PMID- 32142554
OWN - NLM
STAT- MEDLINE
DCOM- 20200622
LR  - 20240423
IS  - 1553-7374 (Electronic)
IS  - 1553-7366 (Print)
IS  - 1553-7366 (Linking)
VI  - 16
IP  - 3
DP  - 2020 Mar
TI  - Monocyte metabolic reprogramming promotes pro-inflammatory activity and 
      Staphylococcus aureus biofilm clearance.
PG  - e1008354
LID - 10.1371/journal.ppat.1008354 [doi]
LID - e1008354
AB  - Biofilm-associated prosthetic joint infections (PJIs) cause significant morbidity 
      due to their recalcitrance to immune-mediated clearance and antibiotics, with 
      Staphylococcus aureus (S. aureus) among the most prevalent pathogens. We 
      previously demonstrated that S. aureus biofilm-associated monocytes are polarized 
      to an anti-inflammatory phenotype and the adoptive transfer of pro-inflammatory 
      macrophages attenuated biofilm burden, highlighting the critical role of 
      monocyte/macrophage inflammatory status in dictating biofilm persistence. The 
      inflammatory properties of leukocytes are linked to their metabolic state, and 
      here we demonstrate that biofilm-associated monocytes exhibit a metabolic bias 
      favoring oxidative phosphorylation (OxPhos) and less aerobic glycolysis to 
      facilitate their anti-inflammatory activity and biofilm persistence. To shift 
      monocyte metabolism in vivo and reprogram cells to a pro-inflammatory state, a 
      nanoparticle approach was utilized to deliver the OxPhos inhibitor oligomycin to 
      monocytes. Using a mouse model of S. aureus PJI, oligomycin nanoparticles were 
      preferentially internalized by monocytes, which significantly reduced S. aureus 
      biofilm burden by altering metabolism and promoting the pro-inflammatory 
      properties of infiltrating monocytes as revealed by metabolomics and RT-qPCR, 
      respectively. Injection of oligomycin alone had no effect on monocyte metabolism 
      or biofilm burden, establishing that intracellular delivery of oligomycin is 
      required to reprogram monocyte metabolic activity and that oligomycin lacks 
      antibacterial activity against S. aureus biofilms. Remarkably, monocyte metabolic 
      reprogramming with oligomycin nanoparticles was effective at clearing established 
      biofilms in combination with systemic antibiotics. These findings suggest that 
      metabolic reprogramming of biofilm-associated monocytes may represent a novel 
      therapeutic approach for PJI.
FAU - Yamada, Kelsey J
AU  - Yamada KJ
AUID- ORCID: 0000-0003-1071-8836
AD  - Department of Pathology and Microbiology, University of Nebraska Medical Center, 
      Omaha, Nebraska, United States of America.
FAU - Heim, Cortney E
AU  - Heim CE
AD  - Department of Pathology and Microbiology, University of Nebraska Medical Center, 
      Omaha, Nebraska, United States of America.
FAU - Xi, Xinyuan
AU  - Xi X
AUID- ORCID: 0000-0003-3272-1761
AD  - Department of Pharmaceutical Sciences, University of Nebraska Medical Center, 
      Omaha, Nebraska, United States of America.
FAU - Attri, Kuldeep S
AU  - Attri KS
AD  - Eppley Institute, University of Nebraska Medical Center, Omaha, Nebraska, United 
      States of America.
FAU - Wang, Dezhen
AU  - Wang D
AD  - Eppley Institute, University of Nebraska Medical Center, Omaha, Nebraska, United 
      States of America.
FAU - Zhang, Wenting
AU  - Zhang W
AUID- ORCID: 0000-0002-6406-5220
AD  - Department of Pharmaceutical Sciences, University of Nebraska Medical Center, 
      Omaha, Nebraska, United States of America.
FAU - Singh, Pankaj K
AU  - Singh PK
AD  - Eppley Institute, University of Nebraska Medical Center, Omaha, Nebraska, United 
      States of America.
FAU - Bronich, Tatiana K
AU  - Bronich TK
AUID- ORCID: 0000-0003-4192-8422
AD  - Department of Pharmaceutical Sciences, University of Nebraska Medical Center, 
      Omaha, Nebraska, United States of America.
FAU - Kielian, Tammy
AU  - Kielian T
AUID- ORCID: 0000-0001-7624-670X
AD  - Department of Pathology and Microbiology, University of Nebraska Medical Center, 
      Omaha, Nebraska, United States of America.
LA  - eng
GR  - P30 GM110768/GM/NIGMS NIH HHS/United States
GR  - U01 CA198910/CA/NCI NIH HHS/United States
GR  - P30 GM127200/GM/NIGMS NIH HHS/United States
GR  - P30 CA036727/CA/NCI NIH HHS/United States
GR  - P01 AI083211/AI/NIAID NIH HHS/United States
GR  - P20 GM103427/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200306
PL  - United States
TA  - PLoS Pathog
JT  - PLoS pathogens
JID - 101238921
RN  - 0 (Oligomycins)
SB  - IM
MH  - Animals
MH  - Biofilms/*drug effects
MH  - Cellular Reprogramming/*drug effects
MH  - Implants, Experimental/*microbiology
MH  - Inflammation/drug therapy/metabolism/pathology
MH  - Mice
MH  - Monocytes/*metabolism/pathology
MH  - Oligomycins/*pharmacology
MH  - Oxidative Phosphorylation/drug effects
MH  - Staphylococcal Infections/drug therapy/*metabolism/pathology
MH  - Staphylococcus aureus/*physiology
PMC - PMC7080272
COIS- I have read the journal's policy and the authors of this manuscript have the 
      following competing interests: A provisional patent has been filed with the US 
      Patent and Trademark Office covering the application of nanoparticle targeting of 
      monocyte metabolism for the treatment of biofilm-associated infections 
      (62/730,229; TK, TKB, KJY, XX).
EDAT- 2020/03/07 06:00
MHDA- 2020/06/23 06:00
PMCR- 2020/03/06
CRDT- 2020/03/07 06:00
PHST- 2019/07/09 00:00 [received]
PHST- 2020/01/27 00:00 [accepted]
PHST- 2020/03/18 00:00 [revised]
PHST- 2020/03/07 06:00 [pubmed]
PHST- 2020/06/23 06:00 [medline]
PHST- 2020/03/07 06:00 [entrez]
PHST- 2020/03/06 00:00 [pmc-release]
AID - PPATHOGENS-D-19-01259 [pii]
AID - 10.1371/journal.ppat.1008354 [doi]
PST - epublish
SO  - PLoS Pathog. 2020 Mar 6;16(3):e1008354. doi: 10.1371/journal.ppat.1008354. 
      eCollection 2020 Mar.