The innate immune response during urinary tract infection and pyelonephritis

Abstract

Despite its proximity to the fecal flora, the urinary tract is considered sterile. The precise mechanisms by which the urinary tract maintains sterility are not well understood. Host immune responses are critically important in the antimicrobial defense of the urinary tract. During recent years, considerable advances have been made in our understanding of the mechanisms underlying immune homeostasis of the kidney and urinary tract. Dysfunctions in these immune mechanisms may result in acute disease, tissue destruction and overwhelming infection. The objective of this review is to provide an overview of the innate immune response in the urinary tract in response to microbial assault. In doing so, we focus on the role of antimicrobial peptides-a ubiquitous component of the innate immune response.

Figure 1. Innate immune mechanisms in the urinary tract

Microbes enter the urinary tract and encounter constitutively expressed AMPs that can inhibit attachment to the urothelium (A) or cause bacterial lysis (B). If bacteria attach to the urothelium, they can induce AMP production, which results in destruction of adherent bacteria (C). When bacteria bind and invade the urothelium, they can elicit the production of chemokines (D/E) that attract inflammatory cells across the urothelium (F). These cells control infection by phagocytosis (G) and secretion of intracellular AMPs (H) [14,45,46].

Figure 2. Signaling pathway of toll-like receptors in urinary tract infection

Activation of TLRs expressed on the cell membrane by a bacterial ligand sets in motion a series of processes that leads to the release of inflammatory chemokines, cytokines and AMPs [14,19].

Figure 3. Proposed antimicrobial mechanisms of antimicrobial peptides

AMPs can kill bacteria by disrupting the microbial membrane (A–C) or translocating across the membrane and binding to intracellular targets (D). Models of membrane disruption include the following: (A) Barrel-stave model: (A1) Cationic AMPs (+) bind to the negatively charged bacteria lipid bilayer (−) and disrupt the microbial membrane by forming an aqueous channel or “barrel-stave” (A2). (B) Carpet Model: AMPs blanket the microbial membrane and disrupt it by forming micelles. (C) Torodial Pore Model: AMPs bind to phospholipid head group on the microbial membrane allowing its hydrophobic portion to intercalate into the microbial membrane and cause the lipid bilayer to fold back on itself [50].

Figure 4. Defined antimicrobial peptides in the human kidney and urinary tract

Left Panel: AMPs identified in the human lower and upper urinary tract. Right Panel: AMPs identified in the nephron and collecting tubule of the human kidney [45].

Figure 5. Urinary antimicrobial peptide concentrations

Mean urinary AMP levels in culture negative and culture positive urine samples [74].