BACKGROUND: Mechanisms by which spontaneous clearance of acute hepatitis C(AHC) 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 signalling in AHC, correlates with clinical outcomes. METHODS: Participants identified from the ATAHC-I and Networks studies were followed longitudinally from time of diagnosis of AHC. Peripheral blood mononuclear cells(PBMCs) and plasma were collected at diagnosis and two time points post-diagnosis. At each time point, TLR2, TLR4 and CD86 expression on peripheral blood monocytes, natural killer(NK) cells and NKT cells was measured, as well as response of PBMCs to stimulation with TLR ligands. Cytokine/chemokine levels were measured in stimulated PBMCs and plasma. RESULTS: We identified twenty participants with AHC(10 mono-infected,10 HCV/HIV co-infected). Eleven(55%) participants spontaneously cleared HCV. AHC and spontaneous clearance was associated with lower TLR4 expression on monocytes(p=0.009) and NK cells(p=0.029). AHC and spontaneous clearance was also associated with reduced IFN-gamma response to TLR4(p=0.038) and TLR7/8 stimulation(p=0.035), reduced IL-6 response to TLR7/8 stimulation(p=0.037) and reduced IP-10 response to TLR2 stimulation(p=0.042). Lower plasma IP-10 levels were associated with spontaneous clearance(p=0.001). CONCLUSION: These findings implicate TLR4 signaling as playing a critical role in the outcomes of AHC.
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