Vitamin B ₆ Is Required for Full Motility and Virulence in Helicobacter pylori

Abstract

Despite recent advances in our understanding of how Helicobacter pylori causes disease, the factors that allow this pathogen to persist in the stomach have not yet been fully characterized. To identify new virulence factors in H. pylori, we generated low-infectivity variants of a mouse-colonizing H. pylori strain using the classical technique of in vitro attenuation. The resulting variants and their highly infectious progenitor bacteria were then analyzed by global gene expression profiling. The gene expression levels of five open reading frames (ORFs) were significantly reduced in low-infectivity variants, with the most significant changes observed for ORFs HP1583 and HP1582. These ORFs were annotated as encoding homologs of the Escherichia coli vitamin B6 biosynthesis enzymes PdxA and PdxJ. Functional complementation studies with E. coli confirmed H. pylori PdxA and PdxJ to be bona fide homologs of vitamin B6 biosynthesis enzymes. Importantly, H. pylori PdxA was required for optimal growth in vitro and was shown to be essential for chronic colonization in mice. In addition to having a well-known metabolic role, vitamin B6 is necessary for the synthesis of glycosylated flagella and for flagellum-based motility in H. pylori. Thus, for the first time, we identify vitamin B6 biosynthesis enzymes as novel virulence factors in bacteria. Interestingly, pdxA and pdxJ orthologs are present in a number of human pathogens, but not in mammalian cells. We therefore propose that PdxA/J enzymes may represent ideal candidates for therapeutic targets against bacterial pathogens.

The Vitamin B 6 Biosynthesis Pathway in Streptococcus pneumoniae Is Controlled by Pyridoxal 5′-Phosphate and the Transcription Factor PdxR and Has an Impact on Ear Infection

“…Recently, it has been shown that the vitamin B 6 biosynthesis is essential for virulence of M. tuberculosis (17) and H. pylori (16). However, in our mouse infection experiment, the ⌬pdxS mutant only showed a moderate attenuation and is not statistically significant.…”

“…However, these pathways have not been efficiently explored in pathogenic bacteria. In Helicobacter pylori, it was reported that the DXP-dependent vitamin B 6 biosynthesis pathway plays a role in optimal bacterial growth, chronic colonization of mice, glycosylated flagellum synthesis, and flagellum-based motility (16). The DXP-dependent vitamin B 6 biosynthesis pathway of Mycobacterium tuberculosis is essential for its survival and virulence (17).…”

Involvement of Vitamin B6Biosynthesis Pathways in the Insecticidal Activity of Photorhabdus luminescens

“…Two Gram-positive human-pathogenic bacteria, Mycobacterium tuberculosis and Streptococcus pneumoniae, are known to have a DXP-independent de novo vitamin B 6 pathway, which is required for growth in vitamin B 6 -free medium and host colonization in the mammalian model (31,32). Two Gram-negative pathogenic bacteria, Helicobacter pylori and Campylobacter jejuni, are known to have a DXP-dependent de novo B6 pathway, and the role of PLP as a cofactor for a virulence-related enzyme is partially understood (30,33). In H. pylori, PLP is a cofactor that aids PseC's aminotransferase activity.…”

“…PLP is known as a cofactor for more than 140 enzymes (21,22) and has been recently considered a virulence factor (30)(31)(32)(33). Two Gram-positive human-pathogenic bacteria, Mycobacterium tuberculosis and Streptococcus pneumoniae, are known to have a DXP-independent de novo vitamin B 6 pathway, which is required for growth in vitamin B 6 -free medium and host colonization in the mammalian model (31,32).…”

Helicobacter pylori Adaptation In Vivo in Response to a High-Salt Diet

“…The proteins exhibiting the greatest differences in abundance are listed in Table 1. Specifically, the two HSO strains (HSO123 and HSO1) produced higher levels of catalase (37), an iron-regulated outer membrane protein reported to bind heme and hemoglobin (FrpB1 [38,39]), an iron-dicitrate transport protein (FecA1 [40]), and a protein involved in vitamin B 6 biosynthesis (PdxA; 4-hydroxythreonine-4-phosphate dehydrogenase [41]) than the input and RSO strains. Concordant with the results obtained at the protein level, the katA, frpB1, fecA1, and pdxA transcript levels were significantly higher in HSO1 and HSO123 than in RSO241, RSO242, and the input strain (P Ͻ 0.05) (Fig.…”