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

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