Swee Lin G Chen Yi Mei1, Jodie Burchell2, Narelle Skinner3, Rosie Millen3, Gail Matthews4, Margaret Hellard5, Gregory J Dore4, Paul V Desmond6, Vijaya Sundararajan2, Alexander J Thompson1, Kumar Visvanathan1, Joe Sasadeusz7. 1. Department of Gastroenterology, St Vincent's Hospital Immunology Research Centre, Department of Medicine, St Vincent's Hospital and the University of Melbourne. 2. Centre of Research Excellence, Department of Medicine, St Vincent's Hospital, Melbourne. 3. Immunology Research Centre, Department of Medicine, St Vincent's Hospital and the University of Melbourne. 4. Kirby Institute, University of New South Wales, Sydney. 5. Centre for Population Health, Burnet Institute Department of Infectious Diseases, the Alfred Hospital, Melbourne, Australia. 6. Department of Gastroenterology, St Vincent's Hospital. 7. Department of Infectious Diseases, Royal Melbourne Hospital.
Abstract
BACKGROUND: Mechanisms by which spontaneous clearance of acute hepatitis C occurs are unclear. A critical role for the innate immune system and IFNL4 polymorphisms has been proposed. This study investigates whether Toll-like receptor (TLR) expression and signaling during acute hepatitis C correlates with clinical outcomes. METHODS: Participants identified from the Australian Trial in Acute Hepatitis C and the Networks study were followed longitudinally from the time of diagnosis of acute hepatitis C. Peripheral blood mononuclear cells (PBMCs) and plasma were collected at and 2 time points after diagnosis. At each time point, TLR2, TLR4, and CD86 expression on peripheral blood monocytes, natural killer (NK) cells, and NK T cells was measured, as well as the response of PBMCs to stimulation with TLR ligands. Cytokine and chemokine levels were measured in stimulated PBMCs and plasma. RESULTS: We identified 20 participants with acute hepatitis C (10 with hepatitis C virus [HCV] monoinfection and 10 with HCV and human immunodeficiency virus coinfection). Eleven participants (55%) spontaneously cleared HCV. Acute hepatitis C and spontaneous clearance was associated with lower TLR4 expression on monocytes (P = .009) and NK cells (P = .029). Acute hepatitis C and spontaneous clearance was also associated with a reduced interferon γ response to TLR4 (P = .038) and TLR7/8 stimulation (P = .035), a reduced interleukin 6 response to TLR7/8 stimulation (P = .037), and reduced IFN-γ-inducible protein 10 (IP-10) response to TLR2 stimulation (P = .042). Lower plasma IP-10 levels were associated with spontaneous clearance (P = .001). CONCLUSIONS: These findings implicate TLR4 signaling as playing a critical role in the outcome of acute hepatitis C.
BACKGROUND: Mechanisms by which spontaneous clearance of acute hepatitis C occurs are unclear. A critical role for the innate immune system and IFNL4 polymorphisms has been proposed. This study investigates whether Toll-like receptor (TLR) expression and signaling during acute hepatitis C correlates with clinical outcomes. METHODS:Participants identified from the Australian Trial in Acute Hepatitis C and the Networks study were followed longitudinally from the time of diagnosis of acute hepatitis C. Peripheral blood mononuclear cells (PBMCs) and plasma were collected at and 2 time points after diagnosis. At each time point, TLR2, TLR4, and CD86 expression on peripheral blood monocytes, natural killer (NK) cells, and NK T cells was measured, as well as the response of PBMCs to stimulation with TLR ligands. Cytokine and chemokine levels were measured in stimulated PBMCs and plasma. RESULTS: We identified 20 participants with acute hepatitis C (10 with hepatitis C virus [HCV] monoinfection and 10 with HCV and human immunodeficiency virus coinfection). Eleven participants (55%) spontaneously cleared HCV. Acute hepatitis C and spontaneous clearance was associated with lower TLR4 expression on monocytes (P = .009) and NK cells (P = .029). Acute hepatitis C and spontaneous clearance was also associated with a reduced interferon γ response to TLR4 (P = .038) and TLR7/8 stimulation (P = .035), a reduced interleukin 6 response to TLR7/8 stimulation (P = .037), and reduced IFN-γ-inducible protein 10 (IP-10) response to TLR2 stimulation (P = .042). Lower plasma IP-10 levels were associated with spontaneous clearance (P = .001). CONCLUSIONS: These findings implicate TLR4 signaling as playing a critical role in the outcome of acute hepatitis C.
