| dc.description.abstract | Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection and hospitalization in children below the age of two years. RSV acute respiratory infection during infancy strongly correlates with subsequent childhood recurrent wheezing and asthma. Gut and airway microbial communities, specifically members of the genus Lactobacillus, have been shown to protect from RSV disease severity and outcomes in infants and animal models. However, limited data are available to establish the mechanisms of Lactobacillus-mediated protection of early-life RSV disease outcomes. The cotton rat (genus Sigmodon) is the gold-standard animal model for respiratory viral diseases, especially RSV immuno-pathology.
Recently, I have comprehensively characterized the gut microbiome (16S and metagenomics) of two inbred cotton rat species, S. hispidus and S. fulviventer, to show distinct species-level differences in gut microbiome communities: S. hispidus has a strikingly higher abundance of Lactobacillus (~2.5 log2fold higher). Isolation of Lactobacillus from S. hispidus and gavage into Lactobacillus-deficient S. fulviventer revealed reduced lung histopathology upon RSV infection without affecting lung or nose viral titers. Based on these findings, I hypothesize that presence and abundance of Lactobacillus in gut is protective for severe RSV disease in cotton rats through systemic immunomodulation (gut-lung axis).
Studies employing gene expression analysis in cotton rats have been limited due to the lack of a sequenced genome. To this end, I generated a multi-tissue, de novo transcriptome reference for two species of cotton rats (S. fulviventer and S. hispidus) with nearly 120,000 gene annotations for each species. Using these transcriptome references, I examined gene changes in both the gut and lung upon Lactobacillus and RSV challenge to better understand these interactions. Treatment with oral Lactobacillus upregulated protective chemokines and lung integrity while downregulating inflammatory and proapoptotic factors.
To determine the more specific mechanisms of protection, I conducted Lactobacillus metabolite conditioning of RSV-infected epithelial cell lines using a previously described Lactobacillus-secreted protein p40 to reveal viral pathway interference, reduction of viral load, and protection against viral-mediated apoptosis. Further experimentation in animal models will improve our understanding the mechanisms of host-microbiome-mediated protection against severe RSV outcomes. | |
