Cytoplasmic and nuclear ERK signaling are essential for *Campylobacter jejuni* invasion and IL-8 secretion
Background
Acute Campylobacter jejuni infection is a leading cause of human gastroenteritis globally, relying on bacterial effector proteins delivered to gut epithelial cells via its flagellar apparatus. While the C. jejuni Campylobacter invasion antigen D (CiaD) effector protein has been linked to host extracellular signal-regulated kinase (ERK) activation, the precise contribution of subcellular ERK to establishing acute bacterial infection and proinflammatory cytokine production has remained underexplored. Understanding these distinct roles is crucial for identifying novel therapeutic targets beyond direct antimicrobial approaches.
Study Design
Epithelial cells were infected with either wild-type C. jejuni or specific effector mutants to investigate the role of ERK signaling. The study utilized focal adhesion inhibitors to prevent ERK1/2 activation and a phosphomimetic peptide designed to disrupt ERK nuclear translocation. Researchers measured key markers of C. jejuni infection, including bacterial cell invasion using a gentamicin-protection assay and interleukin-8 (IL-8) cytokine secretion via ELISA. This design allowed for the differentiation of cytoplasmic versus nuclear ERK contributions to the infection process.
Results
The study demonstrated that inhibitors targeting ERK1/2 activation drastically reduced both C. jejuni internalization into epithelial cells and subsequent IL-8 secretion. Furthermore, ERK1/2 activation was found to be dependent on its association with the focal adhesion protein paxillin, a process mediated by the C. jejuni CiaD effector. Blocking ERK nuclear translocation with the phosphomimetic peptide resulted in a significant reduction in IL-8 secretion. Surprisingly, this blockade also led to a significant reduction in bacterial invasion, indicating a broader role for nuclear ERK than initially hypothesized. These findings clarify the distinct yet complementary roles of ERK in different cellular compartments during infection. The most impactful finding highlights the dual necessity of ERK signaling:
Both cytoplasmic and nuclear
ERKare necessary for maximal C. jejuni cell invasion, while nuclearERKis specifically required for C. jejuni-inducedIL-8secretion.
Key Findings
- Inhibitors of
ERK1/2activation drastically reduced C. jejuni internalization. - Inhibitors of
ERK1/2activation drastically reducedIL-8secretion. ERK1/2activation depends on its association with paxillin, mediated by C. jejuniCiaD.- Blocking
ERKnuclear translocation significantly reducedIL-8secretion. - Blocking
ERKnuclear translocation surprisingly reduced bacterial invasion.
Why It Matters
This research identifies host ERK signaling as a critical and potentially targetable pathway in Campylobacter jejuni infection. By demonstrating that both cytoplasmic and nuclear ERK are essential for bacterial invasion and IL-8 secretion, the study opens new avenues for therapeutic intervention. Targeting host ERK signaling could offer a novel strategy to reduce the severity of C. jejuni-mediated enteritis, potentially complementing or even replacing traditional antimicrobial approaches that face increasing resistance. While currently an in-vitro finding, this mechanistic insight suggests future drug development could focus on host-directed therapies that modulate ERK activity, moving beyond direct bacterial killing to mitigate disease pathology.
campylobacter-jejuni
erk1/2
il-8
bacterial-infection
gastroenteritis
in-vitro