title: Fur is the master regulator of the extraintestinal pathogenic Escherichia coli response to serum.
abstract: Drug-resistant extraintestinal pathogenic Escherichia coli (ExPEC) strains are the major cause of colisepticemia (colibacillosis), a condition that has become an increasing public health problem in recent years. ExPEC strains are characterized by high resistance to serum, which is otherwise highly toxic to most bacteria. To understand how these bacteria survive and grow in serum, we performed system-wide analyses of their response to serum, making a clear distinction between the responses to nutritional immunity and innate immunity. Thus, mild heat inactivation of serum destroys the immune complement and abolishes the bactericidal effect of serum (inactive serum), making it possible to examine nutritional immunity. We used a combination of deep RNA sequencing and proteomics in order to characterize ExPEC genes whose expression is affected by the nutritional stress of serum and by the immune complement. The major change in gene expression induced by serum-active and inactive-involved metabolic genes. In particular, the serum metabolic response is coordinated by three transcriptional regulators, Fur, BasR, and CysB. Fur alone was responsible for more than 80% of the serum-induced transcriptional response. Consistent with its role as a major serum response regulator, deletion of Fur renders the bacteria completely serum sensitive. These results highlight the role of metabolic adaptation in colisepticemia and virulence.
  
  
  OBJECTIVE
  Drug-resistant extraintestinal pathogenic Escherichia coli (ExPEC) strains have emerged as major pathogens, especially in community- and hospital-acquired infections. These bacteria cause a large spectrum of syndromes, the most serious of which is septicemia, a condition with a high mortality rate. These bacterial strains are characterized by high resistance to serum, otherwise highly toxic to most bacteria. To understand the basis of this resistance, we carried out system-wide analyses of the response of ExPEC strains to serum by using proteomics and deep RNA sequencing. The major changes in gene expression induced by exposure to serum involved metabolic genes, not necessarily implicated in relation to virulence. One metabolic regulator-Fur-involved in iron metabolism was responsible for more than 80% of the serum-induced response, and its deletion renders the bacteria completely serum sensitive. These results highlight the role of metabolic adaptation in virulence.
authors.affiliation: Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Sagi
authors.initials: S
authors.lastname: Huja
authors.affiliation: Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Yaara
authors.initials: Y
authors.lastname: Oren
authors.affiliation: Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Dvora
authors.initials: D
authors.lastname: Biran
authors.affiliation: Institute for Microbiology, Ernst-Moritz-Arndt-Universität, Greifswald, Germany.
authors.forename: Susann
authors.initials: S
authors.lastname: Meyer
authors.affiliation: Institute of Hygiene, Westfälische Wilhelms-Universität, Münster, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Dobrindt
authors.affiliation: Institute for Microbiology, Ernst-Moritz-Arndt-Universität, Greifswald, Germany.
authors.forename: Joerg
authors.initials: J
authors.lastname: Bernhard
authors.affiliation: Institute for Microbiology, Ernst-Moritz-Arndt-Universität, Greifswald, Germany.
authors.forename: Doerte
authors.initials: D
authors.lastname: Becher
authors.affiliation: Institute for Microbiology, Ernst-Moritz-Arndt-Universität, Greifswald, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hecker
authors.affiliation: Department of Molecular Genetics Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Rotem
authors.initials: R
authors.lastname: Sorek
authors.affiliation: eliora@post.tau.ac.il.
authors.forename: Eliora Z
authors.initials: EZ
authors.lastname: Ron
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics* / Q000502:physiology*; D001770:Blood Bactericidal Activity; D003165:Complement System Proteins / Q000276:immunology; D004926:Escherichia coli / Q000235:genetics / Q000254:growth & development* / Q000472:pathogenicity*; D029968:Escherichia coli Proteins / Q000235:genetics*; D020869:Gene Expression Profiling; D015964:Gene Expression Regulation, Bacterial; D016680:Genome, Bacterial; D006801:Humans; D008297:Male; D040901:Proteomics; D012097:Repressor Proteins / Q000235:genetics* / Q000502:physiology*; D018805:Sepsis / Q000382:microbiology; D017423:Sequence Analysis, RNA; D044967:Serum / Q000382:microbiology*
chemical_list: D001426:Bacterial Proteins; C062886:CysB protein, Bacteria; D029968:Escherichia coli Proteins; D012097:Repressor Proteins; C068477:ferric uptake regulating proteins, bacterial; D003165:Complement System Proteins