Bacterial Protein Toll-Like-Receptor Agonists: A Novel Perspective on Vaccine Adjuvants

Abstract

Adjuvants have been used in vaccines for over a century, however, the search for safe and effective vaccine adjuvants continues. In recent decades toll-like-receptor (TLR) agonists have been investigated as potential vaccine adjuvants. In this regard, the majority of the currently investigated TLR agonists are non-protein microbial components such as lipopolysaccharides, oligonucleotides, and lipopeptides. On the other hand, a growing number of studies reveal that TLR signaling and immune responses can be activated by numerous bacterial proteins. However, their potential roles as adjuvants have been somewhat overlooked. Herein, we discuss several such bacterial proteins which exhibit adjuvant properties, including the activation of TLR signaling, antigen presenting cell maturation, pro-inflammatory cytokine production and adaptive immune response. The protein nature of these TLR agonists presents several unique features not shared by non-protein TLR agonists. These properties include the amenability for modifying the structure and function as necessary for optimal immunogenicity and minimal toxicity. Protein adjuvants can be genetically fused to protein antigens which ensure the co-delivery of adjuvant-antigen not only into the same cell but also in the same endocytic cargo, leading to more effective activation of innate and adaptive immune response.

Keywords: TLR; TLR agonist; adjuvant; antigen presenting cells; cell-mediated immunity; vaccine.

Figure 1

Mechanism of action of adjuvants. Following administration adjuvants induce a local (A) pro-inflammatory niche which is characterized by (B) influx of leukocytes, (C) pro-inflammatory cytokines, (D) activation of APCs, and (E) migration of APCs to draining lymph nodes.

Figure 2

Immunological consequences of interaction between antigen-TLR agonist fusion protein and antigen presenting cells. (A) Antigens physically linked to TLR agonists are endocytosed along with the related receptor, the TLR dependent signaling in endosomes results in rapid maturation of phagosome, antigen processing, MHCII invariant chain processing, loading of processed antigens to MHCII and display of MHCII-peptide. (B) TLR signaling initiated by binding of antigen-TLR agonist results in maturation of APCs and surface expression of co-stimulatory molecules (CD80/86). (C) TLR signaling elicits cytokine secretion. (D) The APCs displaying co-stimulatory markers and MHCII-peptide activate naïve T cells. (E) The synergistic effects of A, B C and D cumulate in the generation of polarized T cells (Th1, Th2, or Th17) depending on the kind of cytokine secreted by APCs in response to respective TLR ligands.