The impact of soil-transmitted helminth and respiratory viral infections on Streptococcus pneumoniae nasopharyngeal carriage

The burden of invasive disease caused by S. pneumoniae is greatest in resource-constrained, low-income regions of the world where soil-transmitted helminth (STH) and respiratory viral infections are also highly prevalent. Research has indicated an ability of STHs and respiratory viral infections to worsen pneumococcal disease, however our understanding of the effect of these co-infecting pathogens on the immunological mechanisms that govern pneumococcal colonisation, a prerequisite for invasive disease development, is limited. Hence, the potential of concurrent STH and respiratory virus infection to alter host immune responses crucial to the control of S. pneumoniae nasopharyngeal carriage was investigated, using a combination of mouse models, in vitro assays and human studies based in low-income settings. This thesis presents the first measure of pneumococcal and STH co-infection in a field-setting, providing baseline data on pneumococcal carriage prevalence and density in children with simultaneous helminth infection. Concurrent STH infection was associated with increased pneumococcal carriage density amongst a cohort of children in Ecuador, supporting observations, made in this thesis, of high-density colonisation in mice co-infected with the murine whipworm, T. muris. Increased colonisation densities, alongside high carriage prevalence rates, were also evident in individuals with concurrent respiratory virus infection in a second clinical study, conducted in Malawi. For both STH and respiratory viral co-infection, an enhanced inflammatory phenotype was linked to high-density colonisation, characterised by elevated pro-inflammatory cytokine production and muted tolerogenic responses. Together, data here suggest that the epidemiology of pneumococcal carriage and disease may be influenced by widespread co-infection with respiratory viruses and STHs, providing insight into the differences in pneumococcal dynamics between high and low-income countries. The ability of co-infection to disrupt the balance between tolerogenic and inflammatory responses that govern pneumococcal carriage was highlighted, opening exciting avenues for interventions that target the co-infecting pathogen and/or the consequential immune skew, to aid in the control and prevention of pneumococcal disease