title: High-resolution transcriptomic analysis of the adaptive response of Staphylococcus aureus during acute and chronic phases of osteomyelitis.
abstract: Osteomyelitis is a difficult-to-eradicate bone infection typically caused by Staphylococcus aureus. In this study, we investigated the in vivo transcriptional adaptation of S. aureus during bone infection. To this end, we determined the transcriptome of S. aureus during the acute (day 7) and chronic (day 28) phases of experimental murine osteomyelitis using RNA sequencing (RNA-Seq). We identified a total of 180 genes significantly more highly expressed by S. aureus during acute or chronic in vivo infection than under in vitro growth conditions. These genes encoded proteins involved in gluconeogenesis, proteolysis of host proteins, iron acquisition, evasion of host immune defenses, and stress responses. At the regulatory level, sarA and -R and saeR and -S as well as the small RNA RsaC were predominantly expressed by S. aureus during in vivo infection. Only nine genes, including the genes encoding the arginine deiminase (ADI) pathway and those involved in the stringent response, were significantly more highly expressed by S. aureus during the chronic than the acute stage of infection. Analysis by quantitative reverse transcription-PCR (qRT-PCR) of a subset of these in vivo-expressed genes in clinical specimens yielded the same results as those observed in the murine system. Collectively, our results show that during acute osteomyelitis, S. aureus induced the transcription of genes that mediate metabolic adaptation, immune evasion, and replication. During the chronic phase, however, S. aureus switched its transcriptional response from a proliferative to a persistence mode, probably driven by the severe deficiency in nutrient supplies. Interfering with the survival strategies of S. aureus during chronic infection could lead to more effective treatments.
  
  
  OBJECTIVE
  The key to the survival success of pathogens during an infection is their capacity to rapidly adjust to the host environment and to evade the host defenses. Understanding how a pathogen redirects and fine-tunes its gene expression in response to the challenges of infection is central to the development of more efficient anti-infective therapies. Osteomyelitis is a debilitating infection of the bone predominantly caused by S. aureus. In this study, we evaluated the transcriptional response of S. aureus during bone infection. Our results indicate that S. aureus reprograms its genetic repertoire during the acute phase of infection to adapt to nutrient availability and to replicate within the host. During the chronic phase, S. aureus upregulates a survival genetic program activated in response to nutrient starvation. Thus, we have uncovered key survival pathways of S. aureus during acute and chronic osteomyelitis that can be used as therapeutic targets.
authors.affiliation: Infection Immunology Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Szafranska
authors.affiliation: Microbial Interactions and Processes Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Andrew P A
authors.initials: AP
authors.lastname: Oxley
authors.affiliation: Microbial Interactions and Processes Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Diego
authors.initials: D
authors.lastname: Chaves-Moreno
authors.affiliation: Infection Immunology Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Horst
authors.affiliation: Department of Trauma, Hand, and Reconstructive Surgery, University Hospital of Münster, Münster, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Roßlenbroich
authors.affiliation: Institute of Medical Microbiology, University Hospital of Münster, Münster, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Peters
authors.affiliation: Infection Immunology Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Goldmann
authors.affiliation: Central Facility for Microscopy, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Rohde
authors.affiliation: Medical Microbiology and Infection Prevention, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Bhanu
authors.initials: B
authors.lastname: Sinha
authors.affiliation: Microbial Interactions and Processes Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Dietmar H
authors.initials: DH
authors.lastname: Pieper
authors.affiliation: Institute of Medical Microbiology, Jena University Hospital, Jena, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Löffler
authors.affiliation: Microbial Interactions and Processes Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Ruy
authors.initials: R
authors.lastname: Jauregui
authors.affiliation: Microbial Interactions and Processes Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Wos-Oxley
authors.affiliation: Infection Immunology Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany eva.medina@helmholtz-hzi.de.
authors.forename: Eva
authors.initials: E
authors.lastname: Medina
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D004195:Disease Models, Animal; D015870:Gene Expression; D020869:Gene Expression Profiling; D051379:Mice; D010019:Osteomyelitis / Q000382:microbiology*; D060888:Real-Time Polymerase Chain Reaction; D013211:Staphylococcus aureus / Q000235:genetics / Q000502:physiology*; D013312:Stress, Physiological