Sweeten PAMPs: Role of Sugar Complexed PAMPs in Innate Immunity and Vaccine Biology

Abstract

Innate sensors play a critical role in the early innate immune responses to invading pathogens through sensing of diverse biochemical signatures also known as pathogen associated molecular patterns (PAMPs). These biochemical signatures primarily consist of a major family of biomolecules such as proteins, lipids, nitrogen bases, and sugar and its complexes, which are distinct from host molecules and exclusively expressed in pathogens and essential to their survival. The family of sensors known as pattern recognition receptors (PRRs) are germ-line encoded, evolutionarily conserved molecules, and consist of Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), NOD-like receptors (NLRs), C-type lectin-like receptors (CLRs), and DNA sensors. Sensing of PAMP by PRR initiates the cascade of signaling leading to the activation of transcription factors, such as NF-κB and interferon regulatory factors (IRFs), resulting in a variety of cellular responses, including the production of interferons (IFNs) and pro-inflammatory cytokines. In this review, we discuss sensing of different types of glycosylated PAMPs such as β-glucan (a polymeric sugar) or lipopolysaccharides, nucleic acid, and so on (sugar complex PAMPs) by different families of sensors, its role in pathogenesis, and its application in development of potential vaccine and vaccine adjuvants.

Keywords: disease pathogenesis; innate immunity; innate sensors; sugar associated PAMPs; vaccinology.

Figure 1

Sensing of SCPs through membrane associated PRRs, TLRs, and CLRs. In macrophages and dendritic cells plasma membrane localized TLRs (TLR1, TLR2, TLR4, and TLR6) and endosomal localized TLRs (TLR3, TLR7, TLR8, and TLR9) and TLR13 sense various SCPs as homo or heterodimer (shown in Table 1). TLR recruits MyD88, TRIFs, TIRAP, and TRAM adaptors for induction of inflammatory cytokines and type-I IFNs through activation of NF-κB and IRFs (IRF3 and IRF7) via IKKα/β and TBK1/IKK1, respectively. Dectin-1, Dectin-2, Mincle, and MCL are representative CLRs of Dectin-1 and Dectin-2 clusters. Sensing of various SCPs by Dectin-1 and Dectin-2 (shown in Table 1) recruits, Syk adaptor which further recruits PLCγ and activate cascade of signaling for induction of inflammatory cytokines via NF-κB and MAP kinases.

Figure 2

Sensing of SCPs through cytosolic PRRs, RLRs, NLRs, and cytosolic DNA sensors. RLRs family member, RIG-I and MDA5 sense viral dsRNA (shown in Table 2), recruits an adaptor IPS-1 for induction of type-I IFNs and inflammatory cytokines. STING, a molecule plays a pivotal role in sensing of RNA. Several DNA sensors induce inflammatory cytokine and type-I IFNs in STING dependent and independent manner. NLRs family member, NOD1, NOD2, and inflammasome (mainly NLRP1 and NLRP3 and AIM2) induces inflammatory cytokine. NOD1 and NOD2 sense various SCPs (shown in Table 2) recruit an adaptor RIP2 and CARD9 for induction of inflammatory cytokines. Activation of inflammasome complex after stimulation with appropriate SCPs (shown in Table 2) process an inactive, proIL-1 family cytokine to active IL-1 family cytokine.

Figure 3

Role of SCPs in vaccine biology. Immunization of host (mice or human) with vaccine or vaccine adjuvant formulation PTC (PAMPs therapeutic complex) activates innate immune pathways (TLRs, CLRs, RLRs, NLRs, and DNA sensors), induce secretion of inflammatory cytokines and type-I IFNs. These cytokines further activate adaptive immune components through B and T lymphocytes. Adaptive immune memory cells protects host from infection.