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Enteropathogenic hemorrhagic bacteria limit ROCK-dependent epithelial cell extrusion to circumvent barrier immunity

ABSTRACT: Diverse pathogen-encoded virulence factors disable apoptosis, pyroptosis, or ecroptosis, the host cell death programs that remove infected cells. In the intestine, the expulsion of infected cells into the lumen for elimination provides an additional layer of host defense, but no virulence mechanisms targeting this process are known. Here, we show that the Escherichia coli ubiquitin ligase NleL is an inhibitor of intestinal epithelial cell (IEC) expulsion that targets caspase-4, Rho-effector kinase 1 (ROCK1), and ROCK2 for proteasomal degradation. Genetic deletion of Rock1 and Rock2 from cultured IECs diminished inflammasome-induced IEC expulsion. Moreover, mice with Rock1- and Rock2-deficient IECs were less effective than wild-type (WT) mice at constraining Citrobacter rodentium replication in the colon. Importantly, NleL-deficient C. rodentium triggered more IEC expulsion than WT C. rodentium, resulting in diminished colon colonization in infected mice. This work highlights a host-pathogen arms race focused on dynamic regulation of the host epithelial barrier.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Christopher Rose

PROVIDER: MSV000095663 | MassIVE | Tue Aug 20 13:40:00 BST 2024

REPOSITORIES: MassIVE

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Project description:To investigate the early host response triggered by three different strains of Trypanosoma cruzi at a local infection site, changes in host gene expression were monitored in a murine intradermal infection model using Affymetrix oligonucleotide arrays. Robust induction of IFN-stimulated genes (ISGs) was observed in excised skin 24 hours post-infection where the level of ISG induction was parasite strain-dependent with the least virulent strain triggering a muted IFN response. Infection of mice immunodepleted of IFNÎ³-producing cells or infection of IFNÎ³-deficient mice had minimal impact on the IFN response generated in T. cruzi infected mice. In contrast, infection of mice lacking the type I IFN receptor demonstrated that type I IFNs are largely responsible for the IFN response generated at the site of infection. These data highlight type I IFNs as important components of the innate immune response to T. cruzi the site of inoculation and their role in shaping the early transcriptional response to this pathogen. We used microarrays to detail the local host transcriptional response to intradermal T. cruzi infection in WT mice and mice depleted of NK cells, or deficient in IFN-gamma or type I IFN responses. Additionally we compared the local host-transcriptional response generated to infection with 3 different strains of Trypanosoma cruzi (Y, Brazil, and G). Experiment Overall Design: Mice were infected by intradermal injection of 10^6 T. cruzi trypomastigotes in 100uL of saline split between 2 adjacent sites on the shaved side flank. Control mice were injected with an equal volume of saline. 24 hours post-injection approximately 75mm^2 of skin immediately surrounding the injection site was excised and RNA was isolated from the tissue. Balb/c mice were used for most experiments and IFN-gamma KO mice were on the Balb/c background. WT 129 mice were also used as IFNAR-/- mice were on the 129 background. In total 33 arrays were performed. 7 WT (Balb/c) control, 3 Y strain infected, 3 Brazil strain infected, 3 G strain infected, 2 IFN-gamma KO control, 2 IFN-gamma KO infected, 1 NK cell depleted control, 1 NK cell depleted infected, 3 WT (129) control, 3 WT (129) infected, 3 IFNAR KO control, 3 IFNAR KO infected

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Enteropathogenic hemorrhagic bacteria limit ROCK-dependent epithelial cell extrusion to circumvent barrier immunity

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