Type III secretion system effectors form robust and flexible intracellular virulence networks

Abstract

Infections with many Gram-negative pathogens, including Escherichia coli, Salmonella, Shigella, and Yersinia, rely on type III secretion system (T3SS) effectors. We hypothesized that while hijacking processes within mammalian cells, the effectors operate as a robust network that can tolerate substantial contractions. This was tested in vivo using the mouse pathogen Citrobacter rodentium (encoding 31 effectors). Sequential gene deletions showed that effector essentiality for infection was context dependent and that the network could tolerate 60% contraction while maintaining pathogenicity. Despite inducing very different colonic cytokine profiles (e.g., interleukin-22, interleukin-17, interferon-γ, or granulocyte-macrophage colony-stimulating factor), different networks induced protective immunity. Using data from >100 distinct mutant combinations, we built and trained a machine learning 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, which implicates effector networks in host adaptation. These results unveil the extreme robustness of both T3SS effector networks and host responses.

α-Helices in the Type III Secretion Effectors: A Prevalent Feature with Versatile Roles

“…T3SEs do not act individually though—they form robust networks. These networks are flexible enough to tolerate effector losses up to 60% without affecting virulence, while the network composition contributes to host adaptability [ 11 ]. A large subgroup of T3SEs targeting animal cells have evolved domains able to reorganize the host cell cytoskeleton in order to (a) promote bacterial uptake, (b) hamper the fusion of the bacterial containing vacuole to lysosomes, or (c) use actin tails to freely move the bacterium inside the host cell cytoplasm, to name a few.…”

Virulence Factors of Enteric Pathogenic Escherichia coli: A Review

“…The activation of biofilm formation is mediated by Quorum-sensing encoded by the suppressor of the division inhibitor ( SdiA ) gene. However, for biofilm formation, bacteria demand structures to support these characteristic curli fimbriae, type-I fimbriae, and the cellulose encoded in EPEC by csgA, fimA, and bcsA genes, respectively [ 28 ].…”

SWEET genes and TAL effectors for disease resistance in plants: Present status and future prospects

“…The use of the T3SS also differs in pathogens for animal and plant cells. In a recent study, T3SSs and T3Es were examined in bacterial systems causing a variety of diseases in mammals (including humans), although no SWEET genes are involved in this system (Ruano‐Gallego et al, 2021 ). Therefore, it will also be interesting to compare the structures of T3SSs and the mechanisms involved in the secretion of T3Es using the T3SSs in pathogens causing diseases in plants and animals.…”