Activation of NLRP3 Inflammasome by Virus-Like Particles of Human Polyomaviruses in Macrophages

Abstract

Viral antigens can activate phagocytes, inducing inflammation, but the mechanisms are barely explored. The aim of this study is to investigate how viral oligomeric proteins of different structures induce inflammatory response in macrophages. Human THP-1 cell line was used to prepare macrophages that were treated with filamentous nucleocapsid-like particles (NLPs) of paramyxoviruses and spherical virus-like particles (VLPs) of human polyomaviruses. The effects of viral proteins on cell viability, pro-inflammatory cytokines’ production, and NLRP3 inflammasome activation were investigated. Filamentous NLPs did not induce inflammation while spherical VLPs mediated inflammatory response followed by NLRP3 inflammasome activation. Inhibitors of cathepsins and K+ efflux decreased IL-1β release and cell death, indicating a complex inflammasome activation process. A similar activation pattern was observed in primary human macrophages. Single-cell RNAseq analysis of THP-1 cells revealed several cell activation states different in inflammation-related genes. This study provides new insights into the interaction of viral proteins with immune cells and suggests that structural properties of oligomeric proteins may define cell activation pathways.

Race between virus and inflammasomes: inhibition or escape, intervention and therapy

“…For example, MCC950 is a direct inhibitor of NLRP3 protein. It was demonstrated in juvenile mice that after administration of MCC950 in 3 days after IAV infection, the activation of NLRP3 inflammasome was inhibited, which reduced IL-18 secretion into alveolar space and improved the survival of these mice ( Lučiūnaitė et al., 2022 ). Moreover, it was able to reduce lung injury in IAV-induced COPD rats, thereby improving survival time ( Ji et al., 2022 ).…”