Abstract
Salmonella Typhi, the causative agent of typhoid fever, is a monophyletic, human-restricted bacterium that exhibits limited phenotypic variation. S. Typhi from Indonesia are a notable exception, with circulating strains expressing diverse flagella antigens including Hj, Hd and Hz66. Hypothesizing that S. Typhi flagella plays a key role during infection, we constructed an S. Typhi fliC mutant and otherwise isogenic S. Typhi strains expressing the Hj, Hd, Hz66 flagella antigens. Phenotyping revealed differences in flagellum structure, strain motility and immunogenicity, but not in the ability of flagellated isolates to induce TLR5 activity. Invasion assays using epithelial and macrophage cell lines revealed differences in the ability of these S. Typhi derivatives to invade cells or induce cellular restructuring in the form of ruffles. Notably, the Hj variant induced substantial ruffles that were not fully dependent on the GTPases that contribute to this process. These data highlight important differences in the phenotypic properties of S. Typhi flagella variation and how they impact on the pathogenesis of S. Typhi.
Highlights
Salmonella Typhi, the causative agent of typhoid fever, is a monophyletic, human-restricted bacterium that exhibits limited phenotypic variation
The disease caused by the bacterium Salmonella enterica serovar Typhi
Flagellin is the monomer of the flagella filament, the dominant protein of a complex super-molecular structure, the flagellum, which is essential for bacterial motility and chemotaxis[8,9]
Summary
Construction and primary characterization of isogenic S. Typhi derivatives demonstrated different phenotypic qualities we hypothesized that the organisms expressing these flagella antigens might stimulate different responses from the immune system during natural infection To test this hypothesis, IgG against Hd, Hj and Hz66 flagellin was measured in a group of typhoid patients. S. Typhi expressing Hd and Hj flagellin induced highly similar transcription patterns in host cells, with higher numbers of differentially expressed genes, compared to the Hz66 or DfliC derivatives (Table 2). The pathway and gene ontologies of the differential expressed genes groups were determined using InnateDB and could be divided into three main groups with corresponding profiles (Figure 5b) These three main groups were; i) the up-regulation of genes involved in inflammation in cells infected with flagellated bac-. Typhi Hj derivative reproducibly demonstrated a significantly higher capability for invasion (0.42% 6 0.15) (Figure 6a)
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