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Rationale: Respiratory syncytial virus (RSV) can cause severe lower respiratory illness (LRI) in early life. Using data from the Tucson Children's Respiratory Study (TCRS), we previously reported that only smokers who had RSV-LRI in early life were more likely to have asthma as adults than non-smokers with no history of RSV-LRI, whereas those who either smoked or had RSV-LRI in early life were not at increased risk for asthma 1 . Whether this significant interactive effect of early-life RSV-LRI and smoking is associated with changes in the airway microbiome is not known. Methods: Unselected healthy newborns were recruited for TCRS between 1980-1984. RSV-LRIs were identified by either immunofluorescence or culture in the first three years of life. Sputum was collected at ages 32 or 36. DNA was extracted for 16S rRNA gene amplicon sequencing. Exact sequence variants (ESVs), representative of species/subspecies, were identified using Dada2, and beta diversity (unweighted UniFrac) and alpha diversity (observed ESVs) was analyzed in QIIME2. Weighted gene co-expression network analysis (WGCNA) in R was used to identify microbial communities consisting of co-occurring ESVs. Smoking history was assessed prospectively by questionnaire. Results: Smoking was found to alter the pattern of sputum microbial communities, as indicated by a significant difference in alpha and beta diversity between never and current smokers (p fdr <0.05). Among never-smokers, those who had RSV-LRI (n=11) did not differ in alpha or beta diversity from those who did not have RSV-LRI (n=22). However, among current smokers, those who had RSV-LRI (n=4) differed significantly in beta diversity (p fdr <0.05) compared to those who did not have RSV-LRI (n=10), and the current smokers who had RSV-LRI had the overall highest species richness (observed ESVs) (Figure). WGCNA analysis further revealed distinct microbial consortia associated with the different groups, and current smokers who had RSV-LRI were the most associated with the consortium containing Streptococcus, Haemophilus, Granulicatella, and Gemmellaceae. Conclusions: Current smoking alters the sputum microbiome and alterations in microbial communities are even greater for those smokers with a history of early life RSV-LRI, including increased richness of microbial species. These findings suggest interactive effects of RSV-LRI and smoking in determining sputum microbial community diversity. 1

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