Abstract
Opportunistic bacteria strategically dampen their virulence to allow them to survive and propagate in hosts. However, the molecular mechanisms underlying virulence control are not clearly understood. Here, we found that the opportunistic pathogen Vibrio vulnificus biotype 3, which caused an outbreak of severe wound and intestinal infections associated with farmed tilapia, secretes significantly less virulent multifunctional autoprocessing repeats-in-toxin (MARTX) toxin, which is the most critical virulence factor in other clinical Vibrio strains. The biotype 3 MARTX toxin contains a cysteine protease domain (CPD) evolutionarily retaining a unique autocleavage site and a distinct β-flap region. CPD autoproteolytic activity is attenuated following its autocleavage because of the β-flap region. This β-flap blocks the active site, disabling further autoproteolytic processing and release of the modularly structured effector domains within the toxin. Expression of this altered CPD consequently results in attenuated release of effectors by the toxin and significantly reduces the virulence of V. vulnificus biotype 3 in cells and in mice. Bioinformatic analysis revealed that this virulence mechanism is shared in all biotype 3 strains. Thus, these data provide new insights into the mechanisms by which opportunistic bacteria persist in an environmental reservoir, prolonging the potential to cause outbreaks.
Highlights
Unlike obligate pathogens, opportunistic pathogens evolve to increase their fitness in environmental hosts by controlling their virulence, which may facilitate host-to-host spreading [1, 2]
Our previous study showed that the internal cysteine protease domain (CPD) (CPDBAA87) of multifunctional autoprocessing repeats-in-toxin (MARTX) toxin secreted by the V. vulnificus biotype 3 clinical strain BAA87 (MARTXBAA87) does not process its associated effector domains, even though CPDBAA87 itself is autocleaved in the presence of InsP6 [16]
A multiple sequence alignment of CPDs within MARTX toxins expressed by different Vibrio species, including V. vulnificus and Vibrio cholerae, revealed that CPDBAA87 has a distinct unique sequence (A4090-W4091-T4092) instead of the conventional cleavage sequence, which is known as an X1-L-X2 motif [21] (Fig. 1A)
Summary
Received for publication, December 10, 2020, and in revised form, May 6, 2021 Published, Papers in Press, May 14, 2021, https://doi.org/10.1016/j.jbc.2021.100777 Sanghyeon Choi1,2 , Byoung Sik Kim3 , Jungwon Hwang1,* , and Myung Hee Kim1,* From the 1Infection and Immunity Research Laboratory, Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea; 2Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea; 3Department of Food Science and Engineering, Ewha Womans University, Seoul, Korea
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