| Summary: | © 2014 Dr. Mary John Otitis media (OM) is one of the commonest infections of infants and young children, being second only to the common cold. Acute OM (AOM) is also the commonest illness of children for which medical attention is sought in developed countries. Indigenous populations such as Inuits, Australian Aborigines and American Indians are regarded to be high-risk populations. Large numbers of pathogenic bacteria which colonise the nasopharynx of Indigenous children from early life are thought to be the main reason for this high incidence. Following an episode of AOM, Indigenous children often suffer from recurrent acute OM, which may progress to chronic otorrhoea and chronic OM, whereas in non-indigenous children, OM usually resolves without specific treatment. In low-risk populations OM is usually amenable to medical or surgical treatment, whereas in high-risk population these interventions are not as effective. Streptococcus pneumoniae, one of the three main bacterial causes of OM, colonises the nasopharynx prior to disease development. Immunisation with pneumococcal conjugate vaccines is effective against invasive infections, but has a limited impact on OM. Serotype replacement after immunisation and poorly effective treatments also contribute to the high prevalence of OM in high-risk populations. Novel strategies aimed at decreasing the load of OM pathogens and/or colonising the nasopharynx with beneficial bacteria may reduce the prevalence of OM, and are worth investigating. Probiotics are live micro-organisms that offer health benefits by modulating the microbial community and enhancing host immunity. The beneficial effects of probiotics in some gastrointestinal tract illness are well documented. By contrast, limited data are available on the effect of probiotics on upper respiratory tract infections. Probiotics isolated from the upper respiratory tract are likely to be most effective against upper respiratory tract pathogens. In this context, more specific and enduring health benefits are postulated to occur by using a novel approach called “bacterial therapy” which uses probiotic strains of species that are indigenous to the target tissue. A strain of Streptococcus. salivarius, isolated from the oral cavity of a healthy child is commercially available as BLIS K12. BLIS is an acronym for bacteriocin-like inhibitory substance and is an early candidate for bacterial therapy. The inhibitory activity of this probiotic against β-haemolytic streptococci is attributed to lantibiotics encoded by a megaplasmid carried by the K12 strain. Preliminary studies have shown that following oral intake, BLIS can persistently colonise the upper respiratory tract, and inhibit pathogenic bacteria. BLIS also has an excellent safety record. The promising benefits of S. salivarius probiotic warrant further investigation, however, as the data available are limited and inconclusive. For this thesis, I explored the potential of S. salivarius to inhibit pneumococcal colonisation and OM using in vitro assays and a mouse model of OM. I also evaluated the capacity of BLIS K12 to colonise the upper respiratory tract of healthy adult volunteers. Colonisation of the respiratory epithelium by S. pneumoniae is the first step in the pathogenesis of OM. Accordingly, I determined the ability of S. salivarius K12 to inhibit pneumococcal adherence to human epithelial CCL-23 cells at varying doses and times of administration in vitro. These studies revealed dose- and time-dependent inhibition of pneumococcal adherence by S. salivarius K12. In view of these findings, I studied the effects of S. salivarius K12 on nasopharyngeal colonisation by pneumococci and the development of OM in a mouse model. Repeated intranasal doses of S. salivarius K12 were administered to infant C57BL/6 and BALB/c mice in the presence or absence of influenza A virus to assess the short- and long-term effects of S. salivarius on pneumococcal colonisation and OM. These studies showed that S. salivarius caused only a short-lived reduction in pneumococcal colonisation, with no sustained effect on long-term pneumococcal colonisation. S. salivarius also did not reduce the number of pneumococci in the ears of mice that developed OM. Because S. salivarius was originally isolated from a human, I hypothesised that this probiotic may not be able to colonise mice sufficiently well to interfere with S. pneumoniae. Accordingly, I evaluated the capacity of S. salivarius to colonise the upper respiratory tract of adult volunteers. This pilot study showed that S. salivarius colonised the oral cavity of adults for up to two weeks following seven days of oral intake of BLIS K12. The effect of probiotic consumption on salivary IgA and IgG in these volunteers was inconclusive. Nevertheless, this pilot study provides useful information on how to design a randomised, double-blind clinical trial to study the effect of S. salivarius on OM.
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