Abstract
Enterohemorrhagic Escherichia coli (EHEC) are important human pathogens, causing hemorrhagic colitis and hemolytic uraemic syndrome in humans. E. coli O157:H7 is the most common serotype associated with EHEC infections worldwide, although other non-O157 serotypes cause life-threatening infections. Cattle are a main reservoir of EHEC and intervention strategies aimed at limiting EHEC excretion from cattle are predicted to lower the risk of human infection. We have previously shown that immunization of calves with recombinant versions of the type III secretion system (T3SS)-associated proteins EspA, intimin and Tir from EHEC O157:H7 significantly reduced shedding of EHEC O157 from experimentally-colonized calves, and that protection could be augmented by the addition of H7 flagellin to the vaccine formulation. The main aim of the present study was to optimize our current EHEC O157 subunit vaccine formulations by identifying the key combinations of these antigens required for protection. A secondary aim was to determine if vaccine-induced antibody responses exhibited cross-reactive potential with antigens from other EHEC serotypes. Immunization with EspA, intimin and Tir resulted in a reduction in mean EHEC O157 shedding following challenge, but not the mean proportion of calves colonized. Removal of Tir resulted in more prolonged shedding compared with all other groups, whereas replacement of Tir with H7 flagellin resulted in the highest levels of protection, both in terms of reducing both mean EHEC O157 shedding and the proportion of colonized calves. Immunization of calves with recombinant EHEC O157 EspA, intimin and Tir resulted in the generation of antibodies capable of cross-reacting with antigens from non-O157 EHEC serotypes, suggesting that immunization with these antigens may provide a degree of cross-protection against other EHEC serotypes. Further studies are now required to test the efficacy of these vaccines in the field, and to formally test the cross-protective potential of the vaccines against other non-O157 EHEC.
Highlights
Enterohemorrhagic Escherichia coli (EHEC) are worldwide zoonotic pathogens which cause gastro-intestinal disease in humans with potentially life-threatening consequences as a result of systemic Shiga toxin (Stx) activity
To achieve this we addressed the following two questions: (i) Can translocated intimin receptor (Tir) be removed from an EspA, intimin and Tir-based vaccine without any loss in efficacy, resulting in a simplified T3S-based vaccine containing only EspA and intimin?; (ii) Would inclusion of H7 flagellin augment the protection generated by this simplified T3S based vaccine? Given the relatively high sequence similarities between EspA, Intimin and Tir from different EHEC serotypes (BLASTp), a secondary aim of this study was to determine whether antibodies generated against EHEC O157 versions of these proteins are able to crossreact with antigens from other EHEC serotypes
Vaccine efficacy was reduced if H7 flagellin was replaced by Tir, and further reduced if calves were immunized with EspA and intimin531 alone
Summary
Enterohemorrhagic Escherichia coli (EHEC) are worldwide zoonotic pathogens which cause gastro-intestinal disease in humans with potentially life-threatening consequences as a result of systemic Shiga toxin (Stx) activity. In recognition of the growing importance of non-O157 EHEC serotypes, six non-O157 serogroups (O26, O45, O103, O111, O121, and O145) have recently been classified as adulterants in the USA [8], meaning that if they are detected in meat batches destined for retail sale these must be withdrawn at considerable cost to the meat processing industry. Despite these costs, there is little financial incentive for cattle producers themselves to implement interventions, as EHEC infections in cattle are largely asymptomatic and there is currently no evidence that these infections are a direct cause of production losses. To maximise uptake by the livestock industry any intervention in cattle will need to be cost-effective and supported by clear evidence that such treatments reduce the incidence of human infection
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