Co-administered Tag-Less Toxoid Fusion 3xSTa N12S -mnLT R192G/L211A  and CFA/I/II/IV MEFA (Multiepitope Fusion Antigen) Induce Neutralizing Antibodies to 7 Adhesins (CFA/I, CS1-CS6) and Both Enterotoxins (LT, STa) of Enterotoxigenic  Escherichia coli  (ETEC)

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Abstract

Enterotoxigenic Escherichia coli (ETEC) bacteria remain a leading cause of children's diarrhea and travelers' diarrhea. Vaccines that induce antibodies to block ETEC bacterial adherence and to neutralize toxin enterotoxicity can be effective against ETEC-associated diarrhea. Recent studies showed that 6xHis-tagged CFA/I/II/IV multiepitope fusion antigen (MEFA) induced broad-spectrum antibodies to inhibit adherence of the seven most important ETEC adhesins (CFA/I, CS1 to CS6) (Ruan et al., 2014a) and 6xHis-tagged toxoid fusion antigen 3xSTa _N12S-mnLT _R192G/L211A (previously named as 3xSTa _N12S-dmLT) elicited antibodies to neutralize both heat-labile toxin (LT) and heat-stable toxin (STa) produced by ETEC strains (Ruan et al., 2014b). In this study, we constructed two new genes to express tag-less toxoid fusion 3xSTa _N12S-mnLT _R192G/L211A and tag-less CFA/I/II/IV MEFA and then examined immunogenicity of each tag-less protein in mouse immunization. We further combined two tag-less proteins and investigated antigen co-administration in mice. Data showed that mice immunized with tag-less 3xSTa _N12S-mnLT _R192G/L211A or tag-less CFA/I/II/IV MEFA developed antigen-specific IgG antibody responses, and mice co-administered with two tag-less proteins induced neutralizing antibodies against seven adhesins and both toxins. These results indicated tag-less toxoid fusion 3xSTa _N12S-mnLT _R192G/L211A and tag-less CFA/I/II/IV MEFA administered individually or combined induced neutralizing antitoxin and/or anti-adhesin antibodies, and suggested the potential application of two tag-less proteins for ETEC vaccine development.

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Most cited references 29

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Escherichia coli is the predominant nonpathogenic facultative flora of the human intestine. Some E. coli strains, however, have developed the ability to cause disease of the gastrointestinal, urinary, or central nervous system in even the most robust human hosts. Diarrheagenic strains of E. coli can be divided into at least six different categories with corresponding distinct pathogenic schemes. Taken together, these organisms probably represent the most common cause of pediatric diarrhea worldwide. Several distinct clinical syndromes accompany infection with diarrheagenic E. coli categories, including traveler's diarrhea (enterotoxigenic E. coli), hemorrhagic colitis and hemolytic-uremic syndrome (enterohemorrhagic E. coli), persistent diarrhea (enteroaggregative E. coli), and watery diarrhea of infants (entero-pathogenic E. coli). This review discusses the current level of understanding of the pathogenesis of the diarrheagenic E. coli strains and describes how their pathogenic schemes underlie the clinical manifestations, diagnostic approach, and epidemiologic investigation of these important pathogens.

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Esmeralda A J M Soares, Helen L. Guyatt, R. Moore … (2006)

