title: Importance of bacterial replication and alveolar macrophage-independent clearance mechanisms during early lung infection with Streptococcus pneumoniae.
abstract: Although the importance of alveolar macrophages for host immunity during early Streptococcus pneumoniae lung infection is well established, the contribution and relative importance of other innate immunity mechanisms and of bacterial factors are less clear. We have used a murine model of S. pneumoniae early lung infection with wild-type, unencapsulated, and para-amino benzoic acid auxotroph mutant TIGR4 strains to assess the effects of inoculum size, bacterial replication, capsule, and alveolar macrophage-dependent and -independent clearance mechanisms on bacterial persistence within the lungs. Alveolar macrophage-dependent and -independent (calculated indirectly) clearance half-lives and bacterial replication doubling times were estimated using a mathematical model. In this model, after infection with a high-dose inoculum of encapsulated S. pneumoniae, alveolar macrophage-independent clearance mechanisms were dominant, with a clearance half-life of 24 min compared to 135 min for alveolar macrophage-dependent clearance. In addition, after a high-dose inoculum, successful lung infection required rapid bacterial replication, with an estimated S. pneumoniae doubling time of 16 min. The capsule had wide effects on early lung clearance mechanisms, with reduced half-lives of 14 min for alveolar macrophage-independent and 31 min for alveolar macrophage-dependent clearance of unencapsulated bacteria. In contrast, with a lower-dose inoculum, the bacterial doubling time increased to 56 min and the S. pneumoniae alveolar macrophage-dependent clearance half-life improved to 42 min and was largely unaffected by the capsule. These data demonstrate the large effects of bacterial factors (inoculum size, the capsule, and rapid replication) and alveolar macrophage-independent clearance mechanisms during early lung infection with S. pneumoniae.
authors.affiliation: Centre for Inflammation and Tissue Repair, Department of Medicine, University College Medical School, Rayne Institute, London, United Kingdom.
authors.forename: Emilie
authors.initials: E
authors.lastname: Camberlein
authors.affiliation: Infectious Diseases & Microbiology Unit, UCL Institute for Child Health, London, United Kingdom.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Cohen
authors.affiliation: Centre for Inflammation and Tissue Repair, Department of Medicine, University College Medical School, Rayne Institute, London, United Kingdom.
authors.forename: Ricardo
authors.initials: R
authors.lastname: José
authors.affiliation: Centre for Inflammation and Tissue Repair, Department of Medicine, University College Medical School, Rayne Institute, London, United Kingdom.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Hyams
authors.affiliation: Immunobiology Unit, UCL Institute of Child Health, London, United Kingdom.
authors.forename: Robin
authors.initials: R
authors.lastname: Callard
authors.affiliation: Centre for Inflammation and Tissue Repair, Department of Medicine, University College Medical School, Rayne Institute, London, United Kingdom.
authors.forename: Suneeta
authors.initials: S
authors.lastname: Chimalapati
authors.affiliation: Centro Nacional de Microbiologia, Instituto de Salud Carlos III, and CIBER de Enfermedades Respiratorias, Madrid, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: Yuste
authors.affiliation: Centre for Inflammation and Tissue Repair, Department of Medicine, University College Medical School, Rayne Institute, London, United Kingdom.
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Edwards
authors.affiliation: Centre for Inflammation and Tissue Repair, Department of Medicine, University College Medical School, Rayne Institute, London, United Kingdom.
authors.forename: Helina
authors.initials: H
authors.lastname: Marshall
authors.affiliation: Vrije Universiteit, VUMC, Department of Molecular Cell Biology, Faculty of Medicine, Amsterdam, The Netherlands.
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.affiliation: Division of Infection and Immunity, University College London, London, United Kingdom.
authors.forename: Mahdad
authors.initials: M
authors.lastname: Noursadeghi
authors.affiliation: Centre for Inflammation and Tissue Repair, Department of Medicine, University College Medical School, Rayne Institute, London, United Kingdom jeremy.brown@ucl.ac.uk.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Brown
mesh_terms: D010129:4-Aminobenzoic Acid / Q000378:metabolism; D000818:Animals; D016667:Bacterial Capsules / Q000276:immunology; D058491:Bacterial Load / Q000276:immunology; D005260:Female; D006207:Half-Life; D007113:Immunity, Innate; D008168:Lung / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015233:Models, Statistical; D009154:Mutation; D010587:Phagocytosis; D011018:Pneumonia, Pneumococcal / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D012720:Severity of Illness Index; D013296:Streptococcus pneumoniae / Q000235:genetics / Q000254:growth & development / Q000276:immunology*; D013997:Time Factors
chemical_list: D010129:4-Aminobenzoic Acid