Intracytosolic Sensing of Pathogens: Nucleic Acid Receptors, NLRs, and the Associated Responses during Infections and Autoinflammatory Diseases

Abstract

This chapter discusses the current knowledge concerning the cytosolic pattern recognition receptors (PRRs), the responses they trigger, their physiological role during infection, and their regulation. It describes the diseases associated with mutations in several of these PRRs or associated proteins. Viruses can be detected through recognition of their nucleic acids either extracellularly or in the endosomes by Toll-like receptors (TLRs). The host cell signaling pathways that lead to caspase-1 activation in macrophages infected with three bacterial pathogens that replicate in the host cell cytosol-the gram-positive bacterium L. monocytogenes and the gram-negative bacteria S. flexneri and F. tularensis-have been studied so far. The various responses triggered after engagement of cytosolic PRRs are critical to fight infections, but some pathogens have virulence factors that block the innate immune signaling. The chapter reviews some recent examples of positive and negative regulation of cytosolic PRR signaling. It is likely that as we gain more insight into the different intracellular signaling pathways, we will find that many pathogens have evolved mechanisms to modulate and evade these pathways. While these pathways are highly regulated, some PRR mutations lead to a number of autoinflammatory diseases. A better understanding of the role of these PRRs during the normal innate immune response to intracellular pathogens is likely to give us a better understanding of the autoinflammatory diseases and will lead to the development of new therapeutics.