Modulation of innate immune responses by Yersinia type III secretion system translocators and effectors

Abstract

The innate immune system of mammals responds to microbial infection through detection of conserved molecular determinants called 'pathogen-associated molecular patterns' (PAMPs). Pathogens use virulence factors to counteract PAMP-directed responses. The innate immune system can in turn recognize signals generated by virulence factors, allowing for a heightened response to dangerous pathogens. Many Gram-negative bacterial pathogens encode type III secretion systems (T3SSs) that translocate effector proteins, subvert PAMP-directed responses and are critical for infection. A plasmid-encoded T3SS in the human-pathogenic Yersinia species translocates seven effectors into infected host cells. Delivery of effectors by the T3SS requires plasma membrane insertion of two translocators, which are thought to form a channel called a translocon. Studies of the Yersinia T3SS have provided key advances in our understanding of how innate immune responses are generated by perturbations in plasma membrane and other signals that result from translocon insertion. Additionally, studies in this system revealed that effectors function to inhibit innateimmune responses resulting from insertion of translocons into plasma membrane. Here, we review these advances with the goal of providing insight into how a T3SS can activate and inhibit innate immune responses, allowing a virulent pathogen to bypass host defences.

Fig. 1. Model for gene expression and pore formation responses induced by translocon insertion in epithelial cells or macrophages infected with Yersinia

(A) In epithelial cells, the major pathway that stimulates host gene expression following translocon insertion results from activation of Rho GTPases. Invasin-β1 integrin signaling cooperates with translocon insertion to activate Rho. Activated Rho stimulates actin polymerization, leading to pore formation. Two possible pathways of pore formation are shown, one leading to opening of translocons and the other leading to opening of host-derived pores. YopE and YopT directly inhibit Rho. YopH and YopJ inhibit steps in the gene expression response pathway downstream of Rho. (B) In macrophages, insertion of translocons leading to perturbation of the plasma membrane or translocation of a PAMP are alternative but not mutually exclusive pathways leading to host gene expression and production of TNFα. YopJ dampens TNFα expression, suggesting that direct YopJ targets such as MAP kinase kinases (MAPKK) or IκB kinases (IKK) transmit signals in the gene expression response pathway.

Fig. 2. Model for inflammasome activation induced by translocon insertion in macrophages infected with Yersinia

LPS-TLR4 signaling results in expression of pro-IL-1β and inflammasome components (not shown). Perturbation of the plasma membrane by translocon insertion generates a signal or the translocon delivers a PAMP. One or both events lead to activation of NLRP3 or NLRC4 inflammasomes, activation of caspase-1, maturation of IL-1β, pore formation and pyroptosis. YopK inhibits translocon-proximal signals in naïve or LPS-primed macrophages. YopM directly inhibits caspase-1 in LPS-activated macrophages.