HIV-1 tat protein suppresses cholangiocyte toll- like receptor 4 expression and defense against cryptosporidium parvum

Steven P. O'Hara, Aaron J. Small, Gabriella B. Gajdos, Andrew David Badley, Xian Ming Chen, Nicholas F La Russo

Research output: Contribution to journalArticle

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Abstract

Biliary cryptosporidiosis is associated with acquired immunodeficiency syndrome (AIDS) cholangiopathy and occurs almost exclusively in adult patients with AIDS. Infection of biliary epithelial cells (cholangiocytes) with Cryptosporidium parvum induces Toll-like receptor (TLR) 4 expression and stimulates a TLR-dependent response against infection. Here, we tested whether human immunodeficiency virus type 1 (HIV-1) Tat affects TLR expression and, hence, anti-C. parvum defense responses. Using an in vitro model of human biliary cryptosporidiosis, we found that recombinant Tat protein increased TLR4 mRNA expression in both uninfected and C. parvum-infected cholangiocytes. Conversely, Tat decreased TLR4 protein levels and suppressed C. parvum-induced TLR4 protein expression. Using actinomycin to inhibit transcription,wefound that Tat increased the half-life ofTLR4mRNAfrom̃25 to 60 min, and RNA gel-shift assays demonstrated direct binding of Tat to TLR4 mRNA. In vitro transcription/translation studies suggested that Tat does not affect transcription but does decrease TLR4 translation. Importantly, more parasites were foundin Tat-treated cellsthanin control cells48hafter infection. Thesefindingssuggest thatTatinhibits cholangiocyte TLR4proteinexpressionthroughtranslational inhibition. Theseeventsappeartodiminishtheabilityofcholangiocytes to initiate an innate immune response to C. parvum. We suggest that these findings may contribute to the unusual susceptibility of HIV-infected individuals to biliary cryptosporidiosis.

Original languageEnglish (US)
Pages (from-to)1195-1204
Number of pages10
JournalJournal of Infectious Diseases
Volume199
Issue number8
DOIs
StatePublished - Apr 15 2009

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tat Gene Products
Cryptosporidium parvum
Toll-Like Receptor 4
HIV-1
Cryptosporidiosis
Toll-Like Receptors
Acquired Immunodeficiency Syndrome
Messenger RNA
Dactinomycin
Infection Control
Infection
Recombinant Proteins
Innate Immunity
Half-Life
Parasites
Proteins
Gels
Epithelial Cells
HIV
RNA

ASJC Scopus subject areas

  • Infectious Diseases
  • Immunology and Allergy

Cite this

HIV-1 tat protein suppresses cholangiocyte toll- like receptor 4 expression and defense against cryptosporidium parvum. / O'Hara, Steven P.; Small, Aaron J.; Gajdos, Gabriella B.; Badley, Andrew David; Chen, Xian Ming; La Russo, Nicholas F.

In: Journal of Infectious Diseases, Vol. 199, No. 8, 15.04.2009, p. 1195-1204.

Research output: Contribution to journalArticle

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abstract = "Biliary cryptosporidiosis is associated with acquired immunodeficiency syndrome (AIDS) cholangiopathy and occurs almost exclusively in adult patients with AIDS. Infection of biliary epithelial cells (cholangiocytes) with Cryptosporidium parvum induces Toll-like receptor (TLR) 4 expression and stimulates a TLR-dependent response against infection. Here, we tested whether human immunodeficiency virus type 1 (HIV-1) Tat affects TLR expression and, hence, anti-C. parvum defense responses. Using an in vitro model of human biliary cryptosporidiosis, we found that recombinant Tat protein increased TLR4 mRNA expression in both uninfected and C. parvum-infected cholangiocytes. Conversely, Tat decreased TLR4 protein levels and suppressed C. parvum-induced TLR4 protein expression. Using actinomycin to inhibit transcription,wefound that Tat increased the half-life ofTLR4mRNAfrom̃25 to 60 min, and RNA gel-shift assays demonstrated direct binding of Tat to TLR4 mRNA. In vitro transcription/translation studies suggested that Tat does not affect transcription but does decrease TLR4 translation. Importantly, more parasites were foundin Tat-treated cellsthanin control cells48hafter infection. Thesefindingssuggest thatTatinhibits cholangiocyte TLR4proteinexpressionthroughtranslational inhibition. Theseeventsappeartodiminishtheabilityofcholangiocytes to initiate an innate immune response to C. parvum. We suggest that these findings may contribute to the unusual susceptibility of HIV-infected individuals to biliary cryptosporidiosis.",
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