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

ABSTRACT: Many Gram-negative pathogens use type III secretion systems to inject networks of effectors that subvert host cell processes. We modelled the robustness of such network using the mouse pathogen Citrobacter rodentium (encoding 31 effectors) through sequential deletions of effector genes, generating 100 distinct mutant combinations, which were tested in vivo. Counterintuitively, mutants lacking 19 unrelated effectors (CR14) or 10 immune-modulating effectors (CRi9) colonised and induced conserved molecular signatures of infection in intestinal epithelial cells. Specifically, CRi9 triggered heightened colonic secretion of TNF, IL-22, IL-17A and IFN-γ, while CR14 induced high-level secretion of IL-6 and GM-CSF with lower recruitment of myeloid cells. Yet, both CR14 and CRi9 induced sterile immunity. A machine learning model, trained on the mutant phenotypes and effector function, predicted an unprecedented combination of colonisation-failure effector mutations, which was validated experimentally. These results reveal the robustness and combinatorial plasticity of both the effector network and host immunity.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Citrobacter Rodentium Mus Musculus (mouse)

TISSUE(S): Epithelial Cell, Intestinal Epithelium

SUBMITTER: James Wright

LAB HEAD: Jyoti Choudhary

PROVIDER: PXD018740 | Pride | 2022-04-06

REPOSITORIES: Pride

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			Action	DRS
	20190327_DR_Frankel_lab_FSN_set02_.msf	Msf
	20190327_DR_Frankel_lab_FSN_set02_01.raw	Raw
	20190327_DR_Frankel_lab_FSN_set02_02.raw	Raw
	20190327_DR_Frankel_lab_FSN_set02_03.raw	Raw
	20190327_DR_Frankel_lab_FSN_set02_04.raw	Raw

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

Project description: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.

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Project description:In order to promote intracellular survival and infection, Legionella spp. translocate hundreds of effector proteins into eukaryotic host cells using a type IV b protein secretion system (T4bSS). T4bSS are well known to translocate soluble as well as transmembrane domain-containing effector proteins (TMD-effectors) but the mechanisms of secretion are still poorly understood. Herein we investigated the secretion of hydrophobic TMD-effectors, of which about 80 were previously reported to be encoded by L. pneumophila. A proteomic analysis of fractionated membranes revealed that TMD-effectors are targeted to and inserted into the bacterial inner membranes of L. pneumophila independent of the presence of a functional T4bSS. While the T4bSS chaperones IcmS and IcmW were critical for secretion of all tested TMD-effectors, they did not influence inner membrane targeting of these proteins. The translocation of TMD-effectors into host cells proved to be dependent on a C-terminal secretion signal as it is the case for soluble effector proteins and this signal required presentation towards the cytoplasmic side of the inner membrane. A differential secretion behavior of TMD- and soluble effectors and a need for small periplasmic loops within TMD-effectors provided strong evidence that TMD-effectors are secreted in a two-step secretion process with an inner membrane intermediate that is extracted towards the cytoplasm, possibly by aid of the type IV coupling protein complex, for subsequent secretion into eukaryotic host cells by the T4bSS core complex. Overall, our study highlights the amazing versatility of T4bSS to secrete soluble and TMD-effectors from different subcellular locations of the bacterial cell.

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