Kadioglu, ArasAllehyani, Noor2025-11-292025https://hdl.handle.net/20.500.14154/77156Respiratory syncytial virus (RSV) remains a leading cause of severe lower respiratory tract infections in infants, with co-infection by Streptococcus pneumoniae often contributing to worse clinical outcomes. This thesis investigates the cellular and microbial dynamics underlying RSV and RSV-pneumococcal co-infection using a combination of in vitro assays, murine models, and infant clinical samples. Through in vivo and ex vivo experiments, RSV infection was shown to impair alveolar macrophage (AMQ) functionality, particularly reducing phagocytic capacity and promoting M2-like polarisation. Co-infection with S. pneumoniae further amplified inflammation and bacterial dissemination. However, treatment with Bacillus subtilis spores significantly enhanced the recruitment of tissue-resident AMQs, improved bacterial clearance, and reduced RSV viral load, suggesting a promising immunomodulatory intervention. In the clinical arm of the study, 16S rRNA sequencing of nasopharyngeal samples from UK infants revealed that RSV infection, both alone and in co-infection with rhinovirus (RV), significantly increased the relative abundance of pathogenic Proteobacteria, particularly Moraxella. These shifts were accompanied by heightened pro-inflammatory cytokine responses, including IL-6, IL-8, and TNF-α, and elevated levels of anti-inflammatory cytokines such as IL-10 and TGF-β in the RSV and RSV+RV groups Together, the data highlight how RSV alters innate immune responses and reshapes the airway microbiota, favouring pathobiont expansion and increased inflammation. The use of B. subtilis spores represents a novel strategy to bolster macrophage function and limit RSV-associated complications. These findings underscore the 5 importance of host-microbe interactions in determining infection outcomes and offer insights into microbiota-targeted therapies.309enRespiratory syncytial virus (RSV) • Streptococcus pneumoniae • Co-infection • Lower respiratory tract infections (infants) • Alveolar macrophages (AMQs) • Phagocytic dysfunction • M2-like polarisation • Inflammation • Bacterial dissemination • Bacillus subtilis spores • Immunomodulatory therapy • Murine models / in vitro / ex vivo • 16S rRNA sequencing • Nasopharyngeal microbiota • Proteobacteria / Moraxella • Pro-inflammatory cytokines (IL-6IL-8TNF-α) • Anti-inflammatory cytokines (IL-10TGF-β) • Airway microbiota dysbiosis • Host–microbe interactions • Pathobiont expansion • RSV viral load reduction • Infant clinical samples • Microbiota-targeted therapiesThesis