Abstract
Vibrio vulnificus biotype 2-serovar E is a zoonotic clonal complex that can cause death by sepsis in humans and fish. Unlike other biotypes, Bt2 produces a unique type of MARTXVv (Multifunctional-Autoprocessive-Repeats-in-Toxin; RtxA13), which is encoded by a gene duplicated in the pVvBt2 plasmid and chromosome II. In this work, we analyzed the activity of this toxin and its role in human sepsis by performing in vitro, ex vivo, and in vivo assays. First, we demonstrated that the ACD domain, present exclusively in this toxin variant, effectively has an actin-cross-linking activity. Second, we determined that the whole toxin caused death of human endotheliocytes and monocytes by lysis and apoptosis, respectively. Finally, we tested the hypothesis that RtxA13 contributes to human death caused by this zoonotic serovar by triggering an early cytokine storm in blood. To this end, we used a Bt2-SerE strain (R99) together with its rtxA13 deficient mutant, and a Bt1 strain (YJ016) producing RtxA11 (the most studied MARTXVv) together with its rtxA11 deficient mutant, as controls. Our results showed that RtxA13 was essential for virulence, as R99ΔΔrtxA13 was completely avirulent in our murine model of infection, and that R99, but not strain YJ016, induced an early, strong and dysregulated immune response involving the up-regulation of a high number of genes. This dysregulated immune response was directly linked to RtxA13. Based on these results and those obtained ex vivo (human blood), we propose a model of infection for the zoonotic serovar of V. vulnificus, in which RtxA13 would act as a sepsis-inducing toxin.
Highlights
Vibrio vulnificus is an autochthonous inhabitant of marine and estuarine waters located in tropical, subtropical, and temperate ecosystems (Oliver, 2015)
The clinical cases of known-etiology associated with the clonal complex V. vulnificus Bt2-SerE correspond to type I human vibriosis after fish handling
The hypothesis underlying the present work refers to the septicemia associated to these vibriosis cases in humans and is based on previous results obtained in the eel which related the RtxA13 with animal death by an early peracute septic shock (Lee et al, 2013)
Summary
Vibrio vulnificus is an autochthonous inhabitant of marine and estuarine waters located in tropical, subtropical, and temperate ecosystems (Oliver, 2015). The diseases caused by Vibrio species are known as vibrioses. In type I, the pathogen causes severe tissue necrosis after contact of a wound with seawater or fish that can lead to debridement/amputation or even secondary septicaemia (Strom and Paranjpye, 2000; Jones and Oliver, 2009). Fish vibriosis is a haemorrhagic septicaemia produced by contact with water or fish (carrier or diseased) without a relationship with high iron levels in blood (Amaro et al, 2015). The common feature of fish and human vibrioses is that the pathogen invades the blood causing sepsis. Among Bt2 strains, only those belonging to clonal complex Bt2-SerE (serovar) are recognized as being truly zoonotic (Amaro and Biosca, 1996; Sanjuán et al, 2011)
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