Selective HDAC inhibition potentiates host defenses to prevent uropathogenic Escherichia coli infection

Introduction

Uropathogenic E. coli (UPEC) can cause urinary tract infection (UTI) by manipulating multiple aspects of the host immune system, including epigenetic reprogramming of gene expression. Epigenetic mechanisms such as histone acetylation are a dynamically regulated process involved in many aspects of physiological and pathological immune responses. In particular, members of the histone deacetylase (HDAC) family of acetylation "erasers" are key regulators of inflammatory response during bacterial infection. Despite this association, the precise mechanistic understanding of how UPEC utilizes HDAC functions to enhance its survival and dampen host inflammatory responses remains elusive.

Goal

By delving into the functional characterization of distinct HDAC genes using complementary approaches, we aspire to uncover novel mechanisms of UPEC infection in the urinary tract.

Methods

To expedite the identification of conserved HDACs that are commonly targeted during UPEC infection, we established the surrogate insect model Galleria mellonella as a cost-effective, ethically acceptable system. RNA was isolated from UPEC-infected larvae and HDAC expression was analyzed by RT-PCR. Selected HDAC genes exhibiting distinct expression patterns in UPEC-infected larvae, underwent silencing using siRNAs, chemical inhibitors, and CRISPR-Cas9 based gene editing in UPEC-infected human bladder epithelial cells (RT-112). Subsequently, we systematically examined the repercussions of silencing selected HDACs on both UPEC invasion and the host immune response.

Results

We found that pronounced expression of selected HDACs during UPEC infection was associated with the increased mortality of larvae and infectivity in bladder epithelial cells. We report that loss of specific HDAC function led to reduced UPEC invasion in bladder epithelial cells. This is associated with increased expression of several immunity-related genes.

Conclusions

Our study unveils a previously unknown infection mechanism of UPEC to manipulate host responses by targeting HDACs. The results project HDACs as a promising target for developing host-directed, non-antibiotic therapies for treating UTI.