Masters of conquest and pillage: Xenorhabdus nematophila global regulators control transitions from virulence to nutrient acquisition

Abstract

Invertebrate animal models are experimentally tractable and have immunity and disease symptoms that mirror those of vertebrates. Therefore they are of particular utility in understanding fundamental aspects of pathogenesis. Indeed, artificial models using human pathogens and invertebrate hosts have revealed conserved and novel molecular mechanisms of bacterial infection and host immune responses. Additional insights may be gained from investigating interactions between invertebrates and pathogens they encounter in their natural environments. For example, enteric bacteria in the genera Photorhabdus and Xenorhabdus are pathogens of insects that also mutualistically associate with nematodes in the genera Heterorhabditis and Steinernema respectively. These bacteria serve as models to understand naturally occurring symbiotic associations that result in disease in or benefit for animals. Xenorhabdus nematophila is the best-studied species of its genus with regard to the molecular mechanisms of its symbiotic associations. In this review, we summarize recent advances in understanding X. nematophila-host interactions. We emphasize regulatory cascades involved in coordinating transitions between various stages of the X. nematophila life cycle: infection, reproduction and transmission.

Fig. 1. Life cycle of X. nematophila and current model of signal transduction cascades controlling mutualism and pathogenesis genes

Each oval represents an insect larva. The X. nematophila-S. carpocapsae life cycle is divided into three stages: infection, reproduction, and transmission. Biological events occurring during each stage are shown on the left, while X. nematophila regulatory events are shown on the right. X. nematophila life cycle: Infection stage; an infective juvenile stage S. carpocapsae nematode (dark blue) releases X. nematophila (green circles) into the blood of a susceptible insect. X. nematophila replicates in the insect blood, suppresses insect humoral (red lightning bolts) and cellular immunity (represented by orange cells undergoing phagocytosis or aggregation), and causes insect death. Reproduction stage; High densities of X. nematophila bacteria support nematode reproduction through adult stages that mate and lay eggs, that hatch and develop through four juvenile stages (J1-J4), within the insect cadaver. Transmission stage; When nutrients become limiting, S. carpocapsae juvenile nematodes re-associate with and selectively retain X. nematophila, developing into the infective stage which emerge into the soil in search of another insect host. In the regulatory hierarchy models, arrows and cross bars indicate positive and negative regulation respectively that may be either direct or indirect. Direct binding has been demonstrated for Lrp at xhlBA and nilC promoters, as well as for FliZ at flhDC and hemolysin (xaxAB and xhlBA) promoters. All other regulatory relationships are inferred from genetic or bioinformatic analyses. Pathways predicted to be active or inactive in each stage are shown in black and gray respectively. For simplicity, some known regulatory connections are not shown. For example, CpxR negatively regulates the expression of protease, hemolysin, and antibiotic through an unknown mechanism. See text for appropriate references.