Sensing, Signaling, and Secretion: A Review and Analysis of Systems for Regulating Host Interaction in Wolbachia

Abstract

Wolbachia (Anaplasmataceae) is an endosymbiont of arthropods and nematodes that resides within host cells and is well known for manipulating host biology to facilitate transmission via the female germline. The effects Wolbachia has on host physiology, combined with reproductive manipulations, make this bacterium a promising candidate for use in biological- and vector-control. While it is becoming increasingly clear that Wolbachia's effects on host biology are numerous and vary according to the host and the environment, we know very little about the molecular mechanisms behind Wolbachia's interactions with its host. Here, I analyze 29 Wolbachia genomes for the presence of systems that are likely central to the ability of Wolbachia to respond to and interface with its host, including proteins for sensing, signaling, gene regulation, and secretion. Second, I review conditions under which Wolbachia alters gene expression in response to changes in its environment and discuss other instances where we might hypothesize Wolbachia to regulate gene expression. Findings will direct mechanistic investigations into gene regulation and host-interaction that will deepen our understanding of intracellular infections and enhance applied management efforts that leverage Wolbachia.

Keywords: endosymbiont; environmental response; gene regulation; symbiosis; transcriptional regulation; two-component system; type I secretion system; type IV secretion system.

Figure 1

Wolbachia’s systems for sensing, responding to, and modifying the host. Wolbachia cells are surrounded by three membranes: two bacterial-derived membranes (inner and outer), and one host-derived membrane of golgi- or endoplasmic reticular-origin [31,85]. The host-derived membrane may totally enclose Wolbachia, or, it may connect to the rest of the host endomembrane system. Between Wolbachia’s inner and outer membranes is the periplasmic space. The TCS sensor histidine kinases detect changes in the periplasmic space and initiate phosphorelays. (1) The CckA/CtrA TCS, (blue), results in changes to gene expression of target genes. (2) The PleC/PleD TCS (red) regulates levels of c-di-GMP, a ubiquitous bacterial second messenger. (3) The T4SS (black) secretes effector proteins (green) across both Wolbachia-derived membranes. (4) The Sec system (pink) translocates proteins across or into the inner membrane. Unfolded proteins are brought to the SecYEG channel by either SecA/B or SRP/FtsY. SecDF-YajC facilitate movement through the channel and signal peptidases cleave the signal sequence within the periplasm. (5) The T1SS (yellow) is another secretion system that spans both inner and outer membranes for the secretion of proteins. An ABC transporter/ATPase (ABC) is embedded in the inner membrane, which connects to a membrane fusion protein (MFP) that crosses the periplasmic space. Finally, the outer membrane protein (OMP) spans the outer membrane to facilitate the last step of transfer out of the bacterial cell. (6) The Tat system (brown) translocates folded proteins to the periplasm using a complex of TatC and TatA proteins. (7) TFs (grey) modulate gene expression in response to a range of signals (orange star) including reactive oxygen species, heavy metals, the binding of other proteins, and various metabolites.

Figure 2

Wolbachia encode for a suite of proteins that are involved in transcriptional regulation. Cladogram was drawn based on previously published Wolbachia phylogenies to show relationships between strains [132,133,134]. Colors on the heatmap indicate how many putatively functional copies are present within a Wolbachia strain for a given gene, with white indicating no copies, and the grey to red color scale indicating between one and 15 copies. Numbers inside of the heatmap indicate how many additional copies of the gene are present but annotated as pseudogenized or partial. Supergroup membership (monophyletic clades of Wolbachia historically used for designation) of the strains is indicated with the capital letters on the right side of the heatmap. Abbreviations: ss = Single-Stranded; BP = Binding Protein; TF = Transcription Factor; HTH = Helix-Turn-Helix.

Figure 3

Presence of secretion systems across the Wolbachia phylogeny. Cladogram was drawn based off previously published Wolbachia phylogenies to show relationships between strains [132,133,134]. The grey to black scale indicates the number of putatively functional protein copies present within a Wolbachia strain for a given secretion system. Red numbers inside of the heatmap indicate how many additional gene copies are present but annotated as pseudogenized or partial (for example, wPpe encodes for 12 proteins that make up a T4SS, plus an additional two pseudogenized ORFs also corresponding to T4SS proteins). Supergroup membership (monophyletic clades of Wolbachia historically used for designation) of the strains is indicated with the capital letters on the right side of the heatmap.