Cellular and Transcriptional Signature of the Nasal Mucosa is Associated with Susceptibility to Pneumococcal Carriage in Older Adults

Streptococcus pneumoniae colonization in the upper respiratory tract is linked to pneumococcal disease development, predominantly affecting the very young and older adults. As the global population ages and comorbidities increase, there is a heightened concern about this infection. We investigated the immunological responses of older adults to pneumococcal controlled human infection by analysing the cellular composition and gene expression in the nasal mucosa. Our comparative analysis with younger adults revealed distinct gene expression patterns in older individuals susceptible to colonization, highlighted by neutrophil activation and elevated levels of CXCL9 and CXCL10. Unlike younger adults challenged with pneumococcus, older adults did not show recruitment of monocytes into the nasal mucosa following nasal colonization. These findings suggest age-associated cellular changes, in particular enhanced mucosal inflammation, that may predispose older adults to pneumococcal colonization. If similar changes are observed in the lung of susceptible older adults, these may explain the increased risk of pneumococcal disease in vulnerable populations. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by the Melinda Gates Foundation (grant OPP1117728); the UK Medical Research Council (grant MR/M011569/1). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approval was provided by the East Liverpool National Health Service Research and Ethics Committee (reference numbers 15/NW/0146 and 14/NW/1460) and Human Tissue Authority licensing number 12548. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Raw RNA sequencing data have been deposited in the Gene Expression Omnibus repository. All other underlying data are provided in the manuscript.