Viral infection and aging as cofactors for the development of pulmonary fibrosis

Expert Review of Respiratory Medicine

Volumn 4, Issue 6, 2010, Pages 759-771

  Naik, Payal K ^a   Moore, Bethany B ^a  

^a UNIVERSITY OF MICHIGAN MEDICAL SCHOOL   (United States)

Author keywords

collagen; Epstein Barr virus; gammaherpesvirus; lung; murine gammaherpesvirus 68; senescence

Indexed keywords

BLEOMYCIN; COLLAGEN; FLUORESCEIN ISOTHIOCYANATE; GAMMA INTERFERON; SURFACTANT PROTEIN C; VALACICLOVIR; VIRUS ANTIBODY;

ADENOVIRUS; AGING; ANTIBODY AFFINITY; APOPTOSIS; B LYMPHOCYTE; CELL DIFFERENTIATION; CELL INTERACTION; CHRONIC OBSTRUCTIVE LUNG DISEASE; CLINICAL FEATURE; CYTOKINE PRODUCTION; DISEASE ASSOCIATION; DISEASE COURSE; DISEASE EXACERBATION; DISEASE PREDISPOSITION; ENDOPLASMIC RETICULUM STRESS; EPSTEIN BARR VIRUS; FIBROGENESIS; FIBROSING ALVEOLITIS; GAMMAHERPESVIRINAE; GENETIC PREDISPOSITION; HEPATITIS C VIRUS; HERPES VIRUS INFECTION; HUMAN; HUMAN CYTOMEGALOVIRUS; IMMUNOPATHOGENESIS; INNATE IMMUNITY; INTERSTITIAL PNEUMONIA; LIVER CIRRHOSIS; LUNG ALVEOLUS EPITHELIUM; LUNG PARENCHYMA; LUNG SARCOIDOSIS; MACROPHAGE; MESENCHYME CELL; MIXED INFECTION; NEUTROPHIL; NONHUMAN; REVIEW; SEROCONVERSION; SMOKING; T LYMPHOCYTE; TORQUE TENO VIRUS; VIRUS INFECTION; VIRUS REACTIVATION; VIRUS REPLICATION;

EID: 78650050187     PISSN: 17476348     EISSN: 17476356     Source Type: Journal    
DOI: 10.1586/ers.10.73     Document Type: Review

References (105)

