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PLoS Negl Trop Dis. 2015 Jan 28;9(1):e0003446. doi: 10.1371/journal.pntd.0003446. eCollection 2015 Jan.

Conservation and immunogenicity of novel antigens in diverse isolates of enterotoxigenic Escherichia coli.

Author information

1
Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, St. Louis, Missouri, United States of America.
2
International Centre for Diarrhoeal Disease Research, Bangladesh, Mohakhali, Dhaka, Bangladesh.
3
Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
4
Institute for Genome Sciences, Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
5
Molecular Microbiology and Microbial Pathogenesis Program, Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, Missouri, United States of America.
6
Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, St. Louis, Missouri, United States of America; Molecular Microbiology and Microbial Pathogenesis Program, Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, Missouri, United States of America; Medicine Service, Veterans Affairs Medical Center, St. Louis, Missouri, United States of America.

Abstract

BACKGROUND:

Enterotoxigenic Escherichia coli (ETEC) are common causes of diarrheal morbidity and mortality in developing countries for which there is currently no vaccine. Heterogeneity in classical ETEC antigens known as colonization factors (CFs) and poor efficacy of toxoid-based approaches to date have impeded development of a broadly protective ETEC vaccine, prompting searches for novel molecular targets.

METHODOLOGY:

Using a variety of molecular methods, we examined a large collection of ETEC isolates for production of two secreted plasmid-encoded pathotype-specific antigens, the EtpA extracellular adhesin, and EatA, a mucin-degrading serine protease; and two chromosomally-encoded molecules, the YghJ metalloprotease and the EaeH adhesin, that are not specific to the ETEC pathovar, but which have been implicated in ETEC pathogenesis. ELISA assays were also performed on control and convalescent sera to characterize the immune response to these antigens. Finally, mice were immunized with recombinant EtpA (rEtpA), and a protease deficient version of the secreted EatA passenger domain (rEatApH134R) to examine the feasibility of combining these molecules in a subunit vaccine approach.

PRINCIPAL FINDINGS:

EtpA and EatA were secreted by more than half of all ETEC, distributed over diverse phylogenetic lineages belonging to multiple CF groups, and exhibited surprisingly little sequence variation. Both chromosomally-encoded molecules were also identified in a wide variety of ETEC strains and YghJ was secreted by 89% of isolates. Antibodies against both the ETEC pathovar-specific and conserved E. coli antigens were present in significantly higher titers in convalescent samples from subjects with ETEC infection than controls suggesting that each of these antigens is produced and recognized during infection. Finally, co-immunization of mice with rEtpA and rEatApH134R offered significant protection against ETEC infection.

CONCLUSIONS:

Collectively, these data suggest that novel antigens could significantly complement current approaches and foster improved strategies for development of broadly protective ETEC vaccines.

PMID:
25629897
PMCID:
PMC4309559
DOI:
10.1371/journal.pntd.0003446
[Indexed for MEDLINE]
Free PMC Article

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