Medicina molecular y genética

Consecutive Rhinovirus Infection of Epithelial Cells Alters Chrono- Inflammatory Expression Network

Abstract

Weckmann M, Becker T, Pech M, Koch CE, Oster H and Kopp MV

Introduction: Asthma exacerbations are associated with viral upper respiratory tract infections, and rhinovirus (RV) is the major cause of these virus-associated exacerbation. Circadian clocks regulate physiological rhythms via transcriptional networks. These networks contain several feedback mechanisms inducing complex tissue specific patterns of gene activation and repression that help to maintain and regulate important biological processes. For example, the neutrophil inflammation of the lung is gated by epithelial circadian oscillators. We hypothesized that recurrent, human rhinovirus infection (HRVI) of in in vitro cultured cells alter the circadian-gated inflammatory networks and imprint a methylation pattern similar to the network found in asthmatic patients.

Results: We measured the methylation of clock and inflammatory genes in the BEAS2-B cell line after 1, 3 or 5 consecutive rhinovirus infections. Hierarchical clustering of methylation levels identified distinct clusters of numbers of infection (NOI: 1,3 and 5) for clock and inflammatory genes in BEAS2-B cells. Furthermore, a linear regression model of the methylation level was used to identify significantly increased or decreased loci (p<0.01). In non-infected cells, clear clusters of RNA expression of circadian clock genes CRY1, PER2, PER3, CLOCK were found to be negatively associated with interleukin 8 (IL-8) expression. After HRVI a partial reversal is observed and the expression of the CLOCK gene is positively correlated to IL-8 expression Similarly, in asthmatic patients, a strong positive correlation between CLOCK and IL-8 was found.

Conclusion: This study provides first insights in how repeated viral infections (e.g. HRVI exacerbations in asthma) may introduce persistent changes to circadian-gated inflammatory networks involved in governing neutrophil recruitment. This could offer novel diagnostic strategies to identify and define certain asthmatic endotypes and lead to novel therapeutic approaches based on circadian rhythm stabilization.