Vibrio vulnificus PlpA facilitates necrotic host cell death induced by the pore forming MARTX toxin

Changyi Cho; Sanghyeon Choi; Myung Hee Kim; Byoung Sik Kim

doi:10.1007/s12275-022-1448-x

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Vibrio vulnificus PlpA facilitates necrotic host cell death induced by the pore forming MARTX toxin: Changyi Cho ¹, Sanghyeon Choi ^2,3, Myung Hee Kim ², Byoung Sik Kim ^1,2; Journal of Microbiology 2022;60(2):224-233.
DOI: https://doi.org/10.1007/s12275-022-1448-x
Published online: February 1, 2022

¹Department of Food Science and Engineering, Ewha Womans University, Seoul 03760, Republic of Korea, ²Infection and Immunity Research Laboratory, Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea, ³Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea

Corresponding author: Byoung Sik Kim , Tel: +82-2-3277-4031,

Received: 26 August 2021 • Revised: 10 January 2022 • Accepted: 10 January 2022

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Abstract

Opportunistic pathogen Vibrio vulnificus causes severe systemic infection in humans with high mortality. Although multiple exotoxins have been characterized in V. vulnificus, their interactions and potential synergistic roles in pathogen-induced host cell death have not been investigated previously. By employing a series of multiple exotoxin deletion mutants, we investigated whether specific exotoxins of the pathogen functioned together to achieve severe and rapid necrotic cell death. Human epithelial cells treated with V. vulnificus with a plpA deletion background exhibited an unusually prolonged cell blebbing, suggesting the importance of PlpA, a phospholipase A2, in rapid necrotic cell death by this pathogen. Additional deletion of the rtxA gene encoding the multifunctional autoprocessing repeats-in-toxin (MARTX) toxin did not result in necrotic cell blebs. However, if the rtxA gene was engineered to produce an effector-free MARTX toxin, the cell blebbing was observed, indicating that the pore forming activity of the MARTX toxin is sufficient, but the MARTX toxin effector domains are not necessary, for the blebbing. When a recombinant PlpA was treated on the blebbed cells, the blebs were completely disrupted. Consistent with this, MARTX toxin-pendent rapid release of cytosolic lactate dehydrogenase was significantly delayed in the plpA deletion background. Mutations in other exotoxins such as elastase, cytolysin/hemolysin, and/or extracellular metalloprotease did not affect the bleb formation or disruption. Together, these findings indicate that the pore forming MARTX toxin and the phospholipase A2, PlpA, cooperate sequentially to achieve rapid necrotic cell death by inducing cell blebbing and disrupting the blebs, respectively.

Keywords: MARTX toxin, phospholipase, exotoxin, necrotic cell death, cell bleb, Vibrio vulnificus

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Vibrio vulnificus PlpA facilitates necrotic host cell death induced by the pore forming MARTX toxin

J. Microbiol. 2022;60(2):224-233. Published online February 1, 2022

DOI: https://doi.org/10.1007/s12275-022-1448-x

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