SARS-CoV-2 viral remnants and implications for inflammation and post-acute infection sequelae

Abstract

At present, we do not understand precisely how the SARS-CoV-2 coronavirus induces a spectrum of immune responses in different infected hosts, including severe inflammation in some, or how post-acute infection sequelae come about. In this review, we consider a conceptual framework whereby the virus itself is a reservoir of peptide motifs with pro-inflammatory activity. These motifs can potentially be liberated by highly variable proteolytic processing by the host. We focus on the ability of viral peptide motifs that can mimic innate immune peptides (more commonly known as ‘antimicrobial peptides’ (AMPs)). AMPs (and their ‘xenoAMP’ mimics) are not themselves pathogen-associated molecular patterns (PAMPs) that activate innate immunity via recognition by host pattern recognition receptors (PRRs) but can strongly amplify PRR activation via promoting multivalent PAMP presentation. An important mechanism in the host’s immune amplification machinery and is implicated in a range of autoimmune conditions, including lupus and rheumatoid arthritis, which are among the sequelae of COVID-19. We review experiments that show AMPs and SARS-CoV-2-derived xenoAMP can assemble with PAMPs such as dsRNA into pro-inflammatory complexes, resulting in cooperative, multivalent immune recognition by PRRs and grossly amplified inflammatory responses, a phenomenon generally not observed in harmless coronavirus homologs. We also review the persistence of viral remnants from other viral infections and their association with inflammatory sequelae long after the infection has been cleared.