TLR4 promotes cryptosporidium parvum clearance in a mouse model of biliary cryptosporidiosis

Steven P. O'Hara, Pamela S. Tietz Bogert, Christy E. Trussoni, Xian-Ming Chen, Nicholas F. Larusso

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)813-821
Number of pages9
JournalJournal of Parasitology
Volume97
Issue number5
DOIs
StatePublished - Oct 2011

Fingerprint

Cryptosporidium parvum
Cryptosporidiosis
cryptosporidiosis
animal models
Infection
infection
Inbred C57BL Mouse
mice
Aspartate Aminotransferases
Alanine Transaminase
alanine transaminase
interleukin-6
aspartate transaminase
Interleukin-6
Intrahepatic Bile Ducts
Pattern Recognition Receptors
transcription factor NF-kappa B
liver
functional role
bile ducts

All Science Journal Classification (ASJC) codes

  • Parasitology
  • Ecology, Evolution, Behavior and Systematics

Cite this

TLR4 promotes cryptosporidium parvum clearance in a mouse model of biliary cryptosporidiosis. / O'Hara, Steven P.; Tietz Bogert, Pamela S.; Trussoni, Christy E.; Chen, Xian-Ming; Larusso, Nicholas F.

In: Journal of Parasitology, Vol. 97, No. 5, 10.2011, p. 813-821.

Research output: Contribution to journalArticle

O'Hara, Steven P. ; Tietz Bogert, Pamela S. ; Trussoni, Christy E. ; Chen, Xian-Ming ; Larusso, Nicholas F. / TLR4 promotes cryptosporidium parvum clearance in a mouse model of biliary cryptosporidiosis. In: Journal of Parasitology. 2011 ; Vol. 97, No. 5. pp. 813-821.
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