A Synthetic Peptide 2Abz²³S²⁹ Reduces Bacterial Titer and Induces Pro-Inflammatory Cytokines in a Murine Model of Urinary Tract Infection

Abstract

Introduction

A urinary tract infection (UTI), which is often caused by uropathogenic E. coli (UPEC) strains, affects many people worldwide annually. UPEC causes the production of pro-inflammatory cytokines by the bladder epithelial cells; however, it has been proven that the UPEC can inhibit the early activation of the innate immune system.

Methods

This study aimed to examine the antibacterial and immunomodulatory effects of different doses of truncated alpha-defensins (human neutrophil peptide (HNP)-1) analog 2Abz²³S²⁹ on the mouse UTI model. Experimentally uropathogenic E. coli CFT073-infected mice were treated with low-dose 2Abz²³S²⁹ (250µg/mL), high-dose 2Abz²³S²⁹ (750µg/mL), ciprofloxacin (cip) (800µg/mL), or high-dose 2Abz²³S²⁹plus cip once a day 24 h post-infection. The 2Abz²³S²⁹ and cip treatment were given for two consecutive days.

Results

The in vivo results showed that fewer UPEC were recovered from the bladders of mice treated transurethrally with 2Abz²³S²⁹. Moreover, low-dose 2Abz²³S²⁹ significantly decreased the level of the interleukin-6 (IL-6), whereas high-dose 2Abz²³S²⁹ increased pro-inflammatory cytokines including IL-6, macrophage inflammatory protein/2 (MIP/2), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) in infected bladders of mice. Besides, the levels of cytokines IL-6 and MIP/2 in infected mice treated with a combination of high-dose 2Abz²³S²⁹ and cip were significantly higher than the untreated mice. In contrast, CFT073-infected mice treated with a combination of high-dose 2Abz²³S²⁹ and cip showed no changes in cytokines TNF-α and IL-1β levels, indicating that ciprofloxacin may play an anti-inflammatory role.

Conclusion

Collectively, apart from the direct antibacterial role of 2Abz²³S²⁹, our data illustrated that 2Abz²³S²⁹ modulates pro-inflammatory cytokine production of bladder in a dose-dependent manner, which has implications for the development of new anti-infective agents.

Keywords:

• urinary tract infection
• pro-inflammatory cytokines
• human neutrophil peptide (HNP)-1

Abbreviations

UTI, urinary tract infection; UPEC, uropathogenic E. coli; HNP-1, human neutrophil peptide −1; cip, ciprofloxacin; IL-6, interleukin-6; MIP/2, macrophage inflammatory protein/2; TNF-α, tumor necrosis factor-α; IL-1β, interleukin-1β; AMPs, antimicrobial peptides; HDPs, Host defense antimicrobial peptides; MIC, Minimum inhibitory concentration; FIC, fractional inhibitory concentration; TLR, toll-like receptor; IBC, intracellular bacterial communities.

Disclosure

The authors report no conflicts of interest in this work.