Pathogen-Derived Effectors Trigger Protective Immunity via Activation of the Rac2 Enzyme and the IMD or Rip Kinase Signaling Pathway

Abstract

Summary Although infections with virulent pathogens often induce a strong inflammatory reaction, what drives the increased immune response to pathogens compared to non-pathogenic microbes is poorly understood. One possibility is that the immune system senses the level of threat from a microorganism and augments the response accordingly. Here, focussing on cytotoxic necrotizing factor 1 (CNF1), an Escherichia coli-derived effector molecule, we showed the host indirectly sensed the pathogen by monitoring for the effector that modified RhoGTPases. CNF1 modified Rac2, which then interacted with the innate immune adaptors IMD and Rip1-Rip2 in flies and mammalian cells, respectively to drive an immune response. This response was protective and increased the ability of the host to restrict pathogen growth, thus defining a mechanism of effector-triggered immunity that contributes to how metazoans defend against microbes with pathogenic potential.

Nod/Ripk2 signaling in dendritic cells activates IL-17A–secreting innate lymphoid cells and drives colitis inT-bet−/−.Rag2−/−(TRUC) mice

“…This result is consistent with the dominant role of Gram-negative bacteria, which can activate both Nod1 and Nod2, in TRUC pathogenesis (1,2,24). It argues further, that, in TRUC colitis, there is no alternative upstream signal driving Ripk2 activation independently of Nod1 or Nod2 (38). upstream, and genetic ablation of Nod/Ripk2 signaling protects TRUC mice from colitis development.…”

Switching Rho GTPase activation into effective antibacterial defenses requires the caspase-1/IL-1beta signaling axis

“…26 Our work previously established that the activation of Rho GTPases engages protective immune responses in Drosophila. 16 Now, we show that the simultaneous activation of Rho GTPases and TLR signaling pathways engages protective immune responses during bacteremia in mammals. 22 We also show that IL-1beta secretion is synergistically induced by macrophages when CNF1 and LPS treatments are combined.…”

“…[13][14][15] A series of recent studies points to the capacity of host cells to perceive the activity of toxintargeting Rho GTPase, leading to inflammatory responses that are likely detrimental to the persistence of bacteria. [16][17][18][19] This system of recognition of the activity of toxins targeting Rho GTPase is related to Effector-Triggered Immunity (ETI). [19][20][21] Major innate immune signaling hubs comprising NOD and RIP proteins are essential in relaying Rho GTPase signaling to NF-kB.…”

RhoGTPases — NODes for effector-triggered immunity in animals

“…Similarly, the Shigella effector, GEF-H1 was shown to augment NF-κB-dependent immune responses in a NOD1-dependent manner also after modifying RhoGTPases [8]. Finally, the activation of RacGTPase by the CNF1 toxin of uropathogenic Escherichia coli also triggers an immune response [9]. In this case the response is via an innate immune signaling pathway conserved in Drosophila and mammals involving IMD in flies and the related Rip proteins, RIP1 and RIP2, in mammalian cells [9].…”

“…Finally, the activation of RacGTPase by the CNF1 toxin of uropathogenic Escherichia coli also triggers an immune response [9]. In this case the response is via an innate immune signaling pathway conserved in Drosophila and mammals involving IMD in flies and the related Rip proteins, RIP1 and RIP2, in mammalian cells [9]. Moreover, this response can be beneficial for the host and help clear the bacteria as shown in an in vivo fly model.…”