A provisional Transcriptional Regulatory Network for the obliged human pathogen Helicobacter pylori

To adapt to a particular host niche, bacterial pathogens rely on Transcriptional Regulatory Networks (TRNs) that transduce environmental signals into coordinated output expression of virulence factors and housekeeping genes. In virtue of its remarkable paucity of transcriptional regulators, the human gastric pathogen Helicobacter pylori represents a very appealing model system to understand how bacterial TRNs are wired up to govern multiple responses with few regulatory factors. The TRN of H. pylori emerges as a multi-layer hierarchical structure composed of 20 regulators organized in four main regulatory modules (origons), which process related physiological responses needed to colonize the gastric niche: respectively heat and stress response, motility and chemotaxis, acidic and metal ion homeostasis. Experimental verification and logic analysis of the TRN uncovered specific motifs, or patterns of interconnection, between regulators and target genes, which confer distinct response dynamics to the circuit. For example, the stress response origon adopts two regulators, HspR and HrcA, which result to be wired in a rare incoherent Feed-Forward Loop motif, responsible for accelerated response kinetics of GroESL chaperone expression. The flagellar circuit appears essentially as sigma regulatory cascade, where each sigma regulates transcription of a dedicated flagellar gene class with Single Input Motif circuitry, while two metal-dependent regulators, Fur and NikR, appear to operate through a central Bifan motif, connecting the metal responses in a symmetric coordination logic with no obvious hierarchy. Finally, the interconnections between the modules are presented, such as the acid acclimation origon controlled by the response regulator ArsR, whose transcription levels are in turn directly regulated by Fur. The results provide the first provisional description of a TRN for an important human pathogen.