Poly(I:C) and lipopolysaccharide innate sensing functions of circulating human myeloid dendritic cells are affected in vivo in hepatitis C virus-infected patients.
The role of peripheral dendritic cells (DCs) in hepatitis C virus (HCV) infection is unclear. To determine if persistent infection exerts an inhibitory pressure on HCV-specific innate responses, we analyzed DC function in blood through quantification of cell-associated HCV RNA levels in conjunction with multiparametric flow cytometry analysis of pathogen recognition receptor-induced cytokine expression. Independently of the serum viral load, fluorescence-activated cell sorter-purified total DCs had a wide range of cell-associated HCV genomic RNA copy numbers (mean log(10), 5.0 per 10(6) cells; range, 4.3 to 5.8). Here we report that for viremic patients with high viral loads in their total DCs, the myeloid DC (MDC) subset displayed impaired expression of interleukin-12 (IL-12) and tumor necrosis factor alpha (TNF-alpha) but normal IL-6 or chemokine CCL3 expression in response to poly(I:C) and lipopolysaccharide (LPS). IL-6-expressing cells from this subgroup of viremic patients demonstrated a significant increase (sixfold more) in TNF-alpha(-) IL-12(-) cell frequency compared to healthy donors (mean, 38.8% versus 6.5%; P < 0.0001), indicating a functional defect in a subpopulation of cytokine-producing MDCs ( approximately 6% of MDCs). Attenuation of poly(I:C) and LPS innate sensing was HCV RNA density dependent and did not correlate with viremia or deficits in circulating MDC frequencies in HCV-infected patients. Monocytes from these patients were functionally intact, responding normally on a per-cell basis following stimulation, independent of cell-associated HCV RNA levels. Taken together, these data indicate that detection of HCV genomic RNA in DCs and loss of function in the danger signal responsiveness of a small proportion of DCs in vivo are interrelated rather than independent phenomena.
Rodrigue-Gervais
Ian Gaël
IG
Centre Hospitalier de l'Université de Montréal, Hôpital Saint-Luc, 264 Boul. René-Lévesque Est, Rm. EA-312, Montréal, Québec, Canada H2X 1P1.
Jouan
Loubna
L
Beaulé
Geneviève
G
Sauvé
Dominike
D
Bruneau
Julie
J
Willems
Bernard
B
Sékaly
Rafick-Pierre
RP
Lamarre
Daniel
D
D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D005260:Female; D016174:Hepacivirus / Q000235:genetics / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000097:blood* / Q000473:pathology / Q000821:virology; D006801:Humans; D008070:Lipopolysaccharides / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D022423:Myeloid Cells / Q000378:metabolism* / Q000473:pathology; D011070:Poly I-C / Q000378:metabolism*; D012367:RNA, Viral / Q000097:blood
D008070:Lipopolysaccharides; D012367:RNA, Viral; D011070:Poly I-C