Protective Effect of Nasal Colonisation with <i>∆cps/piaA</i> and <i>∆cps/proABC</i><i>Streptococcus pneumoniae</i> Strains against Recolonisation and Invasive Infection
Elisa Ramos-Sevillano,
Giuseppe Ercoli,
José Afonso Guerra-Assunção,
Philip Felgner,
Rafael Ramiro de Assis,
Rie Nakajima,
David Goldblatt,
Kevin Kweku Adjei Tetteh,
Robert Simon Heyderman,
Stephen Brian Gordon,
Daniela Mulari Ferreria,
Jeremy Stuart Brown
Affiliations
Elisa Ramos-Sevillano
Centre for Inflammation and Tissue Repair, UCL Respiratory, Division of Medicine, University College London, Rayne Institute, London WC1E 6JF, UK
Giuseppe Ercoli
Centre for Inflammation and Tissue Repair, UCL Respiratory, Division of Medicine, University College London, Rayne Institute, London WC1E 6JF, UK
José Afonso Guerra-Assunção
Great Ormond Street Institute of Child Health, University College London (UCL), London WC1N 1EH, UK
Philip Felgner
Vaccine Research and Development Center, Department of Physiology and Biophysics, University of California Irvine, Irvine, CA 92697-4560, USA
Rafael Ramiro de Assis
Vaccine Research and Development Center, Department of Physiology and Biophysics, University of California Irvine, Irvine, CA 92697-4560, USA
Rie Nakajima
Vaccine Research and Development Center, Department of Physiology and Biophysics, University of California Irvine, Irvine, CA 92697-4560, USA
David Goldblatt
Immunobiology Section, UCL Great Ormond Street Institute of Child Health, NIHR Biomedical Research Centre, London WC1N 1EH, UK
Kevin Kweku Adjei Tetteh
Faculty of Infectious and Tropical Diseases, London School of Tropical Medicine and Hygiene, London WC1E 7HT, UK
Robert Simon Heyderman
Research Department of Infection, Division of Infection and Immunity, University College London, Rayne Institute, London WC1E 6JF, UK
Stephen Brian Gordon
Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre 30096, Malawi
Daniela Mulari Ferreria
Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK
Jeremy Stuart Brown
Centre for Inflammation and Tissue Repair, UCL Respiratory, Division of Medicine, University College London, Rayne Institute, London WC1E 6JF, UK
Rationale: Nasopharyngeal administration of live virulence-attenuated Streptococcus pneumoniae strains is a potential novel preventative strategy. One target for creating reduced virulence S. pneumoniae strains is the capsule, but loss of the capsule reduces the duration of S. pneumoniae colonisation in mice which could impair protective efficacy against subsequent infection. Objectives: To assess protective efficacy of nasopharyngeal administration of unencapsulated S. pneumoniae strains in murine infection models. Methods: Strains containing cps locus deletions combined with the S. pneumoniae virulence factors psaA (reduces colonisation) or proABC (no effect on colonisation) were constructed and their virulence phenotypes and ability to prevent recolonisation or invasive infection assessed using mouse infection models. Serological responses to colonisation were compared between strains using ELISAs, immunoblots and 254 S. pneumoniae protein antigen array. Measurements and Main Results: The ∆cps/piaA and ∆cps/proABC strains were strongly attenuated in virulence in both invasive infection models and had a reduced ability to colonise the nasopharynx. ELISAs, immunoblots and protein arrays showed colonisation with either strain stimulated weaker serological responses than the wild type strain. Mice previously colonised with these strains were protected against septicaemic pneumonia but, unlike mice colonised with the wild type strain, not against S. pneumoniae recolonisation. Conclusions: Colonisation with the ∆cps/piaA and ∆cps/proABC strains prevented subsequent septicaemia, but in contrast, to published data for encapsulated double mutant strains they did not prevent recolonisation with S. pneumoniae. These data suggest targeting the cps locus is a less effective option for creating live attenuated strains that prevent S. pneumoniae infections.