Diarrhea is a leading cause of mortality worldwide; however, its long-term morbidity is poorly understood. Recently, early childhood diarrhea (ECD) has been associated with impaired physical fitness, growth and cognitive function 6 to 9 years later. We studied the effects of ECD on school functioning in a shantytown in northeastern Brazil. We administered 77 educational surveys. Complete diarrhea surveillance (ie, >90%) in the first 2 years of life and demographic and anthropometric information were available for 73 children. Age at starting school was calculated for 62 children, whereas age appropriateness for the current grade (AFG) was calculated for all 73 children who were >6 years old. Stepwise regression was used to examine the independent effect of ECD on school functioning after controlling for socioeconomic factors, maternal education, breast feeding, growth and cognitive functioning. ECD correlated with age at starting school (r = 0.55, P = 0.0005) and remained a significant predictor even after controlling for family demographics, days of breast feeding, early growth and TONI-3 test of nonverbal intelligence. This was true despite significant correlations of ECD with growth shortfalls and impaired cognitive functioning. ECD also correlated with AFG (r = 0.38, P = 0.001). Only TONI-3 test scores explained this association, suggesting that ECD may hinder school performance, but only in part school readiness, by impairing cognitive function as measured by performance on the TONI-3 nonverbal intelligence test. These findings document effects of early childhood diarrhea on later school readiness and performance and hence potential long-term human and economic costs of ECD, which warrant further attention and far greater investment for the control of ECD and its consequences.

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An assessment of enterotoxigenic Escherichia coli and Shigella vaccine candidates for infants and children.

Richard Walker (2015)

Despite improvements to water quality, sanitation, and the implementation of current prevention and treatment interventions, diarrhea remains a major cause of illness and death, especially among children less than five years of age in the developing world. Rotavirus vaccines have already begun making a real impact on diarrhea, but several more enteric vaccines will be necessary to achieve broader reductions of illness and death. Among the many causes of diarrheal disease, enterotoxigenic Escherichia coli (ETEC) and Shigella are the two most important bacterial pathogens for which there are no currently licensed vaccines. Vaccines against these two pathogens could greatly reduce the impact of disease caused by these infections. This review describes the approaches to ETEC and Shigella vaccines that are currently under development, including a range of both cellular and subunit approaches for each pathogen. In addition, the review discusses strategies for maximizing the potential benefit of these vaccines, which includes the feasibility of co-administration, consolidation, and combination of vaccine candidates, as well as issues related to effective administration of enteric vaccines to infants. Recent impact studies indicate that ETEC and Shigella vaccines could significantly benefit global public health. Either vaccine, particularly if they could be combined together or with another enteric vaccine, would be an extremely valuable tool for saving lives and promoting the health of infants and children in the developing world, as well as potentially providing protection to travelers and military personnel visiting endemic areas.

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Author and article information

Contributors

Qiangde Duan: URI : http://loop.frontiersin.org/people/567510/overview

Carolina Garcia: URI : http://loop.frontiersin.org/people/521461/overview

David A. Sack: URI : http://loop.frontiersin.org/people/107498/overview

Weiping Zhang: URI : http://loop.frontiersin.org/people/77778/overview

Journal

Journal ID (nlm-ta): Front Microbiol

Journal ID (iso-abbrev): Front Microbiol

Journal ID (publisher-id): Front. Microbiol.

Title: Frontiers in Microbiology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1664-302X

Publication date (Electronic): 05 June 2018

Publication date Collection: 2018

Volume: 9

Electronic Location Identifier: 1198

Affiliations

[1] ¹Department of Diagnostic Medicine, Pathobiology, Kansas State University College of Veterinary Medicine , Manhattan, KS, United States

[2] ²Department of International Health, Johns Hopkins University Bloomberg School of Public Health , Baltimore, MD, United States

Author notes

Edited by: Jorge Blanco, Universidade de Santiago de Compostela, Spain

Reviewed by: Elizabeth B. Norton, Tulane University, United States; Juan Marzoa, Universidade de Santiago de Compostela, Spain

*Correspondence: Weiping Zhang wpzhang@ 123456vet.k-state.edu

This article was submitted to Infectious Diseases, a section of the journal Frontiers in Microbiology

Article

DOI: 10.3389/fmicb.2018.01198

PMC ID: 5996201

PubMed ID: 29922268

SO-VID: 4e1205b0-00ad-43b6-b472-711d15fcb612

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 26 January 2018

Date accepted : 16 May 2018

Page count

Figures: 5, Tables: 2, Equations: 0, References: 34, Pages: 11, Words: 7791

Funding

Funded by: National Institutes of Health 10.13039/100000002

Award ID: R01AI121067

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