EspO-mediated neutrophil accumulation drives lethality during Citrobacter rodentium infection in interleukin-22-deficient mice
- 1Department of Life Sciences, Imperial, London, United Kingdom
- 2Functional Proteomics Group, Chester Beatty Laboratories, Institute of Cancer Research, London, United Kingdom
Abstract
Citrobacter rodentium (CR) is a murine-specific enteric pathogen widely used to model infections of the attaching and effacing pathogens enteropathogenic and enterohaemorrhagic Escherichia coli. Infection induces colonic epithelial damage and inflammation that are resolved in resistant mice but result in severe disease and mortality in mice lacking interleukin-22 (IL-22). While IL-22-deficient (Il22−/−) mice succumb to CR infection due to dehydration, in part mediated by disruption of the barrier integrity by the type III secretion system (T3SS) effector EspF, the contribution of immunopathology to infection outcomes is not known. Here, using CR we tested whether dysregulated neutrophil responses drive disease progression in Il22−/− mice. We show that IL-22 deficiency is associated with progressive colonic pathology and increased neutrophil accumulation and activity in the colonic mucosa. Infection of mice with CR lacking the T3SS effector EspO, which is implicated in neutrophil recruitment, resulted in markedly reduced neutrophil accumulation and activity in Il22−/− mice without altering bacterial burden. Notably, CRΔespO infection led to reduced colonic inflammation and complete survival of Il22−/− mice. Consistent with these findings, CXCR2 antagonist treated Il22−/− mice displayed attenuated disease severity and delayed mortality. Together, we identified EspO as the second effector, alongside EspF, whose deletion results in survival of CR-infected Il22−/− mice. Moreover, these findings suggest that excessive neutrophil accumulation and activity are key drivers of lethality during CR infection in Il22−/− mice and that EspO amplifies neutrophil-dependent pathology within a vulnerable epithelial environment. Author summary: The immune system protects the intestine from infection, but excessive inflammation can itself cause severe tissue damage and disease. Interleukin-22 (IL-22) is a key cytokine that supports intestinal epithelial defence during infection with Citrobacter rodentium (CR), a bacterial pathogen commonly used to model human diarrhoeal disease. Mice lacking IL-22 develop severe lethal colitis following CR infection, but the role of immunopathology in this outcome has remained unclear. Here, we show that IL-22-deficient mice develop excessive accumulation and activation of neutrophils in the colon during CR infection. Rather than being protective, these exaggerated neutrophil responses drive lethal immunopathology. Using deletion of the bacterial virulence factor EspO as a pathogen-encoded means to attenuate neutrophil recruitment, we demonstrate that reducing colonic neutrophil accumulation is sufficient to prevent mortality. Our findings identify dysregulated neutrophil responses as key determinants of CR-induced lethality in IL-22-deficient mice and reveal how a bacterial effector can amplify harmful inflammation in a vulnerable host environment.
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BibTeX
@article{mishra2026espomediated,
title = {{EspO-mediated neutrophil accumulation drives lethality during Citrobacter rodentium infection in interleukin-22-deficient mice}},
author = {Vishwas Mishra and Priyanka Biswas and Zuza Kozik and Jyoti Choudhary and Gad Frankel},
journal = {PLOS Pathogens},
year = {2026},
month = sep,
doi = {10.1371/journal.ppat.1014567},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014567},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - EspO-mediated neutrophil accumulation drives lethality during Citrobacter rodentium infection in interleukin-22-deficient mice
AU - Vishwas Mishra
AU - Priyanka Biswas
AU - Zuza Kozik
AU - Jyoti Choudhary
AU - Gad Frankel
PY - 2026
DA - 2026/09/02
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014567
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014567
AB - Citrobacter rodentium (CR) is a murine-specific enteric pathogen widely used to model infections of the attaching and effacing pathogens enteropathogenic and enterohaemorrhagic Escherichia coli. Infection induces colonic epithelial damage and inflammation that are resolved in resistant mice but result in severe disease and mortality in mice lacking interleukin-22 (IL-22). While IL-22-deficient (Il22−/−) mice succumb to CR infection due to dehydration, in part mediated by disruption of the barrier integrity by the type III secretion system (T3SS) effector EspF, the contribution of immunopathology to infection outcomes is not known. Here, using CR we tested whether dysregulated neutrophil responses drive disease progression in Il22−/− mice. We show that IL-22 deficiency is associated with progressive colonic pathology and increased neutrophil accumulation and activity in the colonic mucosa. Infection of mice with CR lacking the T3SS effector EspO, which is implicated in neutrophil recruitment, resulted in markedly reduced neutrophil accumulation and activity in Il22−/− mice without altering bacterial burden. Notably, CRΔespO infection led to reduced colonic inflammation and complete survival of Il22−/− mice. Consistent with these findings, CXCR2 antagonist treated Il22−/− mice displayed attenuated disease severity and delayed mortality. Together, we identified EspO as the second effector, alongside EspF, whose deletion results in survival of CR-infected Il22−/− mice. Moreover, these findings suggest that excessive neutrophil accumulation and activity are key drivers of lethality during CR infection in Il22−/− mice and that EspO amplifies neutrophil-dependent pathology within a vulnerable epithelial environment. Author summary: The immune system protects the intestine from infection, but excessive inflammation can itself cause severe tissue damage and disease. Interleukin-22 (IL-22) is a key cytokine that supports intestinal epithelial defence during infection with Citrobacter rodentium (CR), a bacterial pathogen commonly used to model human diarrhoeal disease. Mice lacking IL-22 develop severe lethal colitis following CR infection, but the role of immunopathology in this outcome has remained unclear. Here, we show that IL-22-deficient mice develop excessive accumulation and activation of neutrophils in the colon during CR infection. Rather than being protective, these exaggerated neutrophil responses drive lethal immunopathology. Using deletion of the bacterial virulence factor EspO as a pathogen-encoded means to attenuate neutrophil recruitment, we demonstrate that reducing colonic neutrophil accumulation is sufficient to prevent mortality. Our findings identify dysregulated neutrophil responses as key determinants of CR-induced lethality in IL-22-deficient mice and reveal how a bacterial effector can amplify harmful inflammation in a vulnerable host environment.
SN - 1553-7374
ER -