Interaction Between Virus-Like Particles (VLPs) and Pattern Recognition Receptors (PRRs) From Dendritic Cells (DCs): Toward Better Engineering of VLPs

Abstract

Virus-like particles (VLPs) have been shown to be strong activators of dendritic cells (DCs). DCs are the most potent antigen presenting cells (APCs) and their activation prompts the priming of immunity mediators based on B and T cells. The first step for the activation of DCs is the binding of VLPs to pattern recognition receptors (PRRs) on the surface of DCs, followed by VLP internalization. Like wild-type viruses, VLPs use specific PRRs from the DC; however, these recognition interactions between VLPs and PRRs from DCs have not been thoroughly reviewed. In this review, we focused on the interaction between proteins that form VLPs and PRRs from DCs. Several proteins that form VLP contain glycosylations that allow the direct interaction with PRRs sensing carbohydrates, prompting DC maturation and leading to the development of strong adaptive immune responses. We also discussed how the knowledge of the molecular interaction between VLPs and PRRs from DCs can lead to the smart design of VLPs, whether based on the fusion of foreign epitopes or their chemical conjugation, as well as other modifications that have been shown to induce a stronger adaptive immune response and protection against infectious pathogens of importance in human and veterinary medicine. Finally, we address the use of VLPs as tools against cancer and allergic diseases.

Keywords: allergy; cancer; epitopes; personalized medicine; translational medicine; tropical viral diseases; viruses.

Figure 1

Production of virus-like particles (VLPs) in baculovirus system. Baculovirus system is one of the most used for the production of VLPs. The design of VLPs is based on the expression of viral proteins that self-assemble by using genetically modified baculoviruses. These proteins are produced during the infection of insect cells with the recombinant baculoviruses. Baculovirus infection induce the expression of VLP proteins, VLPs are formed by means of self-assembly and VLPs together with baculoviruses leave the cell through lysis or budding. Conventional (left) and chimeric (right) VLPs can be produced for several uses: vaccine against pathogens in the case of conventional VLPs; and vaccines against cancer or allergy in the case of chimeric vaccines.

Figure 2

Schematic representation of the interaction between pattern recognition receptors (PRRs) from dendritic cells (DCs) and VLPs. VLPs are recognized by PRRs from DCs (CLRs, TLRs, and FCγR). After this, VLPs are taken up by receptor-mediated endocytosis. VLPs are processed for the presentation of their epitopes through cross-presentation or MHCII. For cross-presentation, VLPs reach the proteasome, are degraded into the cytosol, and the short peptides derived from VLPs are transported to the endoplasmic reticulum by TAP (transporter associated with antigen presentation). MHCI-epitope complexes are moved to the cell surface from DCs to stimulate CD8⁺ T cells which induce lysis of cancer cells or cells infected by intracellular pathogens. The other pathway for antigen presentation is through MHCII molecules. In this case, VLPs are processed into short peptides by lysosomal proteases. In the meantime, the variant chain (li) is processed and loaded into MHCII molecules (class II associated li derived peptides, CLIPs) until their exchange by VLP epitopes. Later, the MCHII-epitope complexes are moved to the cell surface from DCs to stimulate CD4⁺ T cells which help B cells to produce antibodies or to CD8⁺ T cells to enhance their cytotoxicity. Additionally, two signals are required for full activation of adaptive immune system cells: costimulatory molecules (such as CD80) and cytokines (such as IL-12 for CD8⁺ T cells and Th1 cells; and finally, IL-10 and IL-13 for Th2 cells).