1. Adamson IY, Young L, Bowden DH. Relationship of alveolar epithelial injury and repair to the induction of pulmonary fbrosis. Am. J. Pathol. 130(2), 377-383 (1988).
2. Sime PJ, O'Reilly KM. Fibrosis of the lung and other tissues: new concepts in pathogenesis and treatment. Clin. Immunol. 99(3), 308-319 (2001).
3. Gauldie J, Bonniaud P, Sime P, Ask K, Kolb M. TGF-b, Smad3 and the process of progressive fbrosis. Biochem. Soc. Trans. 35, 661-664 (2007).
4. Wilborn J, Bailie M, Coffey M, Burdick M, Strieter R, Peters-Golden M. Constitutive activation of 5-lipoxygenase in the lungs of patients with idiopathic pulmonary fbrosis. J. Clin. Invest. 97(8), 1827-1836 (1996).
5. 2 and to express cyclooxygenase-2. J. Clin. Invest. 95, 1861-1868 (1995).
6. Sisson T, Simon R. The plasminogen activation system in lung disease. Curr. Drug Targets 8, 1016-1029 (2007).
7. Bucala R, Spiegel LA, Chesney J, Hogan M, Cerami A. Circulating fbrocytes defne a new leukocyte subpopulation that mediates tissue repair. Mol. Med. 1(1), 71-81 (1994).
8. Moore BB, Kolodsick JE, Thannickal VJ et al. CCR2-mediated recruitment of fbrocytes to the alveolar space after fbrotic injury. Am. J. Pathol. 166(3), 675-684 (2005).
9. Phillips RJ, Burdick MD, Hong K et al. Circulating fbrocytes traffc to the lungs in response to CXCL12 and mediate fbrosis. J. Clin. Invest., 114(3), 438-446 (2004).
10. Harada T, Nabeshima K, Hamasaki M, Uesugi N, Watanabe K, Iwasaki H. Epithelial-mesenchymal transition in human lungs with usual interstitial pneumonia: quantitative immunohistochemistry. Pathology 60(1), 14-21 (2010).
11. Kim KK, Wei Y, Szekeres C et al. Epithelial cell a3b1 integrin links b-catenin and Smad signaling to promote myofbroblast formation and pulmonary fbrosis. J. Clin. Invest. 119(1), 213-224 (2009).
12. Konigshoff M, Kramer M, Balsara N et al. WNT1-inducible signaling protein-1 mediates pulmonary fbrosis in mice and is upregulated in humans with idiopathic pulmonary fbrosis. J. Clin. Invest. 119(4), 772-787 (2009).
13. Gabbiani G. The myofbroblast: a key cell for wound healing and fbrocontractive diseases. Prog. Clin. Biol. Res. 54, 183-194 (1981).
14. Collard HR, Moore BB, Flaherty KR et al. Acute exacerbations of idiopathic pulmonary fbrosis. Am. J. Respir. Crit. Care Med. 176(7), 636-643 (2007).
15. Martinez FJ, Safrin S, Weycker D et al The clinical course of patients with idiopathic pulmonary fbrosis. Ann. Intern. Med. 142(12 Pt 1), 963-967 (2005).
16. Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and prevalence of idiopathic pulmonary fbrosis. Am. J. Respir. Crit. Care Med. 174(7), 810-816 (2006).
17. Armanios MY, Chen JJ, Cogan JD et al Telomerase mutations in families with idiopathic pulmonary fbrosis. N. Engl J. Med. 356(13), 1317-1326 (2007).
18. Grutters JC, du Bois RM. Genetics of fbrosing lung diseases. Eur. Respir. J. 25(5), 915-927 (2005).
19. Taskar VS, Coultas DB. Is idiopathic pulmonary fbrosis an environmental disease? Proc. Am. Thorac. Soc. 3(4), 293-298 (2006).
20. Thomas AQ, Lane K, Phillips J 3rd et al. Heterozygosity for a surfactant protein C gene mutation associated with usual interstitial pneumonitis and cellular nonspecifc interstitial pneumonitis in one kindred. Am. J. Respir. Crit. Care Med. 165(9), 1322-1328 (2002).
21. Wang XM, Zhang Y, Kim HP et al Caveolin-1: a critical regulator of lung fbrosis in idiopathic pulmonary fbrosis. J. Exp. Med. 203(13), 2895-2906 (2006).
22. Lee JS, Collard HR, Raghu G et al. Does chronic micro aspiration cause idiopathic pulmonary fbrosis? Am. J. Med. 123(4), 304-311 (2010).
23. Vannella KM, Moore BB. Viruses as co-factors for the initiation or exacerbation of lung fbrosis. Fibrogenesis Tissue Repair 1(1), 2 (2008).
24. Kutok JL, Wang F. Spectrum of Epstein-Barr virus-associated diseases. Annu. Rev. Pathol. 1, 375-404 (2006).
25. Egan JJ, Stewart JP, Hasleton PS, Arrand JR, Carroll KB, Woodcock AA. Epstein-Barr virus replication within pulmonary epithelial cells in cryptogenic fbrosing alveolitis. Thorax 50(12), 1234-1239 (1995).
