Susceptibility to pneumococcal colonization: identifying critical pneumococcal and mucosal markers

Abstract

Introduction: Pneumococcal colonization is the pre-requisite for pneumococcal diseases such as pneumonia, otitis media and meningitis. Thus, its control is key. Pneumococcal conjugate vaccines protect against invasive pneumococcal diseases - in part through its effects on pneumococcal colonization prevalence - but present with limited serotype coverage. With the global pneumococcal burden not relenting, the need for more effective intervention strategies, as well as the possibility to test their effect on colonization is high. The experimental human pneumococcal carriage (EHPC) model – while currently limited in serotype coverage - allows the study of pneumococcal colonization control in its natural host. Project aims: Here I aimed to 1.) identify microbial characteristics that associate with experimental human pneumococcal colonization efficiency thereby establishing a tool to pre-select pneumococcal strain candidates for EHPC studies prior to human challenge; 2.) identify mucosal markers of host susceptibility to human pneumococcal colonization and 3.) determine the effect of nasal mucins on human pneumococcal colonization. Main findings: In a retrospective association study superior experimental colonization rates of pneumococcal strain SPN6B/BHN418 associated with high pneumococcal chain length in liquid culture. Implementation of the quantitative assessment of chain length as a tool for selecting pneumococcal strain candidates successfully highlighted a serotype 3 strain, which, when used for human challenge, achieved experimental colonization rates equal to those observed with SPN6B/BHN418. An integral part of the host mucosal barrier, mucins were associated with increased pneumococcal growth and survival in vitro. In vivo baseline MUC5AC levels in nasal wash positively correlated with pneumococcal load following challenge in a subset of volunteers. Nasal MUC5AC also correlated with the formation of pneumococcal aggregates in nasal fluid, highlighting the ambiguous role of mucins in human pneumococcal colonization. Implications: Pre-selection of successful pneumococcal strains for new challenge models is needed to save costs and reduce research waste, while allowing more rapid expansion of the EHPC model. Identification of factors and mechanisms influencing pneumococcal colonization of the human host further provides the basis for the improvement of current vaccines and intervention strategies against the pneumococcus