1887

Abstract

Extra-hepatic compartments might contribute to hepatitis C virus (HCV) persistence and extra-hepatic manifestations. Therefore, we investigated HCV infection in colonic tissue in patients with chronic hepatitis C (CHC) and its relationship with HCV pathogenesis. Colonic biopsies were collected from three groups with CHC infection: treatment naïve (TN; =12), non-responders (NR; =10) to anti-HCV therapy (pegylated interferon-α and ribavirin) and sustained virologic response (SVR; =10) and from a fourth healthy control group (=10). Liver biopsies were examined to assess inflammation and fibrosis. HCV infection and colonic T regulatory (T) frequency were detected by immunohistochemistry. HCV core and NS3 proteins were detected in B cells and macrophage/monocytes of 42 % and 25 % of TN and 50 % and 30 % of NR, respectively, but not in SVR or control group. The numbers of cells expressing HCV proteins were positively correlated with both HCV viral load and colonic T frequency. A significant negative correlation between HCV-expressing cells with both liver inflammation and fibrosis was identified. Our study provides evidence that HCV can infect B cells and macrophages of the colon. The correlations between HCV infection in colonic tissue and HCV viral load and liver pathology underline the significance of this extra-hepatic infection in HCV pathogenesis and response to therapy.

Loading

Article metrics loading...

/content/journal/jmm/10.1099/jmm.0.000272
2016-08-01
2024-03-29
Loading full text...

Full text loading...

/deliver/fulltext/jmm/65/8/703.html?itemId=/content/journal/jmm/10.1099/jmm.0.000272&mimeType=html&fmt=ahah