26. Doherty PC, Christensen JP, Belz GT, Stevenson PG, Sangster MY. Dissecting the host response to a g-herpesvirus. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 356(1408), 581-593 (2001).
27. Lindenbach BD, Rice CM. Unravelling hepatitis C virus replication from genome to function. Nature 436(7053), 933-938 (2005).
28. Ueda T, Ohta K, Suzuki N et al. Idiopathic pulmonary fbrosis and high prevalence of serum antibodies to hepatitis C virus. Am. Rev. Respir. Dis. 146(1), 266-268 (1992).
29. Meliconi R, Andreone P, Fasano L et al. Incidence of hepatitis C virus infection in Italian patients with idiopathic pulmonary fbrosis. Thorax 51(3), 315-317 (1996).
30. Arase Y, Suzuki F, Suzuki Y et al. Hepatitis C virus enhances incidence of idiopathic pulmonary fbrosis. World J. Gastroenterol. 14(38), 5880-5886 (2008).
31. Manganelli P, Salaff F, Pesci A. [Hepatitis C virus and pulmonary fbrosis]. Recenti Prog. Med. 93(5), 322-326 (2002).
32. Idilman R, Cetinkaya H, Savas I et al. Bronchoalveolar lavage fuid analysis in individuals with chronic hepatitis C. J. Med. Virol. 66(1), 34-39 (2002).
33. Irving WL, Day S, Johnston ID. Idiopathic pulmonary fbrosis and hepatitis C virus infection. Am. Rev. Respir. Dis. 148(6 Pt 1), 1683-1684 (1993).
34. Mushahwar IK, Erker JC, Muerhoff AS et al. Molecular and biophysical characterization of TT virus: evidence for a new virus family infecting humans. Proc. Natl Acad. Sci. USA 96(6), 3177-3182 (1999).
35. Okamoto H, Nishizawa T, Ukita M et al. The entire nucleotide sequence of a TT virus isolate from the United States (TUS01): comparison with reported isolates and phylogenetic analysis. Virology 259(2), 437-448 (1999).
36. Gergely P Jr, Perl A, Poor G. Possible pathogenic nature of the recently discovered TT virus: does it play a role in autoimmune rheumatic diseases? Autoimmun. Rev. 6(1), 5-9 (2006).
37. Bando M, Ohno S, Oshikawa K, Takahashi M, Okamoto H, Sugiyama Y Infection of TT virus in patients with idiopathic pulmonary fbrosis. Respir. Med. 95(12), 935-942 (2001).
38. Wold WSM, Horwitz MS. Adenoviruses. In: Fields Virology, 5th Edition. Knipe DM, Howley PM (Eds). Wolters Kluwer/Lippincott Williams and Wilkins, PA, USA, 2395-2436 (2007).
39. Hayashi S, Hogg JC. Adenovirus infections and lung disease. Curr. Opin. Pharmacol. 7(3), 237-243 (2007).
40. Kuwano K, Nomoto Y, Kunitake R et al. Detection of adenovirus E1 A DNA in pulmonary fbrosis using nested polymerase chain reaction. Eur. Respir. J. 10(7), 1445-1449 (1997).
41. Yonemaru M, Kasuga I, Kusumoto H et al Elevation of antibodies to cytomegalovirus and other herpes viruses in pulmonary fbrosis. Eur. Respir. J. 10(9), 2040-2045 (1997).
42. McMillan TR, Moore BB, Weinberg JB et al. Exacerbation of established pulmonary fbrosis in a murine model by gammaherpesvirus. Am. J. Respir. Crit. Care Med. 117(7), 771-780 (2008).
43. Mocarski E, Shenk T, Pass R. Cytomegaloviruses. In: Fields Virology. Knipe D, Howley P (Eds). Lippincott Williams and Wilkins, PA, USA, 2702-2772 (2007).
44. Loewendorf A, Benedict CA. Modulation of host innate and adaptive immune defenses by cytomegalovirus: timing is everything. J. Intern. Med. 267(5), 483-501 (2010).
45. Magro CM, Allen J, Pope-Harman A et al The role of microvascular injury in the evolution of idiopathic pulmonary fbrosis. Am. J. Clin. Pathol. 119(4), 556-567 (2003).
46. Dworniczak S, Ziora D, Kapral M et al Human cytomegalovirus DNA level in patients with idiopathic pulmonary fbrosis. J. Physiol. Pharmacol. 55(Suppl. 3), 67-75 (2004).
47. Tang YW, Johnson JE, Browning PJ et al. Herpesvirus DNA is consistently detected in lungs of patients with idiopathic pulmonary fbrosis. J. Clin. Microbiol. 41(6), 2633-2640 (2003).
48. Vergnon JM, Vincent M, de The G, Mornex JF, Weynants P, Brune J. Cryptogenic fbrosing alveolitis and Epstein-Barr virus: an association? Lancet 2(8406), 768-771 (1984).
49. Manika K, Alexiou-Daniel S, Papakosta D et al. Epstein-Barr virus DNA in broncho alveolar lavage fuid from patients with idiopathic pulmonary fbrosis. Sarcoidosis Vasc. Diffuse Lung Dis. 24(2), 134-140 (2007).
50. Stewart JP, Egan JJ, Ross AJ et al. The detection of Epstein-Barr virus DNA in lung tissue from patients with idiopathic pulmonary fbrosis. Am. J. Respir. Crit. Care Med. 159(4 Pt 1), 1336-1341 (1999).
51. Kelly BG, Lok SS, Hasleton PS, Egan JJ, Stewart JP. A rearranged form of Epstein-Barr virus DNA is associated with idiopathic pulmonary fbrosis. Am. J. Respir. Crit. Care Med. 166(4), 510-513 (2002).
52. Tsukamoto K, Hayakawa H, Sato A, Chida K, Nakamura H, Miura K. Involvement of Epstein-Barr virus latent membrane protein 1 in disease progression in patients with idiopathic pulmonary fbrosis. Thorax 55(11), 958-961 (2000).
53. Malizia AP, Keating DT, Smith SM, Walls D, Doran PP, Egan JJ. Alveolar epithelial cell injury with Epstein-Barr virus upregulates TGFß1 expression. Am. J. Physiol. Lung Cell. Mol. Physiol. 295(3), L451-L460 (2008).
54. Lawson WE, Crossno PF, Polosukhin VV et al. Endoplasmic reticulum stress in alveolar epithelial cells is prominent in IPF: association with altered surfactant protein processing and herpesvirus infection. Am. J. Physiol. Lung Cell. Mol. Physiol. 294(6), L1119-L1126 (2008).
55. Isler JA, Skalet AH, Alwine JC. Human cytomegalovirus infection activates and regulates the unfolded protein response. J. Virol. 79(11), 6890-6899 (2005).
56. Thannickal VJ, Horowitz JC. Evolving concepts of apoptosis in idiopathic pulmonary fbrosis. Proc. Am. Thorac. Soc. 3(4), 350-356 (2006).
57. Wangoo A, Shaw RJ, Diss TC, Farrell PJ, du Bois RM, Nicholson AG. Cryptogenic fbrosing alveolitis: lack of association with Epstein-Barr virus infection. Thorax 52(10), 888-891 (1997).
58. Zamo A, Poletti V, Reghellin D et al. HHV-8 and EBV are not commonly found in idiopathic pulmonary fbrosis. Sarcoidosis Vasc. Diffuse Lung Dis. 22(2), 123-128 (2005).
59. Konishi K, Gibson KF, Lindell KO et al. Gene expression profles of acute exacerbations of idiopathic pulmonary fbrosis. Am. J. Respir. Crit. Care Med. 180(2), 167-175 (2009).
60. Buergelt CD, Hines SA, Cantor G, Stirk A, Wilson JH. A retrospective study of proliferative interstitial lung disease of horses in Florida. Vet. Pathol. 23(6), 750-756 (1986).
61. Donaldson MT, Beech J, Ennulat D, Hamir AN. Interstitial pneumonia and pulmonary fbrosis in a horse. Equine Vet. J. 30(2), 173-175 (1998).
62. Williams K, Malarkey D, Cohn L, Patrick D, Dye J, Toews G. Identifcation of spontaneous feline idiopathic pulmonary fbrosis: morphology and ultrastructural evidence for a type II pneumocyte defect. Chest 125(6), 2278-2288 (2004).
63. Williams KJ, Maes R, Del Piero F et al. Equine multinodular pulmonary fbrosis: a newly recognized herpesvirus-associated fbrotic lung disease. Vet. Pathol. 44(6), 849-862 (2007).
64. Winder C, Ehrensperger F, Hermann M, Howald B, von Fellenberg R. Interstitial pneumonia in the horse: two unusual cases. Equine Vet. J. 20(4), 298-301 (1988).
65. Love DN. Feline herpesvirus associated with interstitial pneumonia in a kitten. Vet. Rec. 89(7), 178-181 (1971).
66. Moore BB, Hogaboam CM. Murine models of pulmonary fbrosis. Am. J. Physiol. Lung Cell. Mol. Physiol. 294, L152-L160 (2008).
67. Virgin HW 4th, Latreille P, Wamsley P et al. Complete sequence and genomic analysis of murine gammaherpesvirus 68. J. Virol. 71(8), 5894-5904 (1997).
68. Efstathiou S, Ho YM, Hall S, Styles CJ, Scott SD, Gompels UA. Murine herpesvirus 68 is genetically related to the gammaherpesviruses Epstein-Barr virus and herpesvirus saimiri. J. Gen. Virol. 71(Pt 6), 1365-1372 (1990).
69. Flano E, Husain SM, Sample JT, Woodland DL, Blackman MA. Latent murine gamma-herpesvirus infection is established in activated B cells, dendritic cells, and macrophages. J. Immunol. 165(2), 1074-1081 (2000).
70. Stewart JP, Janjua NJ, Sunil-Chandra NP, Nash AA, Arrand JR. Characterization of murine gammaherpesvirus 68 glycoprotein B (gB) homolog: similarity to Epstein-Barr virus gB (gp110). J. Virol. 68(10), 6496-6504 (1994).
