Abstract
Cholera continues to be an important public health concern in developing countries where proper hygiene and sanitation are compromised. This severe diarrheal disease is caused by the Gram-negative pathogen Vibrio cholerae belonging to serogroups O1 and O139. Cholera toxin (CT) is the prime virulence factor and is directly responsible for the disease manifestation. The ctxB gene encodes cholera toxin B subunit (CTB) whereas the A subunit (CTA) is the product of ctxA gene. Enzymatic action of CT depends on binding of B pentamers to the lipid-based receptor ganglioside GM1. In recent years, emergence of V. cholerae Haitian variant strains with ctxB7 allele and their rapid spread throughout the globe has been linked to various cholera outbreaks in Africa and Asia. These strains produce classical type (WT) CTB except for an additional mutation in the signal sequence region where an asparagine (N) residue replaces a histidine (H) at the 20th amino acid position (H20N) of CTB precursor (pre-CTB). Here we report that Haitian variant V. cholerae O1 strains isolated in Kolkata produced higher amount of CT compared to contemporary O1 El Tor variant strains under in vitro virulence inducing conditions. We observed that the ctxB7 allele, itself plays a pivotal role in higher CT production. Based on our in silico analysis, we hypothesized that higher accumulation of toxin subunits from ctxB7 allele might be attributed to the structural alteration at the CTB signal peptide region of pre-H20N CTB. Overall, this study provides plausible explanation regarding the hypertoxigenic phenotype of the Haitian variant strains which have spread globally, possibly through positive selection for increased pathogenic traits.
Highlights
Since 1817, cholera has spread into many countries and over the years has caused several pandemics [1]
V. cholerae O1 strains with the signature ctxB7 allele have propagated through many of the cholera endemic regions in Africa and Asia
These strains were identified as the cause for the devastating cholera epidemic in Haiti that killed around 8000 victims
Summary
Since 1817, cholera has spread into many countries and over the years has caused several pandemics [1]. It is well established that the classical biotype was responsible for the fifth and sixth pandemics whereas the ongoing seventh pandemic is due to El Tor biotype [2]. These strains have spread globally in three separate waves [3]. Apart from the presence of additional mutations in the toxin co-regulated pilus subunit A (tcpACIRS) and a null mutation in the rtxA gene encoding a truncated multifunctional auto processing RTX (MARTX) family toxin [11], these Haitian variant strains harbor ctxB7 allele which results in H20N substitution in the CTB signal sequence [12]. The mature CTB monomers which are identical to CTB classical type assemble into pentamers and associate with A subunits to produce holotoxin [13]
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