Abstract

We show that Yersinia enterocolitica strain Ye9 (bio-serotype 2/O:9) utilizes heme-containing molecules as an iron source. The Ye9 genome contains two multigenic clusters, hemPRSTUV-1 and hemPRST-2, encoding putative heme receptors HemR1 and HemR2, that share 62% amino acid identity. Expression of these proteins in an Escherichia coli mutant defective in heme biosynthesis allowed this strain to use hemin and hemoglobin as a source of porphyrin. The hemPRSTUV-1 and hemPRST-2 clusters are organized as operons, expressed from the phem−1 and weaker phem−2 promoters, respectively. Expression of both operons is negatively regulated by iron and the iron-responsive transcriptional repressor Fur. In addition, OmpR, the response regulator of two component system (TCSs) EnvZ/OmpR, represses transcription of both operons through interaction with binding sequences overlapping the −35 region of their promoters. Western blot analysis of the level of HemR1 in ompR, fur, and ompRfur mutants, showed an additive effect of these mutations, indicating that OmpR may regulate HemR expression independently of Fur. However, the effect of OmpR on the activity of the phem−1 promoter and on HemR1 production was observed in both iron-depleted and iron-replete conditions, i.e., when Fur represses the iron-regulated promoter. In addition, a hairpin RNA thermometer, composed of four uracil residues (FourU) that pair with the ribosome-binding site in the 5′-untranslated region (5′-UTR) of hemR1 was predicted by in silico analysis. However, thermoregulated expression of HemR1 could not be demonstrated. Taken together, these data suggest that Fur and OmpR control iron/heme acquisition via a complex mechanism based on negative regulation of hemR1 and hemR2 at the transcriptional level. This interplay could fine-tune the level of heme receptor proteins to allow Y. enterocolitica to fulfill its iron/heme requirements without over-accumulation, which might be important for pathogenic growth within human hosts.

Highlights

  • Yersinia enterocolitica, a member of the genus Yersinia in the family Enterobacteriaceae is a human enteropathogen which causes yersiniosis, i.e., gut-associated diseases such as enteritis, diarrhea, and mesenterial lymphadenitis (Bottone, 1997)

  • In contrast to more highly pathogenic Y. enterocolitica strains from bioserotype 1B/O:8, it lacks the high-pathogenicity island (HPI), a chromosomal cluster of iron-regulated genes involved in the biosynthesis of siderophore yersiniabactin (Ybt) and the uptake of Fe-Ybt into cells (Pelludat et al, 1998; Carniel, 2001)

  • Studies on the role of OmpR in pathogenic Yersinia strains have provided evidence that this response regulator might be involved in the adaptation of yersiniae to diverse environmental conditions, which allows the bacteria to grow in distinct niches within and outside the host body (Brzostek et al, 2003, 2007; Raczkowska et al, 2011a,b, 2015; Brzóstkowska et al, 2012; Skorek et al, 2013)

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Summary

Introduction

A member of the genus Yersinia in the family Enterobacteriaceae is a human enteropathogen which causes yersiniosis, i.e., gut-associated diseases such as enteritis, diarrhea, and mesenterial lymphadenitis (Bottone, 1997). Multiple virulence factors encoded by chromosomal and plasmid pYV-located genes are involved in Y. enterocolitica virulence (Cornelis, 2002). Iron-acquisition systems are considered important pathogenicity determinants. The concentration of iron in the environment is critical for the control of bacterial metabolism. Iron limitation in the host can abolish bacterial growth, whereas a high intracellular iron concentration may damage bacterial cells due to the formation of harmful reactive oxygen species (ROS). The transport, storage, and metabolism of iron have to be tightly controlled to maintain iron homeostasis (Hantke, 2001)

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