HIV‐1 Tat Protein Suppresses Cholangiocyte Toll‐Like Receptor 4 Expression and Defense against<i>Cryptosporidium parvum</i>

O’Hara, Steven P.; Small, Aaron J.; Gajdos, Gabriella B.; Badley, Andrew D.; Chen, Xian Ming; LaRusso, Nicholas F.

doi:10.1086/597387

Cited by 33 publications

(27 citation statements)

References 45 publications

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“…It has been reported that the HIV-1 Tat protein increases the half life of the TLR4 mRNA, but decreases TLR4 translation. 43 Recently, it was reported that exposure to the HIV-1 proteins Tat and gp120 significantly alters TLR expression in astrocytes. 44 Together, these results indicate that HIV-1 proteins alter the innate response, supporting our hypothesis.…”

Section: Discussionmentioning

confidence: 99%

HIV Type 1 Infection Up-Regulates TLR2 and TLR4 Expression and Function in Vivo and in Vitro

Hernández

Stevenson

Latz

et al. 2012

AIDS Research and Human Retroviruses

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Toll-like receptors (TLRs) play a critical role in innate immunity against pathogens. Their stimulation induces the activation of NF-jB, an important inducer of HIV-1 replication. In recent years, an increasing number of studies using several cells types from HIV-infected patients indicate that TLRs play a key role in regulating the expression of proinflammatory cytokines and viral pathogenesis. In the present study, the effect of HIV-1 stimulation of monocyte-derived macrophage (MDM) and peripheral blood mononuclear cell (PBMC) subpopulations from healthy donors on the expression and functions of TLR2 and TLR4 was examined. In addition, and to complete the in vitro study, the expression pattern of TLR2 and TLR4 in 49 HIV-1-infected patients, classified according to viral load and the use of HAART, was determined and compared with 25 healthy subjects. An increase of TLR expression and production of proinflammatory cytokines were observed in MDMs and PBMCs infected with HIV-1 in vitro and in response to TLR stimulation, compared to the mock. In addition, an association between TLR expression and up-regulation of CD80 in plasmacytoid dendritic cells (pDCs) was observed. The ex vivo analysis indicated increased expression of TLR2 and TLR4 in myeloid dendritic cells (mDCs), but only of TLR2 in monocytes obtained from HIV-1-infected patients, compared to healthy subjects. Remarkably, the expression was higher in cells from patients who do not use HAART. In monocytes, there was a positive correlation between both TLRs and viral load, but not CD4 + T cell numbers. Together, our in vitro and ex vivo results suggest that TLR expression and function can be up-regulated in response to HIV-1 infection and could affect the inflammatory response. We propose that modulation of TLRs represents a mechanism to promote HIV-1 replication or AIDS progression in HIV-1-infected patients.

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Section: Discussionmentioning

confidence: 99%

HIV Type 1 Infection Up-Regulates TLR2 and TLR4 Expression and Function in Vivo and in Vitro

Hernández

Stevenson

Latz

et al. 2012

AIDS Research and Human Retroviruses

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“…Although bile is thought to be sterile under normal physiological conditions, biliary epithelial cells lining bile ducts (cholangiocytes) are periodically exposed to potentially pathogenic organisms or products derived from these microbes (1)(2)(3)(4). Indeed, cholangiocytes are exposed to bacteria (5-9), viruses (10 -12), and parasites (13)(14)(15)(16). Cholangiocyte pathogen recognition promotes innate and adaptive immune responses (4,(17)(18)(19) through the expression of adhesion molecules (20 -22) and the secretion of cytokines/chemokines (23,24) and antimicrobial peptides (18,23).…”

mentioning

confidence: 99%

Cholangiocyte N-Ras Protein Mediates Lipopolysaccharide-induced Interleukin 6 Secretion and Proliferation

