• Claire M Smith, Sara Sandrini, Sumit Datta, Primrose Freestone, Sulman Shafeeq, Priya Radhakrishnan, Gwyneth Williams, Sarah M Glenn, Oscar P Kuipers, Robert A Hirst, Andrew J Easton, Peter W Andrew, and Christopher O'Callaghan.
• 1 Respiratory, Critical Care and Anaesthesia, University College London, Institute of Child Health, Great Ormond Street Hospital, London, United Kingdom.
• Am. J. Respir. Crit. Care Med. 2014 Jul 15; 190 (2): 196-207.

RationaleRespiratory syncytial virus (RSV) and Streptococcus pneumoniae are major respiratory pathogens. Coinfection with RSV and S. pneumoniae is associated with severe and often fatal pneumonia but the molecular basis for this remains unclear.ObjectivesTo determine if interaction between RSV and pneumococci enhances pneumococcal virulence.MethodsWe used confocal microscopy and Western blot to identify the receptors involved in direct binding of RSV and pneumococci, the effects of which were studied in both in vivo and in vitro models of infection. Human ciliated respiratory epithelial cell cultures were infected with RSV for 72 hours and then challenged with pneumococci. Pneumococci were collected after 2 hours exposure and changes in gene expression determined using quantitative real-time polymerase chain reaction.Measurements And Main ResultsFollowing incubation with RSV or purified G protein, pneumococci demonstrated a significant increase in the inflammatory response and bacterial adherence to human ciliated epithelial cultures and markedly increased virulence in a pneumonia model in mice. This was associated with extensive changes in the pneumococcal transcriptome and significant up-regulation in the expression of key pneumococcal virulence genes, including the gene for the pneumococcal toxin, pneumolysin. We show that mechanistically this is caused by RSV G glycoprotein binding penicillin binding protein 1a.ConclusionsThe direct interaction between a respiratory virus protein and the pneumococcus resulting in increased bacterial virulence and worsening disease outcome is a new paradigm in respiratory infection.

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