Human rhinovirus elicits differential cytokine response and signal transduction pathways in human macrophages as a function of viral receptor stimulation (609.2)

Major‐ and minor‐group rhinoviruses enter their host by binding to the cell surface molecules ICAM‐1 and LDL‐R, respectively, which are present on both macrophages and epithelial cells. Although epithelial cells are the primary site of productive HRV infection, previous studies have implicated macrophages in establishing the cytokine dysregulation that occurs during rhinovirus‐induced asthma exacerbations. Upon closer examination in human primary macrophages, differential signaling pathway activation was observed between major‐ and minor‐group rhinovirus upon initial HRV binding, indicating a discordant receptor‐dependent response to these rhinovirus types. Differential phosphorylation of kinases (p38, JNK, ERK5) and transcription factors (ATF‐2, CREB, CEBP‐beta) was observed between the major‐ and minor‐ group HRV treatments. Furthermore, major‐ and minor‐ group HRV elicited differential production of the asthma‐relevant cytokines CCL20, CCL2, and IL‐10. This is the first report of genetically similar viruses eliciting dissimilar cytokine release, transcription factor phosphorylation, and MAPK activation from macrophages. These results suggest that receptor dependence plays a role in establishing the inflammatory microenvironment initiated in part by monocytic‐lineage cells in the human airway upon exposure to rhinovirus. Grant Funding Source : Supported by the McNair Program, NIH R15 AI065505‐01A1,NSF 0521112, Excellence in Science Fund