Regulation of MHC II Trafficking and Expression by Host and Viral Factors
Abstract
Antigen presentation by major histocompatibility complex class II (MHC II) to the adaptive immune system is crucial for mounting sterilizing immune responses. This central role has made antigen presentation a target for antagonism by many pathogens. Notably, infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) decrease MHC II expression in several immune cells. The mechanisms responsible for this suppression are unknown but involves either redirecting MHC II molecules away from the cell surface or inhibiting MHC II expression. To understand how pathogens manipulate intracellular MHC II trafficking, we first investigated the role of the Golgi trafficking regulator, ERC1, in this pathway, which we have previously confirmed is necessary for phagosome maturation. Immunofluorescence microscopy demonstrated that ERC1 facilitates the recruitment of MHC II to phagosomes, thereby enabling antigen loading and presentation. Interestingly, SARS-CoV-2 non-structural protein 5 (NSP5) interacts with histone deacetylase 2 (HDAC2)—a regulator of MHC II transcription—suggesting that SARS-CoV-2 may antagonize antigen presentation through epigenetic reprogramming. We hypothesize that SARS-CoV-2 NSP5 downregulates MHC II expression via interactions with HDAC2. RT-qPCR and dual luciferase analyses demonstrated that NSP5 expression was sufficient to downregulate MHC II in primary human dendritic cells and RAW 264.7 macrophages. HDAC2 knockdown alleviated this suppression, indicating that NSP5 utilizes host histone deacetylation machinery to antagonize MHC II transcription. Unexpectedly, point mutations that inactivate the catalytic site of NSP5 failed to revert this phenotype, suggesting that the proteolytic ability of NSP5 is not required for this suppression. This research may identify an important mechanism used by SARS-CoV-2 to evade adaptive immune responses and may indicate a potential use of HDAC2 inhibitors as therapeutics against coronavirus disease 19 (COVID-19).