An Overview of Two-Component Signal Transduction Systems Implicated in Extra-Intestinal Pathogenic E. coli Infections

Abstract

Extra-intestinal pathogenic E. coli (ExPEC) infections are common in mammals and birds. The predominant ExPEC types are avian pathogenic E. coli (APEC), neonatal meningitis causing E. coli/meningitis associated E. coli (NMEC/MAEC), and uropathogenic E. coli (UPEC). Many reviews have described current knowledge on ExPEC infection strategies and virulence factors, especially for UPEC. However, surprisingly little has been reported on the regulatory modules that have been identified as critical in ExPEC pathogenesis. Two-component systems (TCSs) comprise the predominant method by which bacteria respond to changing environments and play significant roles in modulating bacterial fitness in diverse niches. Recent studies have highlighted the potential of manipulating signal transduction systems as a means to chemically re-wire bacterial pathogens, thereby reducing selective pressure and avoiding the emergence of antibiotic resistance. This review begins by providing a brief introduction to characterized infection strategies and common virulence factors among APEC, NMEC, and UPEC and continues with a comprehensive overview of two-component signal transduction networks that have been shown to influence ExPEC pathogenesis.

Keywords: APEC; ExPEC; MAEC/NMEC; UPEC; signal transduction; two-component systems; virulence factors.

Figure 1

Virulence factors involved in ExPEC infections. The Venn Diagram represents the most commonly reported, shared and individual, virulence factors for APEC (blue), MAEC/NMEC (purple), and UPEC (orange). (Knöbl et al., ; Johnson et al., ; Lloyd et al., ; Wiles et al., ; Zhu et al., ; Nazemi et al., ; Spurbeck et al., ; Logue et al., ; Zhu Ge et al., ; Huja et al., ; Wang et al., ; Wijetunge et al., 2015).

Figure 2

ExPEC infection strategies. Diagram depicts a generalized schematic of the known and relevant aspects of ExPEC infections. The leftmost green arrow depicts the typical route of infection from point of entry. APEC attach to upper respiratory epithelial cells using type 1 pili. APEC can replicate and transverse the respiratory tract to the bloodstream by means of avian macrophages. NMEC/MAEC exit the bloodstream and attach via type 1 pili to brain micro-vascular endothelial cells that comprise the blood brain barrier. NMEC enter the endothelial cells through OmpA receptor-mediated entry. From here, NMEC are able to colonize the brain and meninges. UPEC attach to urothelial cells in a type 1 pili-dependent manner. UPEC are then endocytosed and escape into the cytosol where they replicate into intracellular bacterial communities (IBC). UPEC escape the IBC state by filamenting and fluxing out of the infected host cell. Dispersing UPEC can infect neighboring or underlying transitional cells, and/or can ascend the ureters to colonize and infect the kidneys.

Figure 3

Two-component systems involved in UPEC pathogenesis. The two-component systems are listed in the general order in which they are reported as critical for each infection strategy. (A) depicts a generalized view of APEC pathogenesis infecting an avian respiratory tract. Early infection is denoted by green color. Late infection is outlined by purple color. (B) depicts a generalized view of MAEC/NMEC infection in a human brain by crossing the blood brain barrier. Following bacteria entering the blood stream, early meningitis infection is denoted by blue background where E. coli cells bind and traverse the blood brain barrier. Late infection is outlined by green background, which includes infection of the meninges. There are no publications on TCS involved in MAEC/NMEC pathogenesis; however, capsule, pili, and other virulence factors are required for pathogenesis and these are known to be regulated in part by TCS. (C) depicts a generalized view of UPEC infecting a human urinary tract. Blue background indicates entry and initiation of UPEC infection. Green depicts infection in the bladder. Purple depicts the ascension into and infection of the kidney.

Figure 4

Overview of two-component system signal transduction. In most cases studied to date, the sensor histidine kinase is membrane-embedded. The sensor kinase detects signals or stimuli and undergoes auto-phosphorylation at a conserved histidine residue. The phosphoryl-group is then transferred to the cognate cytoplasmic response regulator at a conserved aspartate residue. Phosphorylated response regulators form an active dimer that can then regulate gene transcription. Following the appropriate cellular response, the sensor exhibits phosphatase or reverse phosphotransferase activity removing the phosphoryl-group from the response regulator to “reset” the system. While most kinases are found as a dimer in the membrane, dynamic interactions between the mono- and di-meric state may occur.