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. 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.

Quantitative Assessment of an Artificial Neural Network for the Variation in Immunity to Salmonella Infection Among Sudanese and Chinese Populations and the Relationship Between HLA-DQB1 and Antibody: A Preliminary Study

“…Cases of the disease among African children decrease, and increase in the acquisition of the antibody to start all complement-dependent killing of Salmonella, and subsequently, more effective blood phagocytes and opsoniza-tion (4)(5)(6). Measuring and detecting serum antibody markers in the clinical laboratory to evaluate a patient's health status is an important and valuable issue (6)(7)(8)(9)(10)(11). The affinity of an antibody to its antigen describes and characterizes the strength of the interaction between the antibody and the antigen and plays a critical role in the recovery of infection.…”

Typhoid Fever as a Challenge for Developing Countries and Elusive Diagnostic Approaches Available for the Enteric Fever

“…During natural infection, antibodies are raised against LPS and the detection of S. typhi O-antigen antibodies forms the basis of the diagnostic Widal test for typhoid [36]. The composition of the O-antigen can be modified by the activity of Glycosyltransferase (gtr) operons acquired by horizontal gene transfer [30].…”

“…The O polysaccharide have a core structure that is common to all enterobacteria and side chains of sugars attached to the core determine O specificity [22]. The O-antigen side chain of the lipo polysaccharide is an immunodominant antigen, can define hostpathogen interactions [30].…”

“…The O-antigen is immunogenic and may be a functional target for novel vaccines [33,34]. The S. enterica subspecies is comprised of over 2,600 serovars, which are based on differences in the antigenic properties of the O-and H (flagellar)-antigens and form the basis of the Kauffman-White serotyping system [18,30].…”

“…Vi antigen: The Vi capsular polysaccharide (Vi) is a component of several members of the family Enterobacteriaceae, including Salmonella typhi, Salmonella paratyphi C the Vi polysaccharide acts as a virulence factor by inhibiting phagocytosis, resisting compliment activation and bacterial lysis by alternative pathway and peroxidase mediated killing [18,30,37,38,15].…”