Defining STING Interactions that are Required for Rhinovirus Replication

Rhinoviruses (RVs) are responsible for the majority of upper respiratory tract infections in humans yearly. Recently, several reports, including one from our lab, have identified stimulator of interferon genes (STING) as a pro-viral factor during RV replication. Still, the STING-mediated interactions and associated function(s) that are required for robust RV replication remain unknown. Current data suggest that STING traffics to membranous structures called replication organelles (ROs) during RV infection. RO formation is orchestrated by virus- mediated manipulation of host proteins, cellular membranes, and lipid metabolism pathways and the resulting lipid composition of ROs is both unique and critical for efficient RV replication. Elevated phosphatidylinositol 4- phosphate (PI4P) levels, for example, are a hallmark of RV ROs and PI4P synthesis at sites of viral replication requires RV to recruit PI4-kinase beta (PI4Kβ). Notably, recent work investigating STING function has described an interaction between STING and PI4Kβ through Armadillo Like Helical Domain Containing 3 (ARMH3). These data suggest RV may utilize STING to nucleate a PI4Kβ-containing complex and/or link key host factors to promote PI4P enrichment at the site of replication. Additional new data has revealed STING as a regulator of lipid metabolism and have shown STING to promote lipid peroxidation and ferroptosis. This is important since lipid peroxidation has significant impacts on viral replication and is pro-viral for other enteroviruses. Taken together, we propose a model whereby STING translocation to ROs 1) promotes STING–ARMH3 interaction, thereby facilitating PI4P enrichment at the site of RV replication and 2) alters STING interaction with fatty acid synthesis pathways, tipping fatty acid synthesis towards the production of polyunsaturated fatty acids and driving increases in lipid peroxidation which further support efficient viral replication. Thus, the aims of this grant will test the hypothesis that STING is required during RV infection to establish the proper lipid environment for viral replication through multiple pathways and further capture novel STING partners during RV infection through unbiased screening. Successful completion of these aims will further define the mechanism underlying the pro- viral role of STING during RV infection and provide novel insights into evolutionarily conserved functions of STING which maintain homeostasis in mammalian cells. Such advances will facilitate the design of therapeutics against rhinovirus and multiple degenerative diseases in which the cGAS-STING pathway is involved. Project Number: 1R21AI188804-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Margaret Scull | Institution: UNIV OF MARYLAND, COLLEGE PARK, COLLEGE PARK, MD | Award Amount: $423,803 | Activity Code: R21 | Study Section: Molecular and Cellular Biology of Virus Infection Study Section[MCV] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R21AI18880401