Title: Salmonella enterica Serovar Typhi Lipopolysaccharide O-Antigen Modification Impact on Serum Resistance and Antibody Recognition

Abstract

Salmonella enterica serovar Typhi is a human-restricted Gram-negative bacterial pathogen responsible for causing an estimated 27 million cases of typhoid fever annually, leading to 217,000 deaths, and current vaccines do not offer full protection. The O-antigen side chain of the lipopolysaccharide is an immunodominant antigen, can define host-pathogen interactions, and is under consideration as a vaccine target for some Gram-negative species. The composition of the O-antigen can be modified by the activity of glycosyltransferase (gtr) operons acquired by horizontal gene transfer. Here we investigate the role of two gtr operons that we identified in the S. Typhi genome. Strains were engineered to express specific gtr operons. Full chemical analysis of the O-antigens of these strains identified gtr-dependent glucosylation and acetylation. The glucosylated form of the O-antigen mediated enhanced survival in human serum and decreased complement binding. A single nucleotide deviation from an epigenetic phase variation signature sequence rendered the expression of this glucosylating gtr operon uniform in the population. In contrast, the expression of the acetylating gtrC gene is controlled by epigenetic phase variation. Acetylation did not affect serum survival, but phase variation can be an immune evasion mechanism, and thus, this modification may contribute to persistence in a host.more » In murine immunization studies, both O-antigen modifications were generally immunodominant. Our results emphasize that natural O-antigen modifications should be taken into consideration when assessing responses to vaccines, especially O-antigen-based vaccines, and that the Salmonella gtr repertoire may confound the protective efficacy of broad-ranging Salmonella lipopolysaccharide conjugate vaccines.« less

Authors:

Kintz, Erica  ^[1];

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• Search DOE PAGES for ORCID "0000-0002-6829-5701"

Heiss, Christian ^[2]; Black, Ian ^[2]; Donohue, Nicholas ^[1]; Brown, Naj ^[1]; Davies, Mark R. ^[1]; Azadi, Parastoo ^[2]; Baker, Stephen ^[3]; Kaye, Paul M. ^[1]; van der Woude, Marjan  ^[1];

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• Search DOE PAGES for ORCID "0000-0002-0446-8829"

Bäumler, Andreas J.

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+ Show Author Affiliations

1. Univ. of York (United Kingdom). Centre for Immunology and Infection, Hull York Medical School and Department of Biology
2. Univ. of Georgia, Athens, GA (United States). Complex Carbohydrate Research Center
3. Oxford University Clinical Research Unit, Ho Chi Minh City (Vietnam). The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme

Publication Date:

Mon Feb 06 00:00:00 EST 2017

Research Org.:

Univ. of Georgia, Athens, GA (United States)

Sponsoring Org.:

USDOE

OSTI Identifier:

1426155

Grant/Contract Number:  

SC0015662

Resource Type:

Accepted Manuscript

Journal Name:

Infection and Immunity

Additional Journal Information:

Journal Volume: 85; Journal Issue: 4; Journal ID: ISSN 0019-9567

Publisher:

American Society for Microbiology

Country of Publication:

United States

Language:

English

Subject:

59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; O-antigen; Salmonella enterica; lipopolysaccharide; phase variation; serum resistance