Chapter 16 : Role of Flagella in Mucosal Colonization

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In recent years, different studies of bacterial flagella have unmasked novel features regarding their complex and sophisticated structure as well as their biological relevance beyond motility. This chapter focuses on these new structural and functional features of flagella, with emphasis on their ability to favor adherence, colonization, penetration, and translocation by bacterial pathogens and the resulting activation of innate immunity. For most bacterial pathogens, flagella and flagellum-driven motility are recognized as essential elements in their virulence scheme. Klose and Mekalanos constructed an rpoN (encoding s)-null mutant of and found that this strain was defective in motility, flagellation, and colonization in the infant-mouse colonization assay. In this study, they also identified three flagellar regulatory genes (flrABC), among which flrA and flrC encode σ-activators; mutations in these two genes yielded mutants defective in colonization. Flagella purified from enterohemorrhagic (EHEC) and K-12 showed similar levels of interleukin-8 (IL-8) induction as those for H6 flagella, suggesting that this is a property of flagella of some pathogenic bacteria as well as some members of the normal flora. It is possible that the conserved regions play an important role in generating an optimal conformation of the hypervariable domain within the flagellin molecule and, in turn, on the flagellum filament in order to display proinflammatory epitopes effectively. Flagellar genes are highly conserved among gram-negative bacteria, and much similarity in structure and function exists.

Citation: Girón J. 2005. Role of Flagella in Mucosal Colonization, p 213-236. In Nataro J, Cohen P, Mobley H, Weiser J (ed), Colonization of Mucosal Surfaces. ASM Press, Washington, DC. doi: 10.1128/9781555817619.ch16
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Figure 1

Schematic representation of the flagellar structure and the TTSS. The basal body is composed of a series of rings (L, P, S, M, and C), which span the inner and outer membranes and represent the motor that propels the flagellum filament. The filament is connected to the basal body through a hook structure. The flagellin subunits are exported across the cell envelope through the basal body to be assembled in a helical pattern at the tip of the growing filament. The tubular structure is formed by 11 strands of protofilaments of longitudinal helical arrays of flagellin subunits. The cap protein serves as a modulator of flagellum synthesis and secretion of proteins. The virulence-associated TTSS is structurally similar to the flagellar apparatus. Shown here is the TTSS of EPEC, which is composed of several Esc proteins and directs the secretion and translocation of secreted proteins (Esp and Tir) to the host cell cytoplasm. Like flagella, the presence of coiled-coil domains present in EspA suggests the possibility of formation of protofilaments yielding an EspA tubular helical structure. OM, outer membrane; IM, inner membrane; CW, cell wall; CM, cell membrane.

Citation: Girón J. 2005. Role of Flagella in Mucosal Colonization, p 213-236. In Nataro J, Cohen P, Mobley H, Weiser J (ed), Colonization of Mucosal Surfaces. ASM Press, Washington, DC. doi: 10.1128/9781555817619.ch16
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Figure 2

Schematic representation of the role of flagella of EPEC in adherence and IL-8 induction. Intimin, bundle-forming pilus (BFP), and EspA fiber are well-recognized EPEC adhesins. The EspA fibers connected to the TTSS secrete proteins (Esp and Tir) involved in attaching and effacing (A/E) lesion formation. The extracellular bacteria are tethered through the bundle-forming pilus and possibly via rod-like pili. The wavy flagellar filaments interconnect the bacteria and may mediate direct binding to a receptor on the cell membrane and hypothetically pierce the cell membrane and inject flagellins or other proteins to the cytosol. It is documented that the flagella may activate IL-8 and induce inflammation, but it is uncertain whether this activation employs the TLR5 signaling pathway.

Citation: Girón J. 2005. Role of Flagella in Mucosal Colonization, p 213-236. In Nataro J, Cohen P, Mobley H, Weiser J (ed), Colonization of Mucosal Surfaces. ASM Press, Washington, DC. doi: 10.1128/9781555817619.ch16
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Image of Figure 3
Figure 3

Role of flagella in biofilm formation. Shown is the model for biofilm formation by . The initial attachment of the bacteria to the abiotic surface is promoted by functional flagella and motility. Once attached, the bacteria employ type IV pilus-mediated twitching motility to spread out on the surface, with subsequent formation of aggregates that form three-dimensional domes or columns surrounded by exopolysaccharide material, which renders the bacteria resistant to many antimicrobials. The bacteria may dissociate from the columns to initiate a new community.

Citation: Girón J. 2005. Role of Flagella in Mucosal Colonization, p 213-236. In Nataro J, Cohen P, Mobley H, Weiser J (ed), Colonization of Mucosal Surfaces. ASM Press, Washington, DC. doi: 10.1128/9781555817619.ch16
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Figure 4

Schematic representation of the mechanism of flagella-mediated inflammation by S. enterica. The salmonellae utilize flagellum-driven motility to cross the intestinal mucus barrier. These bacteria secrete abundant flagellin to the extracellular milieu; flagellin then translocates to the basolateral surface of epithelial cells, where it interacts specifically with TLR5, leading to MAPK/NF-κB activation pathways, resulting in the induction of proinflammatory molecules (IL-8 and CCL20), synthesis of nitric oxide synthase and human β-defensin 2. (hBD-2). FliC may also induce TNF-α release from PMN, monocytes (MN), promonocytes (ProMN), and dendritic cells (DC) via activation of TLR5. CCL20 is a potent activator of DC, while IL-8 is a potent recruiter of neutrophils (Ns). The end result is inflammation.

Citation: Girón J. 2005. Role of Flagella in Mucosal Colonization, p 213-236. In Nataro J, Cohen P, Mobley H, Weiser J (ed), Colonization of Mucosal Surfaces. ASM Press, Washington, DC. doi: 10.1128/9781555817619.ch16
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