Abstract
Histone deacetylase 6 (HDAC6) is a non-canonical, mostly cytosolic histone deacetylase that has a variety of interacting partners and substrates. Previous work using cell-culture based assays coupled with pharmacological inhibitors and gene-silencing approaches indicated that HDAC6 promotes the actin- and microtubule-dependent invasion of host cells by uropathogenic Escherichia coli (UPEC). These facultative intracellular pathogens are the major cause of urinary tract infections. Here, we examined the involvement of HDAC6 in bladder colonization by UPEC using HDAC6 knockout mice. Though UPEC was unable to invade HDAC6−/− cells in culture, the bacteria had an enhanced ability to colonize the bladders of mice that lacked HDAC6. This effect was transient, and by six hours post-inoculation bacterial titers in the HDAC6−/− mice were reduced to levels seen in wild type control animals. Subsequent analyses revealed that the mutant mice had greater bladder volume capacity and fluid retention, along with much higher levels of acetylated α-tubulin. In addition, infiltrating neutrophils recovered from the HDAC6−/− bladder harbored significantly more viable bacteria than their wild type counterparts. Cumulatively, these changes may negate any inhibitory effects that the lack of HDAC6 has on UPEC entry into individual host cells, and suggest roles for HDAC6 in other urological disorders such as urinary retention.
Highlights
Urinary tract infections (UTIs) are one of the most prevalent bacterial infections, with strains of uropathogenic Escherichia coli (UPEC) being the primary etiological agents [1,2]
We reported that pharmacological inhibition of Histone deacetylase 6 (HDAC6) activity or the silencing of HDAC6 expression greatly increased the amounts of acetylated α-tubulin within cultured bladder epithelial cells and significantly reduced UPEC invasion frequencies [11]
Our results indicate that the requirements for HDAC6 during the invasion process can be circumvented, but this conclusion is confounded by data showing that HDAC6 affects the architecture of the bladder mucosa and smooth muscle layers, as well as the functionality of infiltrating neutrophils
Summary
Urinary tract infections (UTIs) are one of the most prevalent bacterial infections, with strains of uropathogenic Escherichia coli (UPEC) being the primary etiological agents [1,2]. These pockets of latent bacteria are protected from antibiotic treatments and many host defenses, and likely serve as important sources for the recurrent, or relapsing UTIs that afflict many individuals [8] In both in vivo and cell culture-based assays, type 1 pili-mediated UPEC entry into host cells occurs by an actin- and microtubule-dependent zipper mechanism [5,9,10]. In addition to these cytoskeletal filaments, numerous other host factors have been implicated as regulators of the entry process. Our results indicate that the requirements for HDAC6 during the invasion process can be circumvented, but this conclusion is confounded by data showing that HDAC6 affects the architecture of the bladder mucosa and smooth muscle layers, as well as the functionality of infiltrating neutrophils
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