Toll-like Receptor Expression and Signaling in Peripheral Blood Mononuclear Cells Correlate With Clinical Outcomes in Acute Hepatitis C Virus Infection.
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.



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.



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).



These findings implicate TLR4 signaling as playing a critical role in the outcome of acute hepatitis C.
Department of Gastroenterology, St Vincent's Hospital Immunology Research Centre, Department of Medicine, St Vincent's Hospital and the University of Melbourne.
Swee Lin G
SL
Chen Yi Mei
Centre of Research Excellence, Department of Medicine, St Vincent's Hospital, Melbourne.
Jodie
J
Burchell
Immunology Research Centre, Department of Medicine, St Vincent's Hospital and the University of Melbourne.
Narelle
N
Skinner
Immunology Research Centre, Department of Medicine, St Vincent's Hospital and the University of Melbourne.
Rosie
R
Millen
Kirby Institute, University of New South Wales, Sydney.
Gail
G
Matthews
Centre for Population Health, Burnet Institute Department of Infectious Diseases, the Alfred Hospital, Melbourne, Australia.
Margaret
M
Hellard
Kirby Institute, University of New South Wales, Sydney.
Gregory J
GJ
Dore
Department of Gastroenterology, St Vincent's Hospital.
Paul V
PV
Desmond
Centre of Research Excellence, Department of Medicine, St Vincent's Hospital, Melbourne.
Vijaya
V
Sundararajan
Department of Gastroenterology, St Vincent's Hospital Immunology Research Centre, Department of Medicine, St Vincent's Hospital and the University of Melbourne.
Alexander J
AJ
Thompson
Department of Gastroenterology, St Vincent's Hospital Immunology Research Centre, Department of Medicine, St Vincent's Hospital and the University of Melbourne.
Kumar
K
Visvanathan
Department of Infectious Diseases, Royal Melbourne Hospital.
Joe
J
Sasadeusz
D000328:Adult; D001315:Australia; D051940:B7-2 Antigen / Q000032:analysis; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006526:Hepatitis C / Q000276:immunology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000737:chemistry / Q000276:immunology*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000032:analysis*; D051197:Toll-Like Receptor 4 / Q000032:analysis*; D016896:Treatment Outcome
D051940:B7-2 Antigen; C497964:CD86 protein, human; D016207:Cytokines; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4
cytokines; hepatitis C; toll-like receptors