Pneumolysin as a potential therapeutic target in severe pneumococcal disease

- Pneumolysin (Ply) is being increasingly implicated in the pathogenesis of acute lung and cardiac injury.
- These harmful activities of Ply have been attributed to cytotoxic, pro-inflammatory and platelet-activating properties.
- Although challenging, therapeutic targeting of Ply is an attainable adjunctive strategy in severe pneumococcal disease.
- Currently, macrolides in particular appear to be the most effective Ply-neutralising agents.

SummaryAcute pulmonary and cardiac injury remain significant causes of morbidity and mortality in those afflicted with severe pneumococcal disease, with the risk for early mortality often persisting several years beyond clinical recovery. Although remaining to be firmly established in the clinical setting, a considerable body of evidence, mostly derived from murine models of experimental infection, has implicated the pneumococcal, cholesterol-binding, pore-forming toxin, pneumolysin (Ply), in the pathogenesis of lung and myocardial dysfunction. Topics covered in this review include the burden of pneumococcal disease, risk factors, virulence determinants of the pneumococcus, complications of severe disease, antibiotic and adjuvant therapies, as well as the structure of Ply and the role of the toxin in disease pathogenesis. Given the increasing recognition of the clinical potential of Ply-neutralisation strategies, the remaining sections of the review are focused on updates of the types, benefits and limitations of currently available therapies which may attenuate, directly and/or indirectly, the injurious actions of Ply. These include recently described experimental therapies such as various phytochemicals and lipids, and a second group of more conventional agents the members of which remain the subject of ongoing clinical evaluation. This latter group, which is covered more extensively, encompasses macrolides, statins, corticosteroids, and platelet-targeted therapies, particularly aspirin.