title: The bacterial DNA repair protein Mfd confers resistance to the host nitrogen immune response.
abstract: Production of reactive nitrogen species (NO) is a key step in the immune response following infections. NO induces lesions to bacterial DNA, thus limiting bacterial growth within hosts. Using two pathogenic bacteria, Bacillus cereus and Shigella flexneri, we show that the DNA-repair protein Mfd (Mutation-Frequency-Decline) is required for bacterial resistance to the host-NO-response. In both species, a mutant deficient for mfd does not survive to NO, produced in vitro or by phagocytic cells. In vivo, the ∆mfd mutant is avirulent and unable to survive the NO-stress. Moreover, NO induces DNA-double-strand-breaks and point mutations in the Δmfd mutant. In overall, these observations demonstrate that NO damages bacterial DNA and that Mfd is required to maintain bacterial genomic integrity. This unexpected discovery reveals that Mfd, a typical housekeeping gene, turns out to be a true virulence factor allowing survival and growth of the pathogen in its host, due to its capacity to protect the bacterium against NO, a key molecule of the innate immune defense. As Mfd is widely conserved in the bacterial kingdom, these data highlight a mechanism that may be used by a large spectrum of bacteria to overcome the host immune response and especially the mutagenic properties of NO.
authors.affiliation: Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Guillemet
authors.affiliation: Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Leréec
authors.affiliation: Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France.
authors.forename: Seav-Ly
authors.initials: SL
authors.lastname: Tran
authors.affiliation: INRA, UMR 203, 11 Av J. Capelle, 69621 Villeurbanne, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Royer
authors.affiliation: Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Barbosa
authors.affiliation: INSERM U786, Institut Pasteur, 28 rue du Dr Roux, 75724 Paris Cedex 15, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Sansonetti
authors.affiliation: Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Lereclus
authors.affiliation: Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France.
authors.forename: Nalini
authors.initials: N
authors.lastname: Ramarao
mesh_terms: D000818:Animals; D001409:Bacillus cereus / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism*; D012831:Bombyx; D004249:DNA Damage; D004260:DNA Repair; D004269:DNA, Bacterial / Q000235:genetics; D004926:Escherichia coli / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D007113:Immunity, Innate; D016685:Mitomycin / Q000737:chemistry; D009000:Monocytes / Q000378:metabolism; D016296:Mutagenesis; D009154:Mutation; D009504:Neutrophils; D009584:Nitrogen; D010587:Phagocytosis; D010641:Phenotype; D026361:Reactive Nitrogen Species / Q000378:metabolism*; D012763:Shigella flexneri / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D037521:Virulence Factors / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D004269:DNA, Bacterial; D026361:Reactive Nitrogen Species; D014157:Transcription Factors; D037521:Virulence Factors; C072103:transcription repair coupling factor protein, Bacteria; D016685:Mitomycin; D009584:Nitrogen