PMID- 34154417
OWN - NLM
STAT- MEDLINE
DCOM- 20211112
LR  - 20211215
IS  - 2150-7511 (Electronic)
VI  - 12
IP  - 3
DP  - 2021 Jun 29
TI  - Hierarchical Cell Death Program Disrupts the Intracellular Niche Required for 
      Burkholderia thailandensis Pathogenesis.
PG  - e0105921
LID - 10.1128/mBio.01059-21 [doi]
LID - e01059-21
AB  - Burkholderia infections can result in serious diseases with high mortality, such 
      as melioidosis, and they are difficult to treat with antibiotics. Innate immunity 
      is critical for cell-autonomous clearance of intracellular pathogens like 
      Burkholderia by regulating programmed cell death. Inflammasome-dependent 
      inflammatory cytokine release and cell death contribute to host protection 
      against Burkholderia pseudomallei and Burkholderia thailandensis; however, the 
      contribution of apoptosis and necroptosis to protection is not known. Here, we 
      found that bone marrow-derived macrophages (BMDMs) lacking key components of 
      pyroptosis died via apoptosis during infection. BMDMs lacking molecules required 
      for pyroptosis, apoptosis, and necroptosis (PANoptosis), however, were 
      significantly resistant to B. thailandensis-induced cell death until later stages 
      of infection. Consequently, PANoptosis-deficient BMDMs failed to limit B. 
      thailandensis-induced cell-cell fusion, which permits increased intercellular 
      spread and replication compared to wild-type or pyroptosis-deficient BMDMs. 
      Respiratory B. thailandensis infection resulted in higher mortality in 
      PANoptosis-deficient mice than in pyroptosis-deficient mice, indicating that, in 
      the absence of pyroptosis, apoptosis is essential for efficient control of 
      infection in vivo. Together, these findings suggest both pyroptosis and apoptosis 
      are necessary for host-mediated control of Burkholderia infection. 
      IMPORTANCEBurkholderia infections result in a high degree of mortality when left 
      untreated; therefore, understanding the host immune response required to control 
      infection is critical. In this study, we found a hierarchical cell death program 
      utilized by infected cells to disrupt the intracellular niche of Burkholderia 
      thailandensis, which limits bacterial intercellular spread, host cell-cell 
      fusion, and bacterial replication. In macrophages, combined loss of key 
      PANoptosis components results in extensive B. thailandensis infection-induced 
      cell-cell fusion, bacterial replication, and increased cell death at later stages 
      of infection compared with both wild-type (WT) and pyroptosis-deficient cells. 
      During respiratory infection, mortality was increased in PANoptosis-deficient 
      mice compared to pyroptosis-deficient mice, identifying an essential role for 
      multiple cell death pathways in controlling B. thailandensis infection. These 
      findings advance our understanding of the physiological role of programmed cell 
      death in controlling Burkholderia infection.
FAU - Place, David E
AU  - Place DE
AD  - Department of Immunology, St. Jude Children's Research Hospital, Memphis, 
      Tennessee, USA.
FAU - Christgen, Shelbi
AU  - Christgen S
AD  - Department of Immunology, St. Jude Children's Research Hospital, Memphis, 
      Tennessee, USA.
FAU - Tuladhar, Shraddha
AU  - Tuladhar S
AD  - Department of Immunology, St. Jude Children's Research Hospital, Memphis, 
      Tennessee, USA.
FAU - Vogel, Peter
AU  - Vogel P
AD  - Animal Resources Center and the Veterinary Pathology Core, St. Jude Children's 
      Research Hospital, Memphis, Tennessee, USA.
FAU - Malireddi, R K Subbarao
AU  - Malireddi RKS
AD  - Department of Immunology, St. Jude Children's Research Hospital, Memphis, 
      Tennessee, USA.
FAU - Kanneganti, Thirumala-Devi
AU  - Kanneganti TD
AD  - Department of Immunology, St. Jude Children's Research Hospital, Memphis, 
      Tennessee, USA.
LA  - eng
GR  - R35 CA253095/CA/NCI NIH HHS/United States
GR  - R01 AI101935/AI/NIAID NIH HHS/United States
GR  - R01 AI124346/AI/NIAID NIH HHS/United States
GR  - R37 AI101935/AI/NIAID NIH HHS/United States
GR  - R01 AR056296/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20210622
PL  - United States
TA  - mBio
JT  - mBio
JID - 101519231
RN  - EC 3.4.22.- (Caspases)
RN  - Burkholderia thailandensis
SB  - IM
MH  - Animals
MH  - Apoptosis/*immunology
MH  - Burkholderia/immunology/*pathogenicity
MH  - Burkholderia Infections/*immunology
MH  - Caspases/classification/genetics/immunology
MH  - Female
MH  - *Immunity, Innate
MH  - Macrophages/*microbiology/*pathology
MH  - Male
MH  - Mice
MH  - Necroptosis/immunology
MH  - Pyroptosis/immunology
PMC - PMC8262894
OTO - NOTNLM
OT  - Burkholderia thailandensis
OT  - MLKL
OT  - NLRC4
OT  - NLRP3
OT  - PANoptosis
OT  - PANoptosome
OT  - RIPK1
OT  - RIPK3
OT  - T6SS
OT  - VgrG5
OT  - apoptosis
OT  - caspase-1
OT  - caspase-11
OT  - caspase-3
OT  - caspase-7
OT  - caspase-8
OT  - cell fusion
OT  - gasdermin D
OT  - inflammasome
OT  - macrophage
OT  - necroptosis
OT  - pyroptosis
OT  - type six secretion system
OT  - virulence
EDAT- 2021/06/23 06:00
MHDA- 2021/11/16 06:00
PMCR- 2021/06/22
CRDT- 2021/06/22 05:29
PHST- 2021/06/23 06:00 [pubmed]
PHST- 2021/11/16 06:00 [medline]
PHST- 2021/06/22 05:29 [entrez]
PHST- 2021/06/22 00:00 [pmc-release]
AID - mBio01059-21 [pii]
AID - 10.1128/mBio.01059-21 [doi]
PST - ppublish
SO  - mBio. 2021 Jun 29;12(3):e0105921. doi: 10.1128/mBio.01059-21. Epub 2021 Jun 22.