PMID- 29957172
OWN - NLM
STAT- MEDLINE
DCOM- 20180817
LR  - 20190802
IS  - 1473-5644 (Electronic)
IS  - 0022-2615 (Print)
IS  - 0022-2615 (Linking)
VI  - 67
IP  - 8
DP  - 2018 Aug
TI  - ASC acts in a caspase-1-independent manner to worsen acute pneumonia caused by 
      Pseudomonas aeruginosa.
PG  - 1168-1180
LID - 10.1099/jmm.0.000782 [doi]
AB  - PURPOSE: Pseudomonas aeruginosa expresses a type III secretion system (T3SS) that 
      activates the host inflammasome-mediated immune response. We examined the role of 
      inflammasome activation in severe infection outcomes. METHODS: We infected 
      C57BL/6 (B6) mice lacking inflammasome components ASC or caspase-1/11 with a 
      highly virulent strain of P. aeruginosa, PSE9, using a mouse model of pneumonia. 
      We evaluated inflammasome activation in vitro by infecting bone marrow-derived 
      macrophages (BMDMs) with PSE9 and measuring cell death and release of 
      inflammasome-dependent cytokines IL-18 and IL-1beta. A bioluminescent reporter assay 
      was used to detect activity of caspase-1 and caspase-3/7 in BMDMs from B6 and 
      ASC-deficient mice.Results/Key Findings. ASC(-/-) mice exhibited significantly 
      improved survival relative to caspase-1/11(-/-) mice and B6 mice, demonstrating 
      that ASC and caspase-1/11 play differential roles in P. aeruginosa infection. We 
      found that ASC(-/-) BMDMs exhibited significantly reduced cell death relative to 
      B6 BMDMs, while caspase-1/11(-/-) BMDMs were resistant to cell death. IL-18 and 
      IL-1beta were both detected from supernatants of infected B6 BMDMs, but cytokine 
      release was abrogated in both ASC(-/-) and caspase-1/11(-/-) BMDMs. We detected a 
      2.5-fold increase in the activation of caspase-3/7 in PSE9-infected B6 BMDMs, but 
      no increase in infected ASC(-/-) BMDMs. Cell death, cytokine release and 
      caspase-3/7 activity were dependent on a functional T3SS. CONCLUSIONS: 
      Collectively, these results are consistent with a model whereby the T3SS 
      apparatus of P. aeruginosa activates the caspase-1-dependent inflammasome and 
      caspase-3/7 through an ASC-dependent mechanism. This activation may have 
      implications for the outcomes of P. aeruginosa infections.
FAU - Hughes, A J
AU  - Hughes AJ
AD  - 1​Department of Microbiology and Immunology, Feinberg School of Medicine, 
      Northwestern University, Chicago, IL, USA.
FAU - Knoten, C A
AU  - Knoten CA
AD  - 1​Department of Microbiology and Immunology, Feinberg School of Medicine, 
      Northwestern University, Chicago, IL, USA.
AD  - dagger​Present address: Academy for Quality and Safety Improvement, Northwestern 
      Medicine, Chicago, IL, USA.
FAU - Morris, A R
AU  - Morris AR
AD  - 1​Department of Microbiology and Immunology, Feinberg School of Medicine, 
      Northwestern University, Chicago, IL, USA.
FAU - Hauser, A R
AU  - Hauser AR
AD  - 2​Department of Medicine, Division of Infectious Diseases, Feinberg School of 
      Medicine, Northwestern University, Chicago, IL, USA.
AD  - 1​Department of Microbiology and Immunology, Feinberg School of Medicine, 
      Northwestern University, Chicago, IL, USA.
LA  - eng
GR  - K24 AI104831/AI/NIAID NIH HHS/United States
GR  - R01 AI053674/AI/NIAID NIH HHS/United States
GR  - R01 AI118257/AI/NIAID NIH HHS/United States
GR  - T32 GM008061/GM/NIGMS NIH HHS/United States
PT  - Journal Article
DEP - 20180629
PL  - England
TA  - J Med Microbiol
JT  - Journal of medical microbiology
JID - 0224131
RN  - 0 (CARD Signaling Adaptor Proteins)
RN  - 0 (Pycard protein, mouse)
RN  - EC 3.4.22.36 (Caspase 1)
SB  - IM
MH  - Animals
MH  - CARD Signaling Adaptor Proteins/deficiency/*metabolism
MH  - Caspase 1/deficiency/*metabolism
MH  - Disease Models, Animal
MH  - *Host-Pathogen Interactions
MH  - Humans
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Pneumonia, Bacterial/microbiology/*pathology
MH  - Pseudomonas Infections/microbiology/*pathology
MH  - Pseudomonas aeruginosa/*pathogenicity
MH  - Survival Analysis
PMC - PMC6152396
OTO - NOTNLM
OT  - Pseudomonas aeruginosa
OT  - T3SS
OT  - apoptosis
OT  - caspase-1
OT  - caspase-3
OT  - inflammasome
OT  - pyroptosis
OT  - type III secretion
COIS- The authors declare that there are no conflicts of interest.
EDAT- 2018/06/30 06:00
MHDA- 2018/08/18 06:00
PMCR- 2019/08/01
CRDT- 2018/06/30 06:00
PHST- 2018/06/30 06:00 [pubmed]
PHST- 2018/08/18 06:00 [medline]
PHST- 2018/06/30 06:00 [entrez]
PHST- 2019/08/01 00:00 [pmc-release]
AID - 000782 [pii]
AID - 10.1099/jmm.0.000782 [doi]
PST - ppublish
SO  - J Med Microbiol. 2018 Aug;67(8):1168-1180. doi: 10.1099/jmm.0.000782. Epub 2018 
      Jun 29.