Regulation of intestinal epithelial cell cytoskeletal remodeling by cellular immunity following gut infection.
Gut infections often lead to epithelial cell damage followed by a healing response. We examined changes in the epithelial cell cytoskeleton and the involvement of host adaptive immunity in these events using an in vivo model of parasitic infection. We found that both ezrin and villin, key components of the actin cytoskeleton comprising the brush border (BB) of intestinal epithelial cells (IECs), underwent significant post-translational changes following gut infection and during the recovery phase of gut infection. Intriguingly, using mice lacking either CD4(+) or CD8(+) T-cell responses, we demonstrated that the mechanisms by which ezrin and villin are regulated in response to infection are different. Both ezrin and villin undergo proteolysis during the recovery phase of infection. Cleavage of ezrin requires CD4(+) but not CD8(+) T cells, whereas cleavage of villin requires both CD4(+) and CD8(+) T-cell responses. Both proteins were also regulated by phosphorylation; reduced levels of phosphorylated ezrin and increased levels of villin phosphorylation were observed at the peak of infection and correlated with reduced BB enzyme activity. Finally, we show that infection also leads to enhanced proliferation of IECs in this model. Cytoskeletal remodeling in IECs can have critical roles in the immunopathology and healing responses observed during many infectious and non-infectious intestinal conditions. These data indicate that cellular immune responses can be significant drivers of these processes.
Department of Biology and Center for Infectious Disease, Georgetown University, Washington, DC, USA. ssolaymanimohammadi@ucsd.edu
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D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002154:Calpain / Q000378:metabolism; D002465:Cell Movement / Q000276:immunology; D049109:Cell Proliferation; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D016829:Giardia lamblia / Q000276:immunology; D005873:Giardiasis / Q000276:immunology / Q000378:metabolism; D007111:Immunity, Cellular; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology; D007422:Intestines / Q000276:immunology / Q000469:parasitology; D051379:Mice; D016513:Mice, SCID; D008840:Microfilament Proteins / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport; D059748:Proteolysis; D000099149:Ezrin
D002154:Calpain; D003598:Cytoskeletal Proteins; D008840:Microfilament Proteins; D000099149:Ezrin; C026615:villin