How not to get bugged by bugs: mechanisms of cellular tolerance to microorganisms

Advances in the characterization of the receptors and signaling pathways involved in the response to infection have led to a more detailed understanding of cellular tolerance to endotoxin and other microbial components. This review summarizes recent progress in the field, particularly in relation to the molecular mechanisms that underlie the development of tolerance to microorganisms.

The identification of Toll-like receptors as major sensors of microbial molecules has led to numerous studies of their function in tolerant cells. Decreased Toll-like receptor expression, altered interactions between the Toll-like receptors and intracellular signal transducers, and decreased expression or activity of downstream signaling molecules have all been implicated. Upregulation of specific proteins that inhibit Toll-like receptor signaling has also been described. Apart from these general mechanisms, special features of the intestinal microenvironment and its resident cells also contribute to making the gut hyporesponsive to microorganisms.

The application of gene knockout technology has highlighted the importance of macrophage tolerance in regulating innate immunity to microbial infection. Such studies have indicated that the failure of tolerance can lead to exaggerated inflammatory responses to intestinal bacteria, raising the possibility that defects in tolerance may be linked to conditions such as inflammatory bowel disease. Further characterization of this link will help in elucidating the pathogenesis of such conditions and in devising new approaches to treatment.