References

  1. Adams D. H., Eksteen B., Curbishley S. M. 2008; Immunology of the gut and liver: a love/hate relationship. Gut 57:838–848 [View Article][PubMed]
    [Google Scholar]
  2. Agnello V., De Rosa F. G. 2004; Extrahepatic disease manifestations of HCV infection: some current issues. J Hepatol 40:341–352 [View Article][PubMed]
    [Google Scholar]
  3. Barth H., Ulsenheimer A., Pape G. R., Diepolder H. M., Hoffmann M., Neumann-Haefelin C., Thimme R., Henneke P., Klein R. et al. 2005; Uptake and presentation of hepatitis C virus-like particles by human dendritic cells. Blood 105:3605–3614 [View Article][PubMed]
    [Google Scholar]
  4. Blackard J. T., Kemmer N., Sherman K. E. 2006; Extrahepatic replication of HCV: insights into clinical manifestations and biological consequences. Hepatology 44:15–22 [View Article][PubMed]
    [Google Scholar]
  5. Blackard J. T., Kong L., Huber A. K., Tomer Y. 2013; Hepatitis C virus infection of a thyroid cell line: implications for pathogenesis of hepatitis C virus and thyroiditis. Thyroid 23:863–870 [View Article][PubMed]
    [Google Scholar]
  6. Blight K. J., McKeating J. A., Rice C. M. 2002; Highly permissive cell lines for subgenomic and genomic hepatitis C virus RNA replication. J Virol 76:13001–13014 [View Article][PubMed]
    [Google Scholar]
  7. Cabrera R., Tu Z., Xu Y., Firpi R. J., Rosen H. R., Liu C., Nelson D. R. 2004; An immunomodulatory role for CD4(+)CD25(+) regulatory T lymphocytes in hepatitis C virus infection. Hepatology 40:1062–1071 [View Article][PubMed]
    [Google Scholar]
  8. Castillo I., Rodríguez-Iñigo E., Bartolomé J., de Lucas S., Ortíz-Movilla N., López-Alcorocho J. M., Pardo M., Carreño V. 2005; Hepatitis C virus replicates in peripheral blood mononuclear cells of patients with occult hepatitis C virus infection. Gut 54:682–685 [View Article][PubMed]
    [Google Scholar]
  9. Chang T. T., Young K. C., Yang Y. J., Lei H. Y., Wu H. L. 1996; Hepatitis C virus RNA in peripheral blood mononuclear cells: comparing acute and chronic hepatitis C virus infection. Hepatology 23:977–981 [View Article][PubMed]
    [Google Scholar]
  10. Coquillard G., Patterson B. K. 2009; Determination of hepatitis C virus-infected, monocyte lineage reservoirs in individuals with or without HIV coinfection. J Infect Dis 200:947–954 [View Article][PubMed]
    [Google Scholar]
  11. Deforges S., Evlashev A., Perret M., Sodoyer M., Pouzol S., Scoazec J. Y., Bonnaud B., Diaz O., Paranhos-Baccalà G. et al. 2004; Expression of hepatitis C virus proteins in epithelial intestinal cells in vivo. J Gen Virol 85:2515–2523 [View Article][PubMed]
    [Google Scholar]
  12. Fletcher N. F., Wilson G. K., Murray J., Hu K., Lewis A., Reynolds G. M., Stamataki Z., Meredith L. W., Rowe I. A. et al. 2012; Hepatitis C virus infects the endothelial cells of the blood-brain barrier. Gastroenterology 142:e636634–643 [View Article][PubMed]
    [Google Scholar]
  13. Frank C., Mohamed M. K., Strickland G. T., Lavanchy D., Arthur R. R., Magder L. S., El Khoby T., Abdel-Wahab Y., Aly Ohn E. S. et al. 2000; The role of parenteral antischistosomal therapy in the spread of hepatitis C virus in Egypt. Lancet 355:887–891 [View Article][PubMed]
    [Google Scholar]
  14. Féray C., Samuel D., Thiers V., Gigou M., Pichon F., Bismuth A., Reynes M., Maisonneuve P., Bismuth H., Bréchot C. 1992; Reinfection of liver graft by hepatitis C virus after liver transplantation. J Clin Invest 89:1361–1365 [View Article][PubMed]
    [Google Scholar]
  15. Gouda I., Nada O., Ezzat S., Eldaly M., Loffredo C., Taylor C., Abdel-Hamid M. 2010; Immunohistochemical detection of hepatitis C virus (genotype 4) in B-cell NHL in an Egyptian population: correlation with serum HCV-RNA. Appl Immunohistochem Mol Morphol 18:29–34 [View Article][PubMed]
    [Google Scholar]
