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University of Liverpool Repository, 2022

DOI: 10.17638/03060836

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Effect of Respiratory Syncytial Virus infection on Streptococcus pneumoniae colonisation and invasive disease

Journal article published in 2022 by K. Shadia
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

Streptococcus pneumoniae (the pneumococcus) and Respiratory Syncytial Virus (RSV) are two major pathogens commonly found to coexist in respiratory secretions in patients with acute upper respiratory tract infections. Though there is increasing evidence of synergistic interplay between these pathobionts, the exact mechanisms remain obscure. The aim of my study was to decipher whether and how RSV viral co-infection alters pneumococcal metabolism and host immunity, and how, altogether, it affects the colonisation and invasive properties of the pneumococcus. To this end, I exploited in vitro respiratory epithelial cell culture and in vivo mouse coinfection models as well as global proteomic analysis. In all in vivo and in vitro models, pneumococcal infection or colonisation was carried out prior to RSV superinfection. Through my murine models, I made the striking observation that upon pneumococcal and viral co-infection, bacterial density was significantly enhanced in the nasopharynx and pneumococci were more prone to disseminate to the lower respiratory tract. Nasopharyngeal carriage was maintained as a result of the combined effect of defective clearance of pneumococci by macrophages and enhanced T regulatory cell response. Upon viral RSV co-infection in a pneumococcal pneumonia mouse model, no immune impairment was observed, though a higher number of viable bacteria were measured in the lungs of co-infected animals. These animals also presented heightened weight loss and delayed recovery compared to mono-infected animals and showed significant differences in pro-inflammatory cytokine levels consistent with their respective infection profile. Using an in vitro transepithelial electrical resistance (TEER) model I also demonstrated that, during RSV coinfection, pneumococcal transmigration through the epithelial barrier occurs at a significantly lower rate than single bacterial infection, in the absence of any variations in epithelial integrity. These observations were supported by my proteomic data showing that RSV-pneumococcal coinfection drives significant changes in both host and bacterial proteomic expression. Significant changes observed in the protein abundance of host interferon signalling pathway, epithelial intermediate filaments and proinflammatory cytokine Interleukin-1β. Similarly, significant variations were noted in the abundance of pneumococcal proteins involved in growth, survival and virulence. My results shed light on the complex interaction between pneumococci, RSV and host and will contribute towards the development of novel preventive and therapeutic strategies against bacterial-viral co-infection.