Human rhinovirus 16 induces an ICAM-1-PKR-ATF2 axis to modulate macrophage functions

Human rhinovirus (HRV) infections are the leading cause of disease exacerbations in individuals with chronic pulmonary diseases, primarily due to impaired macrophage functions, resulting in defective bacterial elimination. We previously demonstrated that HRV16 impairs macrophages' functions in an ARL5b-dependent manner. In permissive cells, ARL5b acted as an HRV16 restriction factor and was repressed. Here, we delve into the dual regulation of ARL5b by HRV16 in both cell types. We analyzed the effect of HRV16 on primary human macrophages using neutralizing antibodies, specific inhibitors, siRNA, and chromatin immune precipitation. Our study reveals that, while the virus does not replicate in macrophages, it induces interferon and pro-inflammatory responses. We identify the ICAM-1-PKR-ATF2 signaling axis as crucial for ARL5b induction in macrophages, whereas only ICAM-1 plays a role in ARL5b repression in permissive cells. Furthermore, HRV16 triggers epigenetic reprogramming in both cell types at the ARL5b promoter. In macrophages, epigenetic changes are ATF2 dependent. In conclusion, our findings highlight previously unknown signaling pathways activated by HRV16 in macrophages. Targeting these pathways could offer novel strategies to improve outcomes for individuals with respiratory conditions.

Human rhinovirus (HRV) infections are the leading cause of disease exacerbations in individuals with chronic pulmonary conditions and are frequently associated with bacterial superinfections due to defective bacterial elimination by macrophages. We previously identified ARL5b-induction by HRV16 to be responsible for the impairment of bacteria elimination. In contrast, in permissive cells, ARL5b is repressed and acts as a restriction factor for HRV16. Here, we investigated the dual regulation of ARL5b by HRV16 in these cells. Our study reveals that the ICAM-1-PKR-ATF2 signaling axis is crucial for ARL5b induction in macrophages. In permissive cells, only ICAM-1 plays a role in ARL5b repression. Moreover, HRV16 triggered epigenetic reprogramming in macrophages. ARL5b promoter was repressed in an ATF2-dependent manner. Collectively, our findings reveal previously unknown signaling pathways activated by HRV16 in macrophages. Targeting these pathways provides novel strategies to target ARL5b expression specifically in macrophages and improve outcomes for individuals with respiratory pathologies.