  16. Griffin S. D., Beales L. P., Clarke D. S., Worsfold O., Evans S. D., Jaeger J., Harris M. P., Rowlands D. J. 2003; The p7 protein of hepatitis C virus forms an ion channel that is blocked by the antiviral drug, Amantadine. FEBS Lett 535:34–38 [View Article][PubMed]
    [Google Scholar]
  17. Gualdi R., Bossard P., Zheng M., Hamada Y., Coleman J. R., Zaret K. S. 1996; Hepatic specification of the gut endoderm in vitro: cell signaling and transcriptional control. Genes Dev 10:1670–1682 [View Article][PubMed]
    [Google Scholar]
  18. Gumber S. C., Chopra S. 1995; Hepatitis C: a multifaceted disease. Review of extrahepatic manifestations. Ann Intern Med 123:615–620 [View Article][PubMed]
    [Google Scholar]
  19. Hetta H. F. 2014; Gut immune response in the presence of hepatitis C virus infection. World J Immunol 4:52–62 [View Article]
    [Google Scholar]
  20. Hetta H. F., Mekky M. A., Khalil N. K., Mohamed W. A., El-Feky M. A., Ahmed S. H., Daef E. A., Nassar M. I., Medhat A. et al. 2015; Association of colonic regulatory T cells with hepatitis C virus pathogenesis and liver pathology. J Gastroenterol Hepatol 30:1543–1551 [View Article][PubMed]
    [Google Scholar]
  21. Kasprzak A., Biczysko W., Adamek A., Wysocki J., Zabel M., Jurczyszyn D., Chmielewski M., Surdyk-Zasada J. 2004; Studies on tissue expression of HCV proteins (NS3 and C) in chronic hepatitis C using the ImmunoMax technique. Scand J Gastroenterol 39:387–388 [View Article][PubMed]
    [Google Scholar]
  22. Keynan Y., Card C. M., McLaren P. J., Dawood M. R., Kasper K., Fowke K. R. 2008; The role of regulatory T cells in chronic and acute viral infections. Clin Infect Dis 46:1046–1052 [View Article][PubMed]
    [Google Scholar]
  23. Kong L., Cardona Maya W., Moreno-Fernandez M. E., Ma G., Shata M. T., Sherman K. E., Chougnet C., Blackard J. T. 2012; Low-level HIV infection of hepatocytes. Virol J 9:157 [View Article][PubMed]
    [Google Scholar]
  24. Kuo G., Choo Q. L., Alter H. J., Gitnick G. L., Redeker A. G., Purcell R. H., Miyamura T., Dienstag J. L., Alter M. J., Stevens C. E. 1989; An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 244:362–364 [View Article][PubMed]
    [Google Scholar]
  25. Lee C. H., Choi Y. H., Yang S. H., Lee C. W., Ha S. J., Sung Y. C. 2001; Hepatitis C virus core protein inhibits interleukin 12 and nitric oxide production from activated macrophages. Virology 279:271–279 [View Article][PubMed]
    [Google Scholar]
  26. Liao W. H., Tung S. Y., Shen C. H., Lee K. F., Wu C. S. 2011; Tissue expression of the hepatitis C virus NS3 protein does not correlate with histological or clinical features in patients with chronic hepatitis C. Chang Gung Med J 34:260–267[PubMed]
    [Google Scholar]
  27. Losikoff P. T., Self A. A., Gregory S. H. 2012; Dendritic cells, regulatory T cells and the pathogenesis of chronic hepatitis C. Virulence 3:610–620 [View Article][PubMed]
    [Google Scholar]
  28. MacDonald A. J., Duffy M., Brady M. T., McKiernan S., Hall W., Hegarty J., Curry M., Mills K. H. 2002; CD4 T helper type 1 and regulatory T cells induced against the same epitopes on the core protein in hepatitis C virus-infected persons. J Infect Dis 185:720–727 [View Article][PubMed]
    [Google Scholar]
  29. Manzin A., Candela M., Paolucci S., Caniglia M. L., Gabrielli A., Clementi M. 1994; Presence of hepatitis C virus (HCV) genomic RNA and viral replicative intermediates in bone marrow and peripheral blood mononuclear cells from HCV-infected patients. Clin Diagn Lab Immunol 1:160–163[PubMed]
    [Google Scholar]
  30. Mayo M. J. 2003; Extrahepatic manifestations of hepatitis C infection. Am J Med Sci 325:135–148 [View Article][PubMed]
    [Google Scholar]
  31. McHutchison J. G., Poynard T., Esteban-Mur R., Davis G. L., Goodman Z. D., Harvey J., Ling M. H., Garaud J. J., Albrecht J. K. et al. 2002; Hepatic HCV RNA before and after treatment with interferon alone or combined with ribavirin. Hepatology 35:688–693 [View Article][PubMed]
