Outrunning the Red Queen: bystander activation as a means of outpacing innate immune subversion by intracellular pathogens

Originally described by the late evolutionary biologist Leigh Van Valen, the Red Queen hypothesis posits that the evolutionary arms race between hosts and their pathogens selects for discrete, genetically encoded events that lead to competitive advantages over the other species. Examples of immune evasion strategies are seen throughout the co-evolution of the mammalian immune system and pathogens, such as the enzymatic inactivation of nuclear factor-κB signaling or host translation by pathogen-encoded virulence factors. Such immunoevasive maneuvers would be expected to select for the evolution of innate immune counterstrategies. Recent advances in our understanding of host immunity and microbial pathogenesis have provided insight into a particular innate immune adaptation, termed bystander activation. Bystander activation occurs as a consequence of infected cells alerting and instructing neighboring uninfected cells to produce inflammatory mediators, either through direct cell contact or paracrine signals. Thus, bystander activation can allow the immune system to overcome the ability of pathogens to disarm immune signaling in directly infected cells. This review presents an overview of the general hallmarks of bystander activation and their emerging role in innate immunity to intracellular pathogens, as well as examples of recent mechanistic discoveries relating to the bystander activation during infection with specific pathogens relevant to human health and disease.