# Bacterial Flagellar Filament: A Supramolecular Multifunctional Nanostructure
## 6 Filament-Host Interaction
### Host Immune Response to Flagella  
Flagella elicit the activation of host inflammatory responses via flagellin interaction with specific molecules through a variety of signaling pathways. Flagellins act as potent agonists of the innate immune system inducing proinflammatory responses, given their ability to stimulate the extracellular Toll-like receptor 5 (TLR5), the intracellular NOD-like receptor (NLR) family 4 (NLRC4)-NAIP 5/6 inflammasome, and an unknown additional third pathway recently proposed that is independent of TLR5, Casp1/11, and MyD88 (Figure 7) [201; 202; 203]. TLR5 features 20 tandem copies of leucine-rich repeats (LRRs) in the ectodomain, which are responsible for flagellin binding [204]. It is expressed by epithelial cells, neutrophils, monocytes, and dendritic cells [205]. TLR5 signaling triggers the transient production of immune mediators by myeloid and epithelial cells. Upon flagellin binding, TLR5 dimerizes and recruits the universal TLR-specific adapter molecule MyD88. They assemble a highly organized scaffold that acts as a signaling complex known as the Mydosome that triggers the activation of downstream molecules such as nuclear factor-kB NK-kB, mitogen-activated protein kinase (MAPK), and interferon (IFN) regulatory pathways, which turns on the transcription of genes involved in innate and adaptive immunity [206]. In human cells, low concentrations of flagellin (ED\({}_{50}\) in the pM range) from _S._ Typhimurium, enteropathogenic and uropathogenic _E. coli, S. enterica_ serotype Dublin, S. enteritidis, P. aeruginosa, L. pneumoniae, Listeria monocytogenes and _Clostridium difficile_,were shown to trigger proinflammatory signaling in sentinel cells such as macrophages, monocytes, DCs, and intestinal epithelium cells. Several published studies support the requirement for TLR5 signaling via MyD88 to induce T cell-dependent antibody responses toward flagellin (reviewed in [207]). Flagellins can also directly activate maturation of dendritic cells (DC) resulting in upregulation of functions related to antigen presentation, co-stimulation, and polarization of T-helper (Th) cell responses, thereby promoting the adaptive immunity response. [PERSON] et al. demonstrated that the flagellin-TLR5 interaction is required for efficient containment of an immune challenge, with consequences for metabolic homeostasis [208]. For instance, they showed that TLR5 knockout mice developed severe intestinal inflammation (colitis). They had an altered gut microbiota profile, which is characterized by changes in the abundance of bacterial species, including elevated levels of proteobacteria, especially enterobacterial species. Flagella-related genes of commensal microbes are upregulated in the gut of TLR5\(-\)/\(-\) mice because of reduced levels of anti-flagellin antibodies in the gut [119]. In contrast to the TLR5 knockout mice, MyD88 knockout mice, with broad deficiency in TLR signaling, lacked evidence of inflammation, suggesting that the inflammation observed in the absence of TLR5 may be caused by stimulation of a compensatory mechanism, in which other TLR signaling pathways are upregulated, ultimately leading to increased inflammation. In addition, TLR5 enhances anti-flagellin T cell-dependent antibody responses in a MyD88-independent manner, suggesting that TLR5 also functions as an endocytic receptor to enhance flagellin processing and presentation by dendritic cells [209]. The TLR5 consensus target sequence is composed of residues 88-98 (LQRIRELAVQA) and located in a conserved site within D1 domain of FliC of \(\beta\)- and \(\gamma\)-proteobacteria. In addition, the C-terminal domain D0 is necessary for TLR5 signaling, as demonstrated by functional studies, as well as the N-terminal D1 motifs (82-101, 110-118) and the C-terminal D1 motif (412-438) that are important for specific interaction of flagellin with TLR5 [210]. In contrast, some important human pathogens such as _H. pylori_, _C.