The human lung immune responses to nasopharyngeal pneumococcal colonisation in healthy adults

Abstract

Pneumococcal pneumonia burden remains high globally, affecting the youngest, the oldest and immunocompromised individuals worldwide. Colonisation of the human nasopharynx with S. pneumoniae is a pre-requisite for the development of pneumococcal disease and the primary reservoir for transmission. Paradoxically, it is also the main source of naturally acquired immunity. Currently, there is limited knowledge on how nasopharyngeal pneumococcal colonisation impacts on the lung immune responses in humans. Experimental human pneumococcal colonisation offers a safe way to study the dynamics between a known start-point colonisation episode and the lung immune responses. The data presented in this thesis show that colonisation of the nasopharynx with S. pneumoniae is an immunising event for the human lung, affecting both the innate and adaptive arm of immunity. Alveolar macrophage activation and function were altered post colonisation, leading to increased opsonophagocytic capacity that persisted for up to three months post the challenge. The overall skewed CD4+ Th-1 responses observed in the lung indicate that CD4+ T cells may prime alveolar macrophage through IFN-γ secretion. In vitro stimulation of lung lymphocytes with pneumococcus suggest that TCR-γδ T cells can stand as an additional source of IFN-γ in vivo. As described before, pneumococcal colonisation seeded the human lung with cognate, IL-17 secreting, CD4+ T cells- the only observed memory population amongst lung T cells. Antibody levels against the capsule of the challenge strain were also elevated post colonisation. Pneumococcal cells found in the lung days to weeks after clearance of nasal colonisation suggest that they may be the stimulus for the observed enhanced lung immunity. Collectively, the data presented here support the use of respiratory tract as route for effective pneumococcal vaccination. On the other hand, they emphasize that heavily colonised individuals with defective alveolar macrophage function or elderly due to lack of colonisation are at increased risk to develop pneumonia