title: The role of host and microbial factors in the pathogenesis of pneumococcal bacteraemia arising from a single bacterial cell bottleneck.
abstract: The pathogenesis of bacteraemia after challenge with one million pneumococci of three isogenic variants was investigated. Sequential analyses of blood samples indicated that most episodes of bacteraemia were monoclonal events providing compelling evidence for a single bacterial cell bottleneck at the origin of invasive disease. With respect to host determinants, results identified novel properties of splenic macrophages and a role for neutrophils in early clearance of pneumococci. Concerning microbial factors, whole genome sequencing provided genetic evidence for the clonal origin of the bacteraemia and identified SNPs in distinct sub-units of F0/F1 ATPase in the majority of the ex vivo isolates. When compared to parental organisms of the inoculum, ex-vivo pneumococci with mutant alleles of the F0/F1 ATPase had acquired the capacity to grow at low pH at the cost of the capacity to grow at high pH. Although founded by a single cell, the genotypes of pneumococci in septicaemic mice indicate strong selective pressure for fitness, emphasising the within-host complexity of the pathogenesis of invasive disease.
authors.affiliation: LAMMB, Department of Biotechnology, University of Siena, Siena, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Gerlini
authors.affiliation: LAMMB, Department of Biotechnology, University of Siena, Siena, Italy.
authors.forename: Leonarda
authors.initials: L
authors.lastname: Colomba
authors.affiliation: LAMMB, Department of Biotechnology, University of Siena, Siena, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Furi
authors.affiliation: LAMMB, Department of Biotechnology, University of Siena, Siena, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Braccini
authors.affiliation: LAMMB, Department of Biotechnology, University of Siena, Siena, Italy.
authors.forename: Ana Sousa
authors.initials: AS
authors.lastname: Manso
authors.affiliation: Department of Pathophysiology, Experimental Medicine and Public Health, University of Siena, Siena, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pammolli
authors.affiliation: Department of Mathematics, University of Leicester, Leicester, United Kingdom.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.affiliation: Centro NMR, University of Siena, Siena, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Vivi
authors.affiliation: Centro NMR, University of Siena, Siena, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Tassini
authors.affiliation: Department of Molecular Cell Biology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.affiliation: LAMMB, Department of Biotechnology, University of Siena, Siena, Italy; UOC Batteriologia, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Pozzi
authors.affiliation: LAMMB, Department of Biotechnology, University of Siena, Siena, Italy.
authors.forename: Susanna
authors.initials: S
authors.lastname: Ricci
authors.affiliation: Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Andrew
authors.affiliation: Department of Neurology, Ludwig-Maximilians University of Munich, München, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Koedel
authors.affiliation: Division of Medical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
authors.forename: E Richard
authors.initials: ER
authors.lastname: Moxon
authors.affiliation: LAMMB, Department of Biotechnology, University of Siena, Siena, Italy; UOC Batteriologia, Azienda Ospedaliera Universitaria Senese, Siena, Italy; Department of Genetics, University of Leicester, Leicester, United Kingdom.
authors.forename: Marco R
authors.initials: MR
authors.lastname: Oggioni
mesh_terms: D000818:Animals; D016470:Bacteremia / Q000235:genetics / Q000276:immunology / Q000382:microbiology*; D005260:Female; D005434:Flow Cytometry; D055786:Gene Knockout Techniques; D054884:Host-Pathogen Interactions / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D011008:Pneumococcal Infections / Q000235:genetics / Q000276:immunology / Q000382:microbiology*; D013296:Streptococcus pneumoniae / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D014774:Virulence