-derived suppressor cell (MDSC)–like phenotype to a small population of mature polymorphonuclear neutrophils (PMNs). In the galea, trajectory analysis identified the progression from two distinct granulocyte-MDSC–like populations to PMN clusters enriched for IFN signaling and cell cycle genes. Based on their abundance in the galea and bone flap, PMNs and MDSCs were depleted using anti-Ly6G, which resulted in increased bacterial burden. This revealed a critical role for PMNs in S. aureus containment because MDSCs were found to attenuate PMN antibacterial activity, which may explain, in part, why craniotomy infection persists in the presence of PMN infiltrates. These results demonstrate the existence of a transcriptionally diverse leukocyte response that likely influences the chronicity of S. aureus craniotomy infection.
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U2 - 10.4049/jimmunol.2001042
DO - 10.4049/jimmunol.2001042
M3 - Article
C2 - 33419769
AN - SCOPUS:85100505586
VL - 206
SP - 751
EP - 765
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 4
ER -