Bacterial flagellin-a potent immunomodulatory agent

Abstract

Flagellin is a subunit protein of the flagellum, a whip-like appendage that enables bacterial motility. Traditionally, flagellin was viewed as a virulence factor that contributes to the adhesion and invasion of host cells, but now it has emerged as a potent immune activator, shaping both the innate and adaptive arms of immunity during microbial infections. In this review, we summarize our understanding of bacterial flagellin and host immune system interactions and the role flagellin as an adjuvant, anti-tumor and radioprotective agent, and we address important areas of future research interests.

Figure 1

Signal transduction by flagellin in mammalian cells. Immune cells respond to extracellular monomeric flagellin through either TLR5 homodimer or heterodimer complexes, resulting in the transcription of a variety of genes that are important for the proper stimulation of immune cells. Signaling through TLR5 occurs through a MyD88-dependent adapter molecule that passes the signal to the MAPK and IkB cascades via IRAK, TRAF6 and TAK1. The MAPK and IkB cascades result in the induction of transcription factors AP-1 and NF-kB, respectively. These two transcription factors induce a variety of genes involved in innate and adaptive immunity. Signaling through TLR5/TLR4 is MyD88-independent and occurs via the IRF3 pathway, which results in the production of IFN-β. Subsequently, IFN-β induces iNOS gene transcription through the activation of STAT1, which culminates in the production of NO. However, when intracellular flagellin is introduced into the host cell cytoplasm via the type III secretory system by some bacteria, it is detected by NLRC4, which culminates in the secretion of IL-1 β via active caspase-1. AP-1, Activator protein-1; GRO, growth-related oncogene; hBD, human beta defensins; IRF3, interferon response factor 3; IRAK, IL-1 receptor associated kinase; LRR, leucine-rich repeats; MAPK, mitogen-activated protein kinase; MCP, monocyte chemoattractant protein; MIP, macrophage inflammatory protein; MyD88, myeloid differentiation factor 88; NBD, nucleotide-binding domain; NF-κB, nuclear factor ‘kappa-light-chain-enhancer’ of activated B cells; PYR, pyrin domain; TAK1, transforming growth factor-beta-activated kinase 1; TBK1. TANK-binding-kinase-1; TLR, Toll-like receptor; TRAF6, TNF receptor associated factor 6; TRIF, TIR domain containing adapter inducing interferon-β STAT1, signal transducer and activator of transcription 1.

Figure 2

Signal transduction by flagellin in plant cells. Plant cells also possess receptors similar to TLR5 called flagellin sensing receptors (FLS2). FLS2 interact with the linear motif of flagellin in the N terminus (shown by arrow), which results in the rapid induction of a phosphorylation cascade of MAP kinases. MAPKs, in turn, activate the transcription factor WRKY22/29, which induces the transcription of genes providing resistance against fungal and bacterial infections. Due to differences in the homology of LLRs in TLR5 and FLS2, the flagellin-interacting motifs are different in these species.

Figure 3

Flagellin interactions with different kinds of immune and non-immune cells. Flagellin directly activates a number of immune and non-immune cells, including T, B, DCs, NK and non-lymphoid cells (macrophages, epithelial, fibroblasts, stromal cells and neutrophils), through TLR5. The cumulative effect of this activation is the augmentation of immune responses through the generation of more potent antibodies and a Th1 response. Moreover, the interaction of flagellin with TLR5 culminates in the production of chemokines from a number of lymphoid and non-lymphoid cells, which results in the generalized recruitment of T and B cells to LNs, which maximizes the chances of an encounter with their cognate antigen and subsequent elicitation of potent immune responses. Instead of TLR5, polymerized flagellin directly stimulates B cells by cross linking BCRs, which might generate antibody responses of the IgM type.