Outer membrane protein A inhibits the degradation of caspase-1 to regulate NLRP3 inflammasome activation and exacerbate the Acinetobacter baumannii pulmonary inflammation

Li, Yumei; Cheng, Peng; Zhao, Dan; Liu, Laibing; Guo, Bing; Shi, Mingjun; Xiao, Ying; Zhou, Yu; Yu, Yan; Sun, Baofei; Wang, Wenjuan; Lin, Jieru E.; Yang, Xiaoyan; Shao, Songjun; Zhang, Xiangyan

doi:10.1016/j.micpath.2021.104788

Cited by 15 publications

(8 citation statements)

References 31 publications

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“…Recently, the virulence-related Omp38 was identified as an activator of NLRP3 inflammasome via Caspase-1 in A . baumannii infections [ 30 ]. We performed a multiple sequence alignment of the Omp38 protein sequence between the strains ATCC 17978, 19696 and BAA 1605 and found no differences in the OmpA-like domain ( S4 Fig ).…”

Section: Discussionmentioning

confidence: 99%

“…Previous work demonstrated the role of virulence factors such as the IAV BP1-F2 [26], the UPEC alpha-hemolysin [27] and toxins of Bacillus cereus [28,29] in determining NLRP3 activation and severe pathogenicity. Recently, the virulence-related Omp38 was identified as an activator of NLRP3 inflammasome via Caspase-1 in A. baumannii infections [30]. We performed a multiple sequence alignment of the Omp38 protein sequence between the strains ATCC 17978, 19696 and BAA 1605 and found no differences in the OmpA-like domain (S4 Fig) . Further analyses would assist with detailed characterisation of additional virulence factors in A. baumannii which may be responsible for Caspase-11 and NLRP3 activation leading to pyroptosis.…”

Section: Plos Onementioning

confidence: 99%

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Differential activation of NLRP3 inflammasome by Acinetobacter baumannii strains

Starrs²,

Mathur³

et al. 2022

PLoS ONE

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Acinetobacter baumannii is an emerging nosocomial, opportunistic pathogen with growing clinical significance globally. A. baumannii has an exceptional ability to rapidly develop drug resistance. It is frequently responsible for ventilator-associated pneumonia in clinical settings and inflammation resulting in severe sepsis. The inflammatory response is mediated by host pattern-recognition receptors and the inflammasomes. Inflammasome activation triggers inflammatory responses, including the secretion of the pro-inflammatory cytokines IL-1β and IL-18, the recruitment of innate immune effectors against A. baumannii infection, and the induction programmed cell death by pyroptosis. An important knowledge gap is how variation among clinical isolates affects the host’s innate response and activation of the inflammasome during A. baumannii infection. In this study, we compared nine A. baumannii strains, including clinical locally-acquired isolates, in their ability to induce activation of the inflammasome and programmed cell death in primary macrophages, epithelial lung cell line and mice. We found a variation in survival outcomes of mice and bacterial dissemination in organs among three commercially available A. baumannii strains, likely due to the differences in virulence between strains. Interestingly, we found variability among A. baumannii strains in activation of the NLRP3 inflammasome, non-canonical Caspase-11 pathway, plasmatic secretion of the pro-inflammatory cytokine IL-1β and programmed cell death. Our study highlights the importance of utilising multiple bacterial strains and clinical isolates with different virulence to investigate the innate immune response to A. baumannii infection.

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Section: Discussionmentioning

confidence: 99%

Section: Plos Onementioning

confidence: 99%

Differential activation of NLRP3 inflammasome by Acinetobacter baumannii strains

Starrs²,

Mathur³

et al. 2022

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…Previous work demonstrated the role of virulence factors such as the IAV BP1-F2 [23], the UPEC alpha-hemolysin [24] and toxins of Bacillus cereus [25,26] in determining NLRP3 activation and severe pathogenicity. Recently, the virulence-related OmpA was identified as an activator of NLRP3 inflammasome via Caspase-1 in A. baumannii infections [27]. We performed a multiple sequence alignment of the Omp38 protein sequence between the strains ATCC 17978, 19696 and BAA 1605 and found no differences in the OmpA domain (data not shown).…”

