title: TLR4 promotes Cryptosporidium parvum clearance in a mouse model of biliary cryptosporidiosis.
abstract: Cholangiocytes, the epithelial cells lining intrahepatic bile ducts, express multiple toll-like receptors (TLRs) and, thus, have the capacity to recognize and respond to microbial pathogens. In previous work, we demonstrated that TLR4, which is activated by gram-negative lipopolysaccharide (LPS), is upregulated in cholangiocytes in response to infection with Cryptosporidium parvum in vitro and contributes to nuclear factor-kappaB (NF-kB) activation. Here, using an in vivo model of biliary cryptosporidiosis, we addressed the functional role of TLR4 in C. parvum infection dynamics and hepatobiliary pathophysiology. We observed that C57BL mice clear the infection by 3 wk post-infection (PI). In contrast, parasites were detected in bile and stool in TLR4-deficient mice at 4 wk PI. The liver enzymes alanine transaminase (ALT) and aspartate transaminase (AST), and the proinflammatory cytokines tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and interleukin (IL)-6 peaked at 1 to 2 wk PI and normalized by 4 wk in infected C57BL mice. C57BL mice also demonstrated increased cholangiocyte proliferation (PCNA staining) at 1 wk PI that was resolved by 2 wk PI. In contrast, TLR4-deficient mice showed persistently elevated serum ALT and AST, elevated hepatic IL-6 levels, and histological evidence of hepatocyte necrosis, increased inflammatory cell infiltration, and cholangiocyte proliferation through 4 wk PI. These data suggest that a TLR4-mediated response is required for efficient eradication of biliary C. parvum infection in vivo, and lack of this pattern-recognition receptor contributes to an altered inflammatory response and an increase in hepatobiliary pathology.
authors.affiliation: Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, and Mayo Clinic Center for Cell Signaling, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: O'Hara
authors.forename: Pamela S Tietz
authors.initials: PS
authors.lastname: Bogert
authors.forename: Christy E
authors.initials: CE
authors.lastname: Trussoni
authors.forename: Xianming
authors.initials: X
authors.lastname: Chen
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: LaRusso
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001649:Bile Duct Diseases / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000469:parasitology; D003457:Cryptosporidiosis / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D016785:Cryptosporidium parvum; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D008099:Liver / Q000201:enzymology / Q000469:parasitology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000502:physiology*
chemical_list: D016207:Cytokines; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase