Abstract
The six group B coxsackieviruses (CVBs) are highly prevalent human pathogens that cause viremia followed by involvement of different organs. Clinical and experimental evidence suggests that CVBs can induce kidney injury, but the susceptibility of human renal cells to these viruses is unknown. By using pure cultures of human glomerular and tubular cells, we demonstrated that all CVBs are capable of productively infecting renal cells of three different histotypes. Distinct pathogenic effects were observed. Proximal tubular epithelial cells and, to a lesser extent, glomerular podocytes were highly susceptible to CVBs; in both cases, infection led to cytolysis. In contrast, glomerular mesangial cells supported the replication of the six CVBs but failed to develop overt cytopathologic changes. Mesangial cells continued to produce infectious progeny for numerous serial subcultures (i.e., more than 50 days), especially with type 1, 3, 4, and 5 viruses. In the above cells, persistent infection induced the de novo synthesis of platelet-derived growth factor A/B and enhanced the release of transforming growth factor beta1/2. These two factors are important mediators of progression from glomerular inflammation to glomerulosclerosis. CVB replication appeared also to impair the phagocytic and contractile activity of mesangial cells. Loss of these properties--which are important in glomerular physiopathology--may contribute to the development of progressive nephropathy. The results show that CVBs induce distinct effects in different types of cultured renal cells and suggest that CVB infections may be associated with both acute and progressive renal injury.
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- Alpers C. E., McClure J., Bursten S. L. Human mesangial cells are resistant to productive infection by multiple strains of human immunodeficiency virus types 1 and 2. Am J Kidney Dis. 1992 Feb;19(2):126–130. doi: 10.1016/s0272-6386(12)70120-8. [DOI] [PubMed] [Google Scholar]
- Ardaillou N., Lelongt B., Turner N., Piedagnel R., Baudouin B., Estrade S., Cassingena R., Ronco P. M. Characterization of a simian virus 40-transformed human podocyte cell line producing type IV collagen and exhibiting polarized response to atrial natriuretic peptide. J Cell Physiol. 1992 Sep;152(3):599–616. doi: 10.1002/jcp.1041520320. [DOI] [PubMed] [Google Scholar]
- Ausiello D. A., Kreisberg J. I., Roy C., Karnovsky M. J. Contraction of cultured rat glomerular cells of apparent mesangial origin after stimulation with angiotensin II and arginine vasopressin. J Clin Invest. 1980 Mar;65(3):754–760. doi: 10.1172/JCI109723. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Baud L., Oudinet J. P., Bens M., Noe L., Peraldi M. N., Rondeau E., Etienne J., Ardaillou R. Production of tumor necrosis factor by rat mesangial cells in response to bacterial lipopolysaccharide. Kidney Int. 1989 May;35(5):1111–1118. doi: 10.1038/ki.1989.98. [DOI] [PubMed] [Google Scholar]
- Bergelson J. M., Cunningham J. A., Droguett G., Kurt-Jones E. A., Krithivas A., Hong J. S., Horwitz M. S., Crowell R. L., Finberg R. W. Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5. Science. 1997 Feb 28;275(5304):1320–1323. doi: 10.1126/science.275.5304.1320. [DOI] [PubMed] [Google Scholar]
- Biancone L., David S., Della Pietra V., Montrucchio G., Cambi V., Camussi G. Alternative pathway activation of complement by cultured human proximal tubular epithelial cells. Kidney Int. 1994 Feb;45(2):451–460. doi: 10.1038/ki.1994.59. [DOI] [PubMed] [Google Scholar]
- Biancone L., Tetta C., Turello E., Montrucchio G., Iorio E. L., Servillo L., Balestrieri C., Camussi G. Platelet-activating factor biosynthesis by cultured mesangial cells is modulated by proteinase inhibitors. J Am Soc Nephrol. 1992 Jan;2(7):1251–1261. [PubMed] [Google Scholar]
- Border W. A., Noble N. A. Transforming growth factor-beta in glomerular injury. Exp Nephrol. 1994 Jan-Feb;2(1):13–17. [PubMed] [Google Scholar]
- Burch G. E., Colcolough H. L. Progressive Coxsackie viral pancarditis and nephritis. Ann Intern Med. 1969 Nov;71(5):963–970. doi: 10.7326/0003-4819-71-5-963. [DOI] [PubMed] [Google Scholar]
- Camussi G., Brentjens J. R., Noble B., Kerjaschki D., Malavasi F., Roholt O. A., Farquhar M. G., Andres G. Antibody-induced redistribution of Heymann antigen on the surface of cultured glomerular visceral epithelial cells: possible role in the pathogenesis of Heymann glomerulonephritis. J Immunol. 1985 Oct;135(4):2409–2416. [PubMed] [Google Scholar]
- Camussi G., Turello E., Tetta C., Bussolino F., Baglioni C. Tumor necrosis factor induces contraction of mesangial cells and alters their cytoskeletons. Kidney Int. 1990 Nov;38(5):795–802. doi: 10.1038/ki.1990.273. [DOI] [PubMed] [Google Scholar]
- Carson S. D., Chapman N. N., Tracy S. M. Purification of the putative coxsackievirus B receptor from HeLa cells. Biochem Biophys Res Commun. 1997 Apr 17;233(2):325–328. doi: 10.1006/bbrc.1997.6449. [DOI] [PubMed] [Google Scholar]
- Coers W., Huitema S., van der Horst M. L., Weening J. J. Puromycin aminonucleoside and adriamycin disturb cytoskeletal and extracellular matrix protein organization, but not protein synthesis of cultured glomerular epithelial cells. Exp Nephrol. 1994 Jan-Feb;2(1):40–50. [PubMed] [Google Scholar]
- Conaldi P. G., Serra C., Mossa A., Falcone V., Basolo F., Camussi G., Dolei A., Toniolo A. Persistent infection of human vascular endothelial cells by group B coxsackieviruses. J Infect Dis. 1997 Mar;175(3):693–696. doi: 10.1093/infdis/175.3.693. [DOI] [PubMed] [Google Scholar]
- Cunningham L., Bowles N. E., Lane R. J., Dubowitz V., Archard L. C. Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA. J Gen Virol. 1990 Jun;71(Pt 6):1399–1402. doi: 10.1099/0022-1317-71-6-1399. [DOI] [PubMed] [Google Scholar]
- Davies M. The mesangial cell: a tissue culture view. Kidney Int. 1994 Feb;45(2):320–327. doi: 10.1038/ki.1994.41. [DOI] [PubMed] [Google Scholar]
- Dekan G., Gabel C., Farquhar M. G. Sulfate contributes to the negative charge of podocalyxin, the major sialoglycoprotein of the glomerular filtration slits. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5398–5402. doi: 10.1073/pnas.88.12.5398. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Delarue F., Virone A., Hagege J., Lacave R., Peraldi M. N., Adida C., Rondeau E., Feunteun J., Sraer J. D. Stable cell line of T-SV40 immortalized human glomerular visceral epithelial cells. Kidney Int. 1991 Nov;40(5):906–912. doi: 10.1038/ki.1991.292. [DOI] [PubMed] [Google Scholar]
- Detrisac C. J., Sens M. A., Garvin A. J., Spicer S. S., Sens D. A. Tissue culture of human kidney epithelial cells of proximal tubule origin. Kidney Int. 1984 Feb;25(2):383–390. doi: 10.1038/ki.1984.28. [DOI] [PubMed] [Google Scholar]
- Elema J. D., Hoyer J. R., Vernier R. L. The glomerular mesangium: uptake and transport of intravenously injected colloidal carbon in rats. Kidney Int. 1976 May;9(5):395–406. doi: 10.1038/ki.1976.49. [DOI] [PubMed] [Google Scholar]
- Girin V. N., Boiko I. I., Kirilenko V. A., Gabura V. V., Plugatyr' V. M. Vspyshka énterovirusnoi Koksaki B infektsii u detei. Lik Sprava. 1994 Feb;(2):79–81. [PubMed] [Google Scholar]
- Heieren M. H., van der Woude F. J., Balfour H. H., Jr Cytomegalovirus replicates efficiently in human kidney mesangial cells. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1642–1646. doi: 10.1073/pnas.85.5.1642. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Heim A., Canu A., Kirschner P., Simon T., Mall G., Hofschneider P. H., Kandolf R. Synergistic interaction of interferon-beta and interferon-gamma in coxsackievirus B3-infected carrier cultures of human myocardial fibroblasts. J Infect Dis. 1992 Nov;166(5):958–965. doi: 10.1093/infdis/166.5.985. [DOI] [PubMed] [Google Scholar]
- Henke A., Mohr C., Sprenger H., Graebner C., Stelzner A., Nain M., Gemsa D. Coxsackievirus B3-induced production of tumor necrosis factor-alpha, IL-1 beta, and IL-6 in human monocytes. J Immunol. 1992 Apr 1;148(7):2270–2277. [PubMed] [Google Scholar]
- Hohenadl C., Klingel K., Mertsching J., Hofschneider P. H., Kandolf R. Strand-specific detection of enteroviral RNA in myocardial tissue by in situ hybridization. Mol Cell Probes. 1991 Feb;5(1):11–20. doi: 10.1016/0890-8508(91)90033-g. [DOI] [PubMed] [Google Scholar]
- Huber S. A., Haisch C., Lodge P. A. Functional diversity in vascular endothelial cells: role in coxsackievirus tropism. J Virol. 1990 Sep;64(9):4516–4522. doi: 10.1128/jvi.64.9.4516-4522.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hyypiä T., Auvinen P., Maaronen M. Polymerase chain reaction for human picornaviruses. J Gen Virol. 1989 Dec;70(Pt 12):3261–3268. doi: 10.1099/0022-1317-70-12-3261. [DOI] [PubMed] [Google Scholar]
- Hänsch G. M., Wagner C., Bürger A., Dong W., Staehler G., Stoeck M. Matrix protein synthesis by glomerular mesangial cells in culture: effects of transforming growth factor beta (TGF beta) and platelet-derived growth factor (PDGF) on fibronectin and collagen type IV mRNA. J Cell Physiol. 1995 Jun;163(3):451–457. doi: 10.1002/jcp.1041630304. [DOI] [PubMed] [Google Scholar]
- Jensen M. M. Viruses and kidney disease. Am J Med. 1967 Dec;43(6):897–911. doi: 10.1016/0002-9343(67)90248-3. [DOI] [PubMed] [Google Scholar]
- Jindal K. K., Trillo A., Bishop G., Hirsch D., Cohen A. Crescentic IgA nephropathy as a manifestation of human immune deficiency virus infection. Am J Nephrol. 1991;11(2):147–150. doi: 10.1159/000168292. [DOI] [PubMed] [Google Scholar]
- Kerjaschki D. Dysfunctions of cell biological mechanisms of visceral epithelial cell (podocytes) in glomerular diseases. Kidney Int. 1994 Feb;45(2):300–313. doi: 10.1038/ki.1994.39. [DOI] [PubMed] [Google Scholar]
- Klingel K., Hohenadl C., Canu A., Albrecht M., Seemann M., Mall G., Kandolf R. Ongoing enterovirus-induced myocarditis is associated with persistent heart muscle infection: quantitative analysis of virus replication, tissue damage, and inflammation. Proc Natl Acad Sci U S A. 1992 Jan 1;89(1):314–318. doi: 10.1073/pnas.89.1.314. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kume K. [Influence of Coxsackie B4 virus on uptake and transport of colloidal carbon by glomerular mesangium]. Nihon Jinzo Gakkai Shi. 1990 Jul;32(7):777–789. [PubMed] [Google Scholar]
- Lee H. W., van der Groen G. Hemorrhagic fever with renal syndrome. Prog Med Virol. 1989;36:62–102. [PubMed] [Google Scholar]
- Matteucci D., Toniolo A., Conaldi P. G., Basolo F., Gori Z., Bendinelli M. Systemic lymphoid atrophy in coxsackievirus B3-infected mice: effects of virus and immunopotentiating agents. J Infect Dis. 1985 Jun;151(6):1100–1108. doi: 10.1093/infdis/151.6.1100. [DOI] [PubMed] [Google Scholar]
- Melchers W. J., Schift R., Stolz E., Lindeman J., Quint W. G. Human papillomavirus detection in urine samples from male patients by the polymerase chain reaction. J Clin Microbiol. 1989 Aug;27(8):1711–1714. doi: 10.1128/jcm.27.8.1711-1714.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mené P., Simonson M. S., Dunn M. J. Physiology of the mesangial cell. Physiol Rev. 1989 Oct;69(4):1347–1424. doi: 10.1152/physrev.1989.69.4.1347. [DOI] [PubMed] [Google Scholar]
- Moutabarrik A., Nakanishi I., Zaid D., Namiki M., Kawaguchi N., Onishi S., Ishibashi M., Okuyama A. Interleukin-1-beta activation of cultured glomerular epithelial cells. Exp Nephrol. 1994 May-Jun;2(3):196–204. [PubMed] [Google Scholar]
- Muir P., Nicholson F., Illavia S. J., McNeil T. S., Ajetunmobi J. F., Dunn H., Starkey W. G., Reetoo K. N., Cary N. R., Parameshwar J. Serological and molecular evidence of enterovirus infection in patients with end-stage dilated cardiomyopathy. Heart. 1996 Sep;76(3):243–249. doi: 10.1136/hrt.76.3.243. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mutoh S., Kumada K., Kume K., Suzuki J., Yokota T., Suzuki H. Detection of coxsackie B4 virus RNA in infected mouse kidneys by in situ hybridization. Nephron. 1994;67(3):340–345. doi: 10.1159/000187990. [DOI] [PubMed] [Google Scholar]
- Oohara N. [Experimental nephritis induced by Coxsackie B4 virus in mice--transient mesangial proliferation associated with acute viremia]. Nihon Jinzo Gakkai Shi. 1986 Apr;28(4):351–364. [PubMed] [Google Scholar]
- Ooi B. S., Cohen D. J., Veis J. H. Biology of the mesangial cell in glomerulonephritis--role of cytokines. Proc Soc Exp Biol Med. 1996 Dec;213(3):230–237. doi: 10.3181/00379727-213-44054. [DOI] [PubMed] [Google Scholar]
- Racusen L. C. Cell shape changes and detachment in cell culture: models of renal injury. Nephrol Dial Transplant. 1994;9 (Suppl 4):22–25. [PubMed] [Google Scholar]
- Ren R., Racaniello V. R. Human poliovirus receptor gene expression and poliovirus tissue tropism in transgenic mice. J Virol. 1992 Jan;66(1):296–304. doi: 10.1128/jvi.66.1.296-304.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ronco P., Verroust P., Morel-Maroger L. Viruses and Glomerulonephritis. Nephron. 1982;31(2):97–102. doi: 10.1159/000182626. [DOI] [PubMed] [Google Scholar]
- Rosen S., Harmon W., Krensky A. M., Edelson P. J., Padgett B. L., Grinnell B. W., Rubino M. J., Walker D. L. Tubulo-interstitial nephritis associated with polyomavirus (BK type) infection. N Engl J Med. 1983 May 19;308(20):1192–1196. doi: 10.1056/NEJM198305193082004. [DOI] [PubMed] [Google Scholar]
- Ryan M. J., Johnson G., Kirk J., Fuerstenberg S. M., Zager R. A., Torok-Storb B. HK-2: an immortalized proximal tubule epithelial cell line from normal adult human kidney. Kidney Int. 1994 Jan;45(1):48–57. doi: 10.1038/ki.1994.6. [DOI] [PubMed] [Google Scholar]
- Schönermark M., Deppisch R., Riedasch G., Rother K., Hänsch G. M. Induction of mediator release from human glomerular mesangial cells by the terminal complement components C5b-9. Int Arch Allergy Appl Immunol. 1991;96(4):331–337. doi: 10.1159/000235517. [DOI] [PubMed] [Google Scholar]
- Sedor J. R. Cytokines and growth factors in renal injury. Semin Nephrol. 1992 Sep;12(5):428–440. [PubMed] [Google Scholar]
- Shultz P. J., DiCorleto P. E., Silver B. J., Abboud H. E. Mesangial cells express PDGF mRNAs and proliferate in response to PDGF. Am J Physiol. 1988 Oct;255(4 Pt 2):F674–F684. doi: 10.1152/ajprenal.1988.255.4.F674. [DOI] [PubMed] [Google Scholar]
- Singhal P. C., Scharschmidt L. A., Gibbons N., Hays R. M. Contraction and relaxation of cultured mesangial cells on a silicone rubber surface. Kidney Int. 1986 Dec;30(6):862–873. doi: 10.1038/ki.1986.266. [DOI] [PubMed] [Google Scholar]
- Sissons J. G., Sinclair J. H., Borysiewicz L. K. Pathogenesis of human cytomegalovirus disease and the kidney. Kidney Int Suppl. 1991 Dec;35:S8–12. [PubMed] [Google Scholar]
- Stone R. Post-polio syndrome: remembrance of viruses past. Science. 1994 May 13;264(5161):909–909. doi: 10.1126/science.8178150. [DOI] [PubMed] [Google Scholar]
- Striker G. E., Mannik M., Tung M. Y. Role of marrow-derived monocytes and mesangial cells in removal of immune complexes from renal glomeruli. J Exp Med. 1979 Jan 1;149(1):127–136. doi: 10.1084/jem.149.1.127. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Striker G. E., Striker L. J. Glomerular cell culture. Lab Invest. 1985 Aug;53(2):122–131. [PubMed] [Google Scholar]
- Tam P. E., Schmidt A. M., Ytterberg S. R., Messner R. P. Duration of virus persistence and its relationship to inflammation in the chronic phase of coxsackievirus B1-induced murine polymyositis. J Lab Clin Med. 1994 Mar;123(3):346–356. [PubMed] [Google Scholar]
- Temonen M., Vapalahti O., Holthöfer H., Brummer-Korvenkontio M., Vaheri A., Lankinen H. Susceptibility of human cells to Puumala virus infection. J Gen Virol. 1993 Mar;74(Pt 3):515–518. doi: 10.1099/0022-1317-74-3-515. [DOI] [PubMed] [Google Scholar]
- Tomko R. P., Xu R., Philipson L. HCAR and MCAR: the human and mouse cellular receptors for subgroup C adenoviruses and group B coxsackieviruses. Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3352–3356. doi: 10.1073/pnas.94.7.3352. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Welling L. W., Welling D. J. Relationship between structure and function in renal proximal tubule. J Electron Microsc Tech. 1988 Jun;9(2):171–185. doi: 10.1002/jemt.1060090205. [DOI] [PubMed] [Google Scholar]