O’Hara

Splinter

Trussoni

et al. 2011

Journal of Biological Chemistry

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Cholangiocytes, the epithelial cells lining the bile ducts in the liver, are periodically exposed to potentially injurious microbes and/or microbial products. As a result, cholangiocytes actively participate in microbe-associated, hepatic proinflammatory responses. We previously showed that infection of cultured human cholangiocytes with the protozoan parasite, Cryptosporidium parvum, or treatment with Gram-negative bacteria-derived LPS, activates NFB in a myeloid differentiation 88 (MyD88)-dependent manner. Here, we describe a novel signaling pathway initiated by Toll-like receptors (TLRs) involving the small GTPase, Ras, that mediates cholangiocyte proinflammatory cytokine production and induction of cholangiocyte proliferation. Using cultured human cholangiocytes and a Ras activation assay, we found that agonists of plasma membrane TLRs (TLR 1, 2, 4, 5, and 6) rapidly (<10 min) activated N-Ras, but not other p21 Ras isoforms, resulting in the rapid (<15 min) phosphorylation of the downstream Ras effector, ERK1/2. RNA interference-induced depletion of TRAF6, a downstream effector of MyD88 and known activator of MAPK signaling, had no effect on N-Ras activation. Following N-Ras activation the proinflammatory cytokine, IL6, is rapidly secreted. Using a luciferase reporter, we demonstrated that LPS treatment induced IL6 promoter-driven luciferase which was suppressed using MEK/ ERK pharmacologic inhibitors (PD98059 or U0126) and RNAiinduced depletion of N-Ras. Finally, we showed that LPS increased cholangiocyte proliferation (1.5-fold), which was inhibited by depletion of N-Ras; TLR agonist-induced proliferation was also inhibited following pretreatment with an IL6 receptor-blocking antibody. Together, our results support a novel signaling axis involving microbial activation of N-Ras likely involved in the cholangiocyte pathogen-induced proinflammatory response.Intrahepatic bile ducts form a complex three-dimensional tubular network that modifies the composition of bile and serves as a conduit for delivery of bile to the duodenum. Although bile is thought to be sterile under normal physiological conditions, biliary epithelial cells lining bile ducts (cholangiocytes) are periodically exposed to potentially pathogenic organisms or products derived from these microbes (1-4). Indeed, cholangiocytes are exposed to bacteria (5-9), viruses (10 -12), and parasites (13-16). Cholangiocyte pathogen recognition promotes innate and adaptive immune responses (4, 17-19) through the expression of adhesion molecules (20 -22) and the secretion of cytokines/chemokines (23, 24) and antimicrobial peptides (18, 23). Thus, cholangiocytes once thought of as an exclusively secretory/absorptive epithelium with a primary role in bile modification, are now recognized as important in the hepatic proinflammatory response to microorganisms or microbially derived products. However, the molecular pathways regulating cholangiocyte recognition and response to microbial insults are obscure and are the focus of the work presented here. Toll-like r...

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“…The two diseases can occur concurrently, with similar opportunistic infections causing each. Bile ducts in AIDS patients appear to be uniquely susceptible to opportunistic infections [11]. Ultrasonogra- "nutritional-like", inflammatory and both of these together [16].…”

Section: Form Non-invasive Inexpensive and Safe Imaging Technique Tmentioning

confidence: 99%

Correlation between Abdominal Ultrasonographic Findings and CD4 Cell Count in Adult Patients with HIV/AIDS in Jos, Nigeria

Eze¹,

Chom²,

Igoh³

et al. 2017

AMI

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CD + counts were studied. Two hundred (40%) of the patients had normal abdominal ultrasound, while 60% (300) had various abnormalities. The common abnormalities included increased liver parenchymal echogenicity in 25.0%, hepatomegaly in 23.4%, splenomegaly in 6.6%, increased splenic echogenicity in 6.2% and thickened gallbladder wall in 12.6%, elevated renal parenchymal echogenicity in 6.4%, enlarged kidneys in 2.6%, lymphadenopathy in 6.0%, and ascites in 2.4%. Pelvic abscess was the least pathology in 0.2%.Most of the findings did not correlate with the patients' 4 CD + count except for lymphadenopathy and ascites. Although abdominal ultrasound examination is invaluable in the management of these patients, however, it has not shown to be useful in predicting the patients' immune status.

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HIV‐1 Tat Protein Suppresses Cholangiocyte Toll‐Like Receptor 4 Expression and Defense againstCryptosporidium parvum

Cited by 33 publications

References 45 publications

HIV Type 1 Infection Up-Regulates TLR2 and TLR4 Expression and Function in Vivo and in Vitro

HIV Type 1 Infection Up-Regulates TLR2 and TLR4 Expression and Function in Vivo and in Vitro

Cholangiocyte N-Ras Protein Mediates Lipopolysaccharide-induced Interleukin 6 Secretion and Proliferation

Correlation between Abdominal Ultrasonographic Findings and CD4 Cell Count in Adult Patients with HIV/AIDS in Jos, Nigeria

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