Both pathogenic and non-pathogenic microbes express common microbe-associated molecular patterns (MAMPs) that can activate innate pro-inflammatory responses. There is evidence to suggest that host immune systems are adapted to minimize unwarranted, potentially damaging pro-inflammatory responses, e.g., to commensals at muscosal surfaces where very high microbe loads are found, while maintaining the ability to mount aggressive responses to invading pathogens. The recognition of bacterial secretion systems by host innate immune pathways may represent one mechanism used by host immune cells to discriminate between pathogen and non-pathogen, or strains with reduced virulence potential. Most recently, it has been shown that the type IV secretion system (T4SS) encoded by virulent cagPAI-positive strains of the pro-carcinogenic pathogen Helicobacter pylori induces the expression of microRNA-155, a known mediator of innate immunity that is also implicated in oncogenesis. The T4SS-specific activation of miR-155 occurred independently of TLR and NOD1/2 pattern-recognition receptor (PRR) signaling. We discuss the potential role of the T4SS-dependent activation of miR-155 as a pathogen-specific immune response and the possible implications of this in the context of gastrointestinal macrophage inflammatory anergy, a phenomenon in which PRR signaling is inhibited in gastrointestinal resident phagocytes. We also touch on the observed anti-apoptotic role of miR-155 during H. pylori infection, and speculate as to its possible pathological consequences.