Abstract
Citrobacter rodentium infection is a model for infection with attaching and effacing pathogens, such as enteropathogenic Escherichia coli. The vasoactive intestinal peptide (VIP) has emerged as an anti-inflammatory agent, documented to inhibit Th1 immune responses and successfully treat animal models of inflammation. VIP is also a mucus secretagogue. Here, we found that colonic levels of VIP decrease during murine C. rodentium infection with a similar time dependency as measurements reflecting mitochondrial function and epithelial integrity. The decrease in VIP appears mainly driven by changes in the cytokine environment, as no changes in VIP levels were detected in infected mice lacking interferon gamma (IFNγ). VIP supplementation alleviated the reduction of activity and levels of mitochondrial respiratory complexes I and IV, mitochondrial phosphorylation capacity, transmembrane potential and ATP generation caused by IFNγ, TNFα and C. rodentium infection, in an in vitro mucosal surface. Similarly, VIP treatment regimens that included the day 5–10 post infection period alleviated decreases in enzyme complexes I and IV, phosphorylation capacity, mitochondrial transmembrane potential and ATP generation as well as increased apoptosis levels during murine infection with C. rodentium. However, VIP treatment failed to alleviate colitis, although there was a tendency to decreased pathogen density in contact with the epithelium and in the spleen. Both in vivo and in vitro, NO generation increased during C. rodentium infection, which was alleviated by VIP. Thus, therapeutic VIP administration to restore the decreased levels during infection had beneficial effects on epithelial cells and their mitochondria, but not on the overall infection outcome.
Highlights
Murine Citrobacter rodentium infection models infection with human enterohemorrhagic (EHEC) and enteropathogenic Escherichia coli (EPEC) [1,2,3]
In line with previous studies [54], the highest C. rodentium density in the feces of infected C57BL/6 wild type (WT) mice occurred around day 10, tended to decrease at day 14 and by day 19 and 22 post infection the number of C. rodentium in feces had decreased by log 5–6 to 100–1000 colony forming units (CFU)/g feces (Fig 2A)
This suggests that vasoactive intestinal peptide (VIP) levels, to mitochondrial function, may be more affected by the cytokine environment than pathogen density, as we previously have shown that the C. rodentium density is similar between WT and IFNγ deficient infected mice at day 10 post infection [14]
Summary
Murine Citrobacter rodentium infection models infection with human enterohemorrhagic (EHEC) and enteropathogenic Escherichia coli (EPEC) [1,2,3]. The attaching and effacing (A/E) pathogen C. rodentium mainly infects the luminal epithelial cells through the formation of a type III secretion system (T3SS), which initiates the host cell death pathway by inducing effector molecules like EspF and Map that translocate into the host mitochondria disrupting mitochondrial function [10,11,12,13]. Enhanced levels of pro-inflammatory cytokines induce mitochondrial dysfunction [14], which contributes to colonic epithelial cell death during infection. The impact of VIP on mitochondrial dysfunction in colonic epithelial cells during C rodentium infection remains uninvestigated. To assess if VIP can restore the cytokine induced mitochondrial dysfunction, we utilized an in vivo-like in vitro mucosal cell line model that forms a polarized epithelial surface and secretes a mucus layer [41]. We started the VIP administration post infection, due to that this is the most likely situation for a therapeutic regimen under non-experimental conditions
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