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Deconstructing a type III secretion system effector network unravels the inherent robustness and plasticity in pathogenesis and immunity

ABSTRACT: Infections with many Gram-negative pathogens rely on type III secretion system effectors. We hypothesized that while hijacking processes within mammalian cells, the effectors operate as a robust network which can tolerate significant contractions; this was tested in vivo using the mouse pathogen Citrobacter rodentium (encoding 31 effectors). Progressive gene deletions showed that effector essentiality for infection is context dependent and that the network can tolerate 60% contraction while maintaining pathogenicity. Despite inducing drastically different colonic cytokine profiles (e.g. IL-22, IL-17, IFN-γ or GM-CSF), different networks induced protective immunity. Using data from >100 distinct mutant combinations, we built and trained an in silico model able to predict colonization outcomes, which were confirmed experimentally. Furthermore, reproducing the human-restricted enteropathogenic E. coli effector repertoire in C. rodentium was not sufficient for efficient colonization, implicating effector networks in host adaptation. These results unveil the extreme robustness of both T3SS effector networks and host responses.

INSTRUMENT(S): Orbitrap Fusion Lumos, Orbitrap Fusion

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Intestine, Epithelial Cell

SUBMITTER: James Wright

LAB HEAD: Jyoti Choudhary

PROVIDER: PXD023145 | Pride | 2022-04-04

REPOSITORIES: Pride

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			Action	DRS
	20200909_JSG_Frankel_lab_LMS1_set01_.msf	Msf
	20200909_JSG_Frankel_lab_LMS1_set01_.pdResult	Other
	20200909_JSG_Frankel_lab_LMS1_set01_1.raw	Raw
	20200909_JSG_Frankel_lab_LMS1_set01_10.raw	Raw
	20200909_JSG_Frankel_lab_LMS1_set01_11.raw	Raw

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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.

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Deconstructing a type III secretion system effector network unravels the inherent robustness and plasticity in pathogenesis and immunity

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