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Category: Bacterial Pathogenesis
Therapeutic Approaches Targeting the Assembly and Function of Chaperone-Usher Pili, Page 1 of 2
< Previous page | Next page > /docserver/preview/fulltext/10.1128/9781683670285/9781683670278_Chap13-1.gif /docserver/preview/fulltext/10.1128/9781683670285/9781683670278_Chap13-2.gifAbstract:
The chaperone-usher (CU) pathway is dedicated to the biogenesis of surface structures termed pili or fimbriae that play indispensable roles in the pathogenesis of a wide range of bacteria ( 1 – 4 ). Pili are hair-like fibers composed of multiple different subunit proteins. They are typically involved in adhesion, allowing bacteria to establish a foothold within the host. Following attachment, pili modulate host cell signaling pathways, promote or inhibit host cell invasion, and mediate bacterium-bacterium interactions leading to formation of community structures such as biofilms ( 5 , 6 ). Gram-negative bacteria express multiple CU pili that contribute to their ability to colonize diverse environmental niches ( 1 , 7 – 10 ). Pili thus function at the host-pathogen interface to both initiate and sustain infection and represent attractive therapeutic targets.
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Ultrastructure and function of CU pili. Electron micrographs of E. coli expressing type 1 pili (A) and Y. pestis expressing F1 capsule (B). Scale bars = 500 nm. (C) Cartoon for pilus-mediated bacterial interactions in the bladder. (i) Type 1-piliated UPEC binds to superficial umbrella cells that line the lumen of the bladder. (ii) Pilus-receptor interactions induce a signaling cascade that promotes internalization of adherent bacteria via a membrane zippering mechanism. (iii) Within bladder epithelial cells, UPEC are trafficked to membrane-bound, acidic compartments similar to lysosomes. (iv) In the superficial umbrella cells, UPEC break into the cytosol and rapidly multiply, forming intracellular biofilm-like communities. (v) Bladder cells containing large numbers of UPEC exfoliate, providing a mechanism for bacterial clearance by the flow of urine. (vi) This, however, leaves the underlying layers of immature bladder epithelial cells exposed. UPEC can invade these immature urothelial cells and persist in a quiescent stage in late endosome-like compartments, avoiding detection by immunosurveillance mechanisms. (D) The Y. pestis F1 capsule plays an antiphagocytic role by preventing opsonizing antibodies from binding to the bacterial surface, blocking Fc receptor phagocytosis. More generally, expression of the F1 capsule can mask bacterial adhesins and other surface structures, preventing interactions that lead to internalization into host cells.
CU pilus assembly pathway and targets for therapeutic intervention. The fim gene cluster coding for type 1 pili, along with names and functions of encoded proteins, is shown at the bottom. Upon entering the periplasm via the SecYEG general secretory machinery, nascent pilus subunits form binary complexes with the pilus chaperone (FimC), which facilitates subunit folding by DSC, completing the Ig fold of the subunit’s pilin domain. The adhesin subunit (FimH, red) is depicted with an additional N-terminal lectin domain, which contains the receptor-binding site. Chaperone-subunit complexes then interact with the OM usher (FimD), which comprises a β-barrel channel domain, a plug domain, an N-terminal periplasmic domain (NTD), and two C terminal domains (CTD1 and CTD2). (a) In the resting usher, the plug domain occludes the channel pore and masks the CTDs. (b and c) The usher is activated by binding of a FimC-FimH chaperone-adhesin complex to the usher NTD. This results in displacement of the plug from the channel and handoff of FimC-FimH to the usher CTDs, freeing the NTD to recruit the next chaperone-subunit complex (FimC-FimG). (d) The newly recruited complex bound to the NTD is oriented perfectly to undergo DSE with the previously recruited complex bound to the CTDs, forming the first link in the pilus fiber. The newly incorporated chaperone-subunit is then handed over from the NTD to the CTDs. (e) Repeated rounds of this process result in assembly and secretion of the pilus fiber. Different steps along this pathway are targets for antipilus therapeutics. (i) Vaccination using a full-length or truncated adhesin subunit inhibits pilus-mediated bacterial adhesion and pathogenesis. (ii) Small-molecule receptor analogs occupy the pilus adhesin binding site, preventing pili from adhering to host receptors. (iii) Pilicides inhibit pilus assembly via different mechanisms, such as interfering with chaperone-subunit or subunit-subunit interactions, interfering with binding of chaperone-subunit complexes to the usher, or inhibiting proper folding of the usher in the bacterial OM. (iv) Coilicides inhibit uncoiling and recoiling of the pilus rod, thus impairing resilience of the fibers during fluid flow.