Programmed Cell Death in the Evolutionary Race against Bacterial Virulence Factors

Innate immune sensors can recognize when host cells are irrevocably compromised by pathogens, and in response can trigger programmed cell death (pyroptosis, apoptosis, and necroptosis). Innate sensors can directly bind microbial ligands; for example, NAIP/NLRC4 detects flagellin/rod/needle, whereas caspase-11 detects lipopolysaccharide. Other sensors are guards that monitor normal function of cellular proteins; for instance, pyrin monitors Rho GTPases, whereas caspase-8 and receptor-interacting protein kinase (RIPK)3 guards RIPK1 transcriptional signaling. Some proteins that need to be guarded can be duplicated as decoy domains, as seen in the integrated decoy domains within NLRP1 that watch for microbial attack. Here, we discuss the evolutionary battle between pathogens and host innate immune sensors/guards, illustrated by the Red Queen hypothesis. We discuss in depth four pathogens, and how they either fail in this evolutionary race (Chromobacterium violaceum, Burkholderia thailandensis), or how the evolutionary race generates increasingly complex virulence factors and host innate immune signaling pathways (Yersinia species, and enteropathogenic Escherichia coli [EPEC]).