Authors: David Butera; Svetlana Marukian; Amy E Iwamaye; Edgardo Hembrador; Thomas J Chambers; Adrian M Di Bisceglie; Edgar D Charles; Andrew H Talal; Ira M Jacobson; Charles M Rice; Lynn B Dustin Journal: Blood Date: 2005-04-28 Impact factor: 22.113
Authors: Hans L Tillmann; Alex J Thompson; Keyur Patel; Manfred Wiese; Hannelore Tenckhoff; Hans D Nischalke; Yuliya Lokhnygina; Ulrike Kullig; Uwe Göbel; Emanuela Capka; Johannes Wiegand; Ingolf Schiefke; Wolfgang Güthoff; Kurt Grüngreiff; Ingrid König; Ulrich Spengler; Jeanette McCarthy; Kevin V Shianna; David B Goldstein; John G McHutchison; Jörg Timm; Jacob Nattermann Journal: Gastroenterology Date: 2010-07-14 Impact factor: 22.682
Authors: Montserrat Laguno; Javier Murillas; José Luis Blanco; Esteban Martínez; Rosa Miquel; José M Sánchez-Tapias; Xavier Bargallo; Angeles García-Criado; Elisa de Lazzari; María Larrousse; Agathe León; Montserrat Loncá; Ana Milinkovic; Josep M Gatell; Josep Mallolas Journal: AIDS Date: 2004-09-03 Impact factor: 4.177
Authors: Richard T Lester; Xiao-Dan Yao; T Blake Ball; Lyle R McKinnon; Rupert Kaul; Charles Wachihi; Walter Jaoko; Francis A Plummer; Kenneth L Rosenthal Journal: AIDS Date: 2008-03-30 Impact factor: 4.177
Authors: David L Thomas; Chloe L Thio; Maureen P Martin; Ying Qi; Dongliang Ge; Colm O'Huigin; Judith Kidd; Kenneth Kidd; Salim I Khakoo; Graeme Alexander; James J Goedert; Gregory D Kirk; Sharyne M Donfield; Hugo R Rosen; Leslie H Tobler; Michael P Busch; John G McHutchison; David B Goldstein; Mary Carrington Journal: Nature Date: 2009-10-08 Impact factor: 49.962
Authors: Ahmed A Al-Qahtani; Mashael R Al-Anazi; Fahad Al-Zoghaibi; Ayman A Abdo; Faisal M Sanai; Mohammed Q Khan; Ali Albenmousa; Hamad I Al-Ashgar; Mohammed N Al-Ahdal Journal: Biomed Res Int Date: 2014-08-10 Impact factor: 3.411
Authors: Campbell K Aitken; Rhonda F McCaw; D Scott Bowden; Samantha L Tracy; Jenny G Kelsall; Peter G Higgs; Michael J Kerger; Hoang Nguyen; J Nick Crofts Journal: J Infect Dis Date: 2004-09-23 Impact factor: 5.226
Authors: Krystal Colón; David W Speicher; Peter Smith; Mack Taylor; David S Metzger; Luis J Montaner; Costin Tomescu Journal: J Acquir Immune Defic Syndr Date: 2019-02-01 Impact factor: 3.731
Authors: Benjamin Krämer; Claudia Finnemann; Beatriz Sastre; Philipp Lutz; Andreas Glässner; Franziska Wolter; Felix Goeser; Pavlos Kokordelis; Dominik Kaczmarek; Hans-Dieter Nischalke; Christian P Strassburg; Ulrich Spengler; Jacob Nattermann Journal: PLoS One Date: 2016-09-01 Impact factor: 3.240
Authors: María Teresa Arias-Loste; Joaquín Cabezas; Susana Llerena; Paula Iruzubieta; David San-Segundo; David Merino; Antonio Cuadrado; José Pedro Vaqué; Marcos López-Hoyos; Javier Crespo Journal: Viruses Date: 2021-04-07 Impact factor: 5.048