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The accessory type III secretion system effectors shape inflammatory infection outcome

ABSTRACT: Injection of effectors via a type III secretion system (T3SS) is an infection strategy shared by many Gram-negative bacterial pathogens. While individual T3SS effectors are well characterized, their network-level organization and the distinction between core and accessory effectors remain incompletely understood. Here, we systematically dissect the T3SS effector network from Citrobacter rodentium (CR), identifying a subset of 12 accessory effectors that, while dispensable for colonization, significantly alter infection outcomes. A strain lacking these effectors (CRM12) remained virulent in susceptible hosts yet resulted in reduced epithelial barrier damage, inflammation and immune cell infiltration in resistant mouse hosts. Deep proteomic analysis specifically targeting CR-attached colonic epithelial cells revealed that, despite lacking 39% of its effector repertoire, infection with CRM12 results in similar changes to global protein expression as seen in mice infected with the wild-type strain, though key regulators of barrier disruption were differentially expressed. Using a host model with impaired barrier repair, we confirmed that accessory effectors shape infection dynamics without significantly impacting virulence. This study thus refines the concept of core and accessory effectors, providing a basis for further studies into effector-driven host adaptation.

INSTRUMENT(S): Orbitrap Ascend

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Graeme Benstead-Hume

LAB HEAD: Jyoti Choudhary

PROVIDER: PXD062886 | Pride | 2025-04-16

REPOSITORIES: Pride

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Project description:Many Gram-negative bacterial pathogens interact with mammalian cells by using type III secretion systems (T3SS) to inject virulence proteins directly into infected host cells. A subset of these injected protein ‘effectors’ are enzymes that modify the structure and inhibit the function of human proteins by catalyzing the addition of unusual post-translational modifications. T3SS effectors play essential roles in bacterial virulence and their modes of action have provided great insight into the functions and the components of the innate immune system. The E. coli and Citrobacter rodentium NleB effectors, as well as the Salmonella enterica SseK effectors are glycosyltransferases that modify host protein substrates with N-acetyl glucosamine (GlcNAc) on arginine residues. Arginine glycosylation is unusual because it occurs on the guanidinium groups of arginines, which are poor nucleophiles. This post-translational modification disrupts the normal functioning of host immune response proteins. T3SS effectors are chaperoned in the bacterium to keep the effectors partially unfolded and competent for secretion, as well as for targeting the effectors to the T3SS sorting platform. The chaperones are then stripped from their effector substrates at the sorting platform and the effectors are secreted in an unfolded conformation. T3SS effectors are thought to be inactive within the bacterium and fold into their active conformations after they are injected into host cells. While performing mass spectrometry experiments to identify glycosylation substrates of NleB orthologs, we unexpectedly observed that the E. coli glutathione synthetase (GshB) is glycosylated on an arginine residue (R256) by NleB. NleB glycosyltransferase activity is essential to C. rodentium survival in oxidative stress conditions because glycosylation of GshB results in enhanced glutathione production. These data represent, to our knowledge, the first intra-bacterial activity for a T3SS effector and show that effector activities thought to be restricted to host cell compartments additionally play important roles in regulating bacterial physiology.

			Action	DRS
	30Aug23_Zuza.sld	Other
	PL21-PB-Frankel.pdStudy	Other
	PL21-PB-Frankel.pdStudy.bak	Other
	PL21-PB-Frankel_.msf	Msf
	PL21-PB-Frankel_.msfView	Msf

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The accessory type III secretion system effectors shape inflammatory infection outcome

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