Respiratory tract microbiota: gatekeeper to respiratory health

Abstract

Respiratory tract infections (RTIs), such as pneumonia, are responsible for a large burden of disease, with the highest incidence and mortality in young children and elderly adults. Yearly, approximately 900,000 children die because of pneumonia globally, making up for ~15% of all deaths in children under the age of 5 years worldwide. Respiratory tract infections are also a major reason for (inappropriate) antibiotic prescriptions, which further underscores the relevance of RTIs. These infections have long been considered in isolation and viewed within the Koch’s one-host one-pathogen paradigm. However, the human body is colonized by vast numbers of specialised bacterial communities, conjointly referred to as the bacterial microbiome. The advent of next-generation sequencing techniques enabled us to characterise the entirety of the microbial community (microbiota) and its functional capacity (microbiome). Among others, the microbiome appears involved in steering immune development, setting an individual on a trajectory towards or away from disease. In addition, diverse resident bacterial communities provide us with ‘colonization resistance’, therewith protecting the human host from incoming or blooming pathogens. In this thesis, we study the role of the (upper) respiratory tract microbiota in health and in respiratory disease. In chapter 3, we characterise the healthy respiratory tract microbiota development in a cohort of healthy, unselected children over the first year of life. We demonstrate that microbiota changes within the first month of life are associated with long term susceptibility to respiratory infections. In chapter 4 and chapter 5 we study dynamics of nasal carriage of Streptococcus pneumoniae, in the context of the live-attenuated influenza vaccine. S. pneumoniae is a commensal with pathogenic potential, being able to cause severe lower RTIs, including pneumonia. Using an experimental human challenge model, we found that vaccination prior to pneumococcal inoculation increases pneumococcal carriage rate and density. Furthermore we found that the nasal microbiota present before pneumococcal challenge/vaccination determined pneumococcal receptiveness. We identified a new host phenotype of low-dense pneumococcal carriers, who seem to be able to control pneumococcal carriage well, resulting in the least microbial perturbations over time. In chapter 7 we studied the oropharyngeal microbiota in pneumonia and healthy adults and elderly, showing that particularly the absence of a group of harmless commensals is associated with pneumonia, more than the presence of pathogens. In chapter 8 we characterise the nasopharyngeal microbiota and host immune response in healthy children and children with a mild or severe infection with respiratory syncytial virus (RSV). Our data suggested that interactions between RSV and nasopharyngeal microbiota might modulate the host immune response, potentially impacting disease severity. Combined, these studies demonstrated the likely role of respiratory microbial communities in carriage of pathogens and susceptibility to RTIs. Furthermore, we also found differences in microbial communities during RTI that might drive inflammation and thereby severity of disease. Further studies are needed to further unravel cause-effect relationships in more detail, however we believe the studies presented in this thesis underline the importance of the respiratory tract microbiota as gatekeeper to respiratory health.