Collectively these experiments proposed that the norovirus VLPs were internalized by M? and processed for antigen presentation. or macrophages (M?) and na?ve 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 M? but not DCs, as indicated by significant changes in the expression of MHC-II, costimulatory factors and related cytokines in M?. Moreover, we found VLPs caused M? to polarize to the M1 type and release inflammatory cytokines, thereby inducing na?ve 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 PTC-028 a theoretical basis for both understanding responses to norovirus infection as well as opportunities for vaccine development. Keywords: norovirus, virus-like particles, macrophages, antigen presentation, phenotypic maturation, Th1 Introduction Norovirus (NoV) infections are a common cause of diarrhea outbreaks in humans and many animals. Presently, human-derived NoVs are one of the main pathogens involved in food-induced diarrhea, causing approximately 699 million infections (1C3) and 200,000 deaths worldwide each year (4). NoVs are extremely contagious, and even a few viral particles may cause infection (5). Epidemic episodes of NoV infection typically occur in semi-closed or closed environments, such as kindergartens, schools, nursing homes, hospitals, restaurants, cruise ships, or the military (2, 6). At present, NoVs are principally classified into seven major genotypes (GI-GIV) based on gene sequences of the RNA-dependent-RNA-polymerase (RdRp) and major capsid proteins (VP1) (7). Of these, GI, most GII, along with a small number of GIV-type NoV can infect humans and cause epidemic acute gastroenteritis (AGE). Other NOV genotypes can infect cattle, pigs (8), dogs (9), PTC-028 cats, sheep and rodents. The currently known GI and GII-type NoV include no less than 31 genotypes (10). Since 2002, most major global epidemics associated with NoV have involved GII.4 (10, 11). However, in the fourth quarter of 2014 and 2015, a GII.17 type of NoV emerged in some Asian countries to become the main cause of diarrheal disease outbreaks (12C14). This highlighted the potential of non-GII.4 genotypes to become causes of major epidemics. Notably, in the winter of 2016, the number of norovirus outbreaks in China increased significantly compared with the previous four years. Of the 56 outbreaks in 2016, 79% of the outbreaks were caused by GII.P16-GII.2 recombinant NoV (7). GII.P16-GII.2 is a Mouse monoclonal to GAPDH new type of Norovirus recombined by the RdRp gene of GII.P16 and the VP1 gene of GII.2 (15). Moreover, as shown by a recent study, the GII.P16-GII.2 recombinant NoV has the same replicability as the current PTC-028 pandemic GII.4 type, projecting the potential of GII.P16-GII.2 to cause new rounds of outbreaks and pandemic infections (15). GII.P16-GII.2 is extremely infectious to children (16). It can cause severe gastroenteritis and lead to adverse clinical outcomes. The results indicated that the first infection with GII.P16-GII.2 may cause a delay in virus clearance in most people (15). Antigen presenting cells (APC) refer to a type of immune cells that ingest and process antigens which are then presented as processed antigens to T and B lymphocytes. Both DC and macrophages function as antigen-presenting cells (APC), which act as messengers between PTC-028 the PTC-028 innate and adaptive responses (APC to T cells) (17). Antigen capture serves to induce APC activation, inducing the expression of surface MHC molecules, costimulatory molecules (including CD80, CD86, CD40) and several related cytokines (18), allowing APC cells to effectively present antigens to T cells for antigen delivery. Macrophages are mainly divided into M1-type and M2-type (19). Previous reports (19) indicate the main functions of M1 macrophages include the mediation of pro-inflammatory responses, Th1 immune responses, antigen presentation, killing pathogens and inhibiting tumor formation. On the other hand, the functions of M2 macrophages include participation in tissue remodeling/reconstruction, mediating Th2-type immune regulation and angiogenesis. Given the emerging significance of GII.P16-GII.2 recombinant NoV and its and potential to cause a pandemic, this study.
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