    [Google Scholar]
  32. Miglioresi L., Riva E., Antonelli G., Russo F., Ricci G. L. 2003; Localization of hepatitis C virus in gastrointestinal mucosa: a possible reservoir for relapse. Hepatology 38:775 [View Article][PubMed]
    [Google Scholar]
  33. Pal S., Sullivan D. G., Kim S., Lai K. K., Kae J., Cotler S. J., Carithers R. L., Wood B. L., Perkins J. D., Gretch D. R. 2006; Productive replication of hepatitis C virus in perihepatic lymph nodes in vivo: implications of HCV lymphotropism. Gastroenterology 130:1107–1116 [View Article][PubMed]
    [Google Scholar]
  34. Pham T. N., King D., Macparland S. A., McGrath J. S., Reddy S. B., Bursey F. R., Michalak T. 2008; Hepatitis C virus replicates in the same immune cell subsets in chronic hepatitis C and occult infection. Gastroenterology 134:812–822 [View Article][PubMed]
    [Google Scholar]
  35. Revie D., Salahuddin S. Z. 2011; Human cell types important for hepatitis C virus replication in vivo and in vitro: old assertions and current evidence. Virol J 8:346 [View Article][PubMed]
    [Google Scholar]
  36. Saleh M. G., Tibbs C. J., Koskinas J., Pereira L. M., Bomford A. B., Portmann B. C., McFarlane I. G., Williams R. 1994; Hepatic and extrahepatic hepatitis C virus replication in relation to response to interferon therapy. Hepatology 20:1399–1404 [View Article][PubMed]
    [Google Scholar]
  37. Sansonno D., Iacobelli A. R., Cornacchiulo V., Iodice G., Dammacco F. 1996; Detection of hepatitis C virus (HCV) proteins by immunofluorescence and HCV RNA genomic sequences by non-isotopic in situ hybridization in bone marrow and peripheral blood mononuclear cells of chronically HCV-infected patients. Clin Exp Immunol 103:414–421 [View Article][PubMed]
    [Google Scholar]
  38. Sansonno D., Gesualdo L., Manno C., Schena F. P., Dammacco F. 1997; Hepatitis C virus-related proteins in kidney tissue from hepatitis C virus-infected patients with cryoglobulinemic membranoproliferative glomerulonephritis. Hepatology 25:1237–1244 [View Article][PubMed]
    [Google Scholar]
  39. Sène D., Limal N., Cacoub P. 2004; Hepatitis C virus-associated extrahepatic manifestations: a review. Metab Brain Dis 19:357–381 [View Article][PubMed]
    [Google Scholar]
  40. Spengler U., Nattermann J. 2007; Immunopathogenesis in hepatitis C virus cirrhosis. Clin Sci 112:141–155 [View Article][PubMed]
    [Google Scholar]
  41. Sturm N., Thélu M. A., Camous X., Dimitrov G., Ramzan M., Dufeu-Duchesne T., Bonorino P., Guillermet C., Brambilla E. et al. 2010; Characterization and role of intra-hepatic regulatory T cells in chronic hepatitis C pathogenesis. J Hepatol 53:25–35 [View Article][PubMed]
    [Google Scholar]
  42. Wang J. T., Sheu J. C., Lin J. T., Wang T. H., Chen D. S. 1992; Detection of replicative form of hepatitis C virus RNA in peripheral blood mononuclear cells. J Infect Dis 166:1167–1169 [View Article][PubMed]
    [Google Scholar]
  43. Yan F., Hao F., Zhao L. 2000a; Study of expression of hepatitis C virus antigens and viral replication in extrahepatic tissues. Zhonghua Gan Zang Bing Za Zhi 8:40–42
    [Google Scholar]
  44. Yan F. M., Chen A. S., Hao F., Zhao X. P., Gu C. H., Zhao L. B., Yang D. L., Hao L. J. 2000b; Hepatitis C virus may infect extrahepatic tissues in patients with hepatitis C. World J Gastroenterol 6:805–811 [View Article][PubMed]
    [Google Scholar]
  45. Yao Z. Q., Nguyen D. T., Hiotellis A., Hahn Y. S. 2001; Hepatitis C virus core protein inhibits human T lymphocyte responses by a complement-dependent regulatory pathway. J Immunol 167:5264–5272 [View Article][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jmm/10.1099/jmm.0.000272
Loading
/content/journal/jmm/10.1099/jmm.0.000272
Loading

Data & Media loading...

Supplements

Supplementary File 1

PDF
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error