GII.P16-GII.2 Recombinant Norovirus VLPs Polarize Macrophages Into the M1 Phenotype for Th1 Immune Responses

Abstract

Norovirus (NoV) is a zoonotic virus that causes diarrhea in humans and animals. Outbreaks in nosocomial settings occur annually worldwide, endangering public health and causing serious social and economic burdens. The latter quarter of 2016 witnessed the emergence of the GII.P16-GII.2 recombinant norovirus throughout Asia. This genotype exhibits strong infectivity and replication characteristics, proposing its potential to initiate a pandemic. There is no vaccine against GII.P16-GII.2 recombinant norovirus, so it is necessary to design a preventive vaccine. In this study, GII.P16-GII.2 type norovirus virus-like particles (VLPs) were constructed using the baculovirus expression system and used to conduct immunizations in mice. After immunization of mice, mice were induced to produce memory T cells and specific antibodies, indicating that the VLPs induced specific cellular and humoral immune responses. Further experiments were then initiated to understand the underlying mechanisms involved in antigen presentation. Towards this, we established co-cultures between dendritic cells (DCs) or macrophages (Mø) and naïve CD4+T cells and simulated the antigen presentation process by incubation with VLPs. Thereafter, we detected changes in cell surface molecules, cytokines and related proteins. The results indicated that VLPs effectively promoted the phenotypic maturation of Mø but not DCs, as indicated by significant changes in the expression of MHC-II, costimulatory factors and related cytokines in Mø. Moreover, we found VLPs caused Mø to polarize to the M1 type and release inflammatory cytokines, thereby inducing naïve CD4+ T cells to perform Th1 immune responses. Therefore, this study reveals the mechanism of antigen presentation involving GII.P16-GII.2 recombinant norovirus VLPs, providing a theoretical basis for both understanding responses to norovirus infection as well as opportunities for vaccine development.

6-Valent Virus-Like Particle-Based Vaccine Induced Potent and Sustained Immunity Against Noroviruses in Mice

“…Previous studies have demonstrated that VLPs effectively promoted the phenotypic maturation of macrophages, which present VLP antigens to naïve CD4 + T cells and induce the differentiation of Th0 cells toward Th1 and Th2 phenotypes ( 52 ). Accordingly, Hexa-VLPs elicited mixed Th1/Th2 responses signified by high-level IFN-γ, TNF-α, IL-2 and IL-4 positive T-cell activation.…”

IGSF6 is a prognostic biomarker associated with the anti-tumor activity of macrophages in lung adenocarcinoma

“…The GSEA enrichment analysis showed that gene sets grouped according to IGSF6 expression were mainly enriched in cytokine-receptor interaction and intercellular interaction. It has been well established that antigen peptide-MHCII complex presented by macrophages and DCs is essential for the activation of Th1 cells [28][29][30][31]. Previous studies have also proposed that IGSF6 may be closely related to antigen uptake, or the recirculation of DCs [13].…”

IGSF6 is a biomarker associated with anti-tumor immune response in lung adenocarcinoma

“…The GSEA enrichment analysis showed that gene sets grouped according to IGSF6 expression were mainly enriched in cytokine-receptor interaction and intercellular interaction. It has been well established that antigen peptide-MHCII complex presented by macrophages and DCs is essential for the activation of Th1 cells [27][28][29][30]. Previous studies have also proposed that IGSF6 may be closely related to antigen uptake, or the recirculation of DCs [13].…”