Section: Discussionmentioning

confidence: 91%

Differential activation of NLRP3 inflammasome by Acinetobacter baumannii strains

Starrs

Mathur

et al. 2022

Preprint

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Acinetobacter baumannii is an emerging nosocomial, opportunistic pathogen with growing clinical significance globally. A. baumannii has an exceptional ability to rapidly develop drug resistance. It is frequently responsible for ventilator-associated pneumonia in clinical settings and inflammation resulting in severe sepsis. The inflammatory response is mediated by host pattern-recognition receptors and the inflammasomes. Inflammasome activation triggers inflammatory responses, including the secretion of the pro-inflammatory cytokines IL-1β and IL-18, the recruitment of innate immune effectors against A. baumannii infection, and the induction programmed cell death by pyroptosis. An important knowledge gap is how variation among clinical isolates affects the host’s innate response and activation of the inflammasome during A. baumannii infection. In this study, we compared nine A. baumannii strains, including clinical locally-acquired isolates, in their ability to induce activation of the inflammasome and programmed cell death pathway in primary macrophages and mice. We found a striking variability in survival outcomes of mice and bacterial dissemination in organs among three ATCC A. baumannii strains, likely due to the differences in virulence between strains. Interestingly, we found a stark contrast in activation of the NLRP3 inflammasome pathway, the non-canonical caspase-11 pathway, plasmatic secretion of the pro-inflammatory cytokines IL-1β and IL-18 between A. baumannii strains. Our study highlights the importance of utilising multiple bacterial strains and clinical isolates with differential virulence to investigate the innate immune response to A. baumannii infection.

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“…A previous study reported that OmpA exacerbated A. baumannii lung inflammation by inhibiting caspase‐1 degradation and modulating NLRP3 inflammasome activation. 24 OmpA‐deficient A. baumannii outer membrane vesicles elicit reduced inflammatory responses. 25 Lee et al reported A. baumannii OmpA induced early‐onset apoptosis and late‐onset necrosis in DCs.…”

Section: Discussionmentioning

confidence: 99%

Acinetobacter baumannii outer membrane protein A induces autophagy in bone marrow‐derived dendritic cells involving the PI3K/mTOR pathway

Tan

Cao

2023

Immunity Inflam & Disease

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Background Outer membrane protein A (OmpA) is the major virulence factor of Acinetobacter baumannii and plays a wide role in the pathogenesis and antimicrobial resistance of A. baumannii . Dendritic cells (DCs) are the most effective antigen‐presenting cells and play a crucial role in regulating the immune response to multiple antigens and immune sentries. We aimed to study the role and molecular mechanisms of OmpA‐induced mouse bone marrow‐derived dendritic cells (BMDCs) autophagy in the immune response of A. baumannii . Methods First, purified A. baumannii OmpA was assessed by sodium dodecyl sulfate‐polyacrylamide gel electrophoresis (SDS‐PAGE) and western blot. OmpA effect on BMDCs viability was evaluated by MTT assay. BMDCs were pretreated with autophagy inhibitor chloroquine or transfected with overexpression plasmids (oe‐NC or oe‐PI3K). Then BMDCs apoptosis, inflammatory cytokines, protein kinase B (PI3K)/mammalian target of rapamycin (mTOR) pathway, and autophagy‐related factors levels were evaluated. Results SDS‐PAGE and western blot verified the successful purification of OmpA. BMDCs viability repressed gradually with the increase of OmpA concentration. OmpA treatment of BMDCs led to apoptosis and inflammation in BMDCs. OmpA caused incomplete autophagy in BMDCs, and light chain 3 (LC3), Beclin1, P62, and LC3II/I levels were significantly elevated with the increase of the time and concentration of OmpA treatment. Chloroquine reversed OmpA effects on autophagy in BMDCs, that was, LC3, Beclin1, and LC3II/I levels were reduced, while P62 level was elevated. Furthermore, chloroquine reversed OmpA effects on apoptosis and inflammation in BMDCs. PI3K/mTOR pathway‐related factor expression was affected by OmpA treatment of BMDCs. After overexpression of PI3K, these effects were reversed. Conclusions A. baumannii OmpA induced autophagy in BMDCs involving the PI3K/mTOR pathway. Our study may provide a novel therapeutic target and theoretical basis for treating infections caused by A. baumannii .

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Outer membrane protein A inhibits the degradation of caspase-1 to regulate NLRP3 inflammasome activation and exacerbate the Acinetobacter baumannii pulmonary inflammation

Cited by 15 publications

References 31 publications

Differential activation of NLRP3 inflammasome by Acinetobacter baumannii strains

Differential activation of NLRP3 inflammasome by Acinetobacter baumannii strains

Differential activation of NLRP3 inflammasome by Acinetobacter baumannii strains

Acinetobacter baumannii outer membrane protein A induces autophagy in bone marrow‐derived dendritic cells involving the PI3K/mTOR pathway

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