Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections and hospital visits during infancy and childhood. Although risk factors for RSV infection have been identified, the role of microbial species in the respiratory tract is only partially known. We aimed to understand the impact of interactions between the nasal microbiome and host transcriptome on the severity and clinical outcomes of RSV infection. We used 16 S rRNA sequencing to characterize the nasal microbiome of infants with RSV infection. We used RNA sequencing to interrogate the transcriptome of CD4+ T cells obtained from the same set of infants. After dimension reduction through principal component (PC) analysis, we performed an integrative analysis to identify significant co-variation between microbial clade and gene expression PCs. We then employed LIONESS (Linear Interpolation to Obtain Network Estimates for Single Samples) to estimate the clade-gene association patterns for each infant. Our network-based integrative analysis identified several clade-gene associations significantly related to the severity of RSV infection. The microbial taxa with the highest loadings in the implicated clade PCs included Moraxella, Corynebacterium, Streptococcus, Haemophilus influenzae, and Staphylococcus. Interestingly, many of the genes with the highest loadings in the implicated gene PCs are encoded in mitochondrial DNA, while others are involved in the host immune response. This study on microbiome-transcriptome interactions provides insights into how the host immune system mounts a response against RSV and specific infectious agents in nasal microbiota.

Author ContributionsEach author has met the Pediatric Research authorship requirements. CSA, EEW, and TJM conceptualized the study. CSA, TJM, CC, QW, EEW, JAM, YR, and GP designed the experiments. TJM, GP, and RM developed the cohort, and collected the specimens. CSA, KD, TJM, CC, JM, YR, and SB generated, analyzed and interpreted the data. CSA, CC, JAM, GP EEW and TJM wrote and/or revised the manuscript.• We showed that RSV demonstrated preferential infection of CX3CR1 positive pediatric epithelial cells• Blocking CX3CR1/RSV interaction significantly decreased productive viral infection in vitro• We found that CX3CR1 transcript are often expressed in both the upper (60%) and lower airways (36%) of pediatric subjects • CX3CR1 tissue localization and intracellular transcript in donor quality pediatric lung specimens, demonstrating an apical RSV receptor on pediatric airways for the first time.• These data demonstrate CX3CR1 is both present in the airways of pediatric subjects where it may serve as a receptor for RSV infection, and plays a mechanistic role in mediating viral infection of pediatric airway epithelial cells in vitro.. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. was not certified by peer review)

Although the retinoic X receptor (RXR) forms heterodimers with many members of the estrogen receptor subfamily, the interaction between RXR and the members of the glucocorticoid receptor subfamily remains unclear. Here we show that the RXR can form a heterodimer with the androgen receptor (AR) under in vitro and in vivo conditions. Functional analyses further demonstrated that the AR, in the presence or absence of androgen, can function as a repressor to suppress RXR target genes, thereby preventing the RXR binding to the RXR DNA response element. In contrast, RXR can function as a repressor to suppress AR target genes in the presence of 9-cis-retinoic acid, but unliganded RXR can function as a weak coactivator to moderately enhance AR transactivation. Together, these results not only reveal a unique interaction between members of the two nuclear receptor subfamilies, but also represent the first evidence showing a nuclear receptor (RXR) may function as either a repressor or a coactivator based on the ligand binding status.