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 a HRV16 restriction factor and was repressed. Here, we delve into the dual regulation of ARL5b by HRV16 in both permissive cells (HeLa OHIO) and macrophages.

We analysed the effect of HRV16 on primary human macrophages using neutralising 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 signalling axis as crucial for ARL5b induction in macrophages, whereas only ICAM-1 plays a role in ARL5b repression in permissive cells HeLa OHIO. 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 signalling pathways activated by HRV16 in macrophages. Targeting these pathways could offer novel strategies to improve outcomes for individuals with respiratory conditions.