71. Stewart JP, Usherwood EJ, Ross A, Dyson H, Nash T. Lung epithelial cells are a major site of murine gammaherpesvirus persistence. J. Exp. Med. 187(12), 1941-1951 (1998).
72. Vannella KM, Luckhardt TR, Wilke CA, van Dyk LF, Toews GB, Moore BB. Latent herpesvirus infection augments experimental pulmonary fbrosis. Am. J. Respir. Crit. Care Med. 181(5), 465-477 (2009).
73. Lok SS, Haider Y, Howell D, Stewart JP, Hasleton PS, Egan JJ. Murine gammaherpes virus as a cofactor in the development of pulmonary fbrosis in bleomycin resistant mice. Eur. Respir. J. 20(5), 1228-1232 (2002).
74. Moore BB, Murray L, Das A, Wilke CA, Herrygers AB, Toews GB. The role of CCL12 in the recruitment of fbrocytes and lung fbrosis. Am. J. Respir. Cell Mol. Biol. 35(2), 175-181 (2006).
75. Schmidt M, Sun G, Stacey M, Mori L, Mattoli S. Identifcation of circulating fbrocytes as precursors of bronchial myofbroblasts in asthma. J. Immunol. 170, 380-389 (2003).
76. Krug LT, Torres-Gonzalez E, Qin Q et al. Inhibition of NF-κB signaling reduces virus load and gammaherpesvirus-induced pulmonary fbrosis. Am. J. Pathol. 177(2), 608-621 (2010).
77. Baud L, Perez J, Denis M, Ardaillou R. Modulation of fbroblast proliferation by sulfdopeptide leukotrienes: effect of indomethacin. J. Immunol. 138, 1190-1195 (1987).
78. Vannella KM, McMillan TR, Charbeneau RP et al. Cysteinyl leukotrienes are autocrine and paracrine regulators of fbrocyte function. J. Immunol. 179(11), 7883-7890 (2007).
79. Wallace WA, Ramage EA, Lamb D, Howie SE. A type 2 (Th2-like) pattern of immune response predominates in the pulmonary interstitium of patients with cryptogenic fbrosing alveolitis (CFA). Clin. Exp. Immunol. 101(3), 436-441 (1995).
80. Diaz A, Jimenez SA. Interferon-γ regulates collagen and fbronectin gene expression by transcriptional and post-transcriptional mechanisms. Int. J. Biochem. Cell. Biol 29(1), 251-260 (1997).
81. Sempowski GD, Derdak S, Phipps RP. Interleukin-4 and interferon-γ discordantly regulate collagen biosynthesis by functionally distinct lung fbroblast subsets. J. Cell. Physiol. 167(2), 290-296 (1996).
82. Ebrahimi B, Dutia BM, Brownstein DG, Nash AA. Murine gammaherpesvirus-68 infection causes multi-organ fbrosis and alters leukocyte traffcking in interferon-γ receptor knockout mice. Am. J. Pathol 158(6), 2117-2125 (2001).
83. Mora AL, Woods CR, Garcia A et al. Lung infection with gamma-herpesvirus induces progressive pulmonary fbrosis in Th2-biased mice. Am. J. Physiol. Lung Cell Mol. Physiol. 289(5), L711-L721 (2005).
84. Mora AL, Torres-Gonzalez E, Rojas M et al. Activation of alveolar macrophages via the alternative pathway in herpesvirus-induced lung fbrosis. Am. J. Respir. Cell Mol. Biol. 35(4), 466-473 (2006).
85. Uh ST, Inoue Y, King TE Jr, Chan ED, Newman LS, Riches DW Morphometric analysis of insulin-like growth factor-I localization in lung tissues of patients with idiopathic pulmonary fbrosis. Am. J. Respir. Crit. Care Med. 158(5 Pt 1), 1626-1635 (1998).
86. Mora AL, Torres-Gonzalez E, Rojas M et al. Control of virus reactivation arrests pulmonary herpesvirus-induced fbrosis in IFN-γ receptor-defcient mice. Am. J. Respir. Crit. Care Med. 175(11), 1139-1150 (2007).
87. Hodgson U, Pulkkinen V, Dixon M et al ELMOD2 is a candidate gene for familial idiopathic pulmonary fbrosis. Am. J. Hum. Genet. 79(1), 149-154 (2006).
88. Pulkkinen V, Bruce S, Rintahaka J et al ELMOD2, a candidate gene for idiopathic pulmonary fbrosis, regulates antiviral responses. FASEB J. 24(4), 1167-1177 (2010).
89. Fell CD, Martinez FJ, Liu LX et al Clinical predictors of a diagnosis of idiopathic pulmonary fbrosis. Am. J. Respir. Crit. Care Med. 181(8), 832-837 (2010).
90. Takeda T Senescence-accelerated mouse (SAM): a biogerontological resource in aging research Neurobiol. Aging 20, 105-110 (1999).
91. Xu J, Gonzalez ET, Iyer SS et al. Use of senescence-accelerated mouse model in bleomycin-induced lung injury suggests that bone marrow-derived cells can alter the outcome of lung injury in aged mice. J. Gerontol. A Biol. Sci. Med. Sci. 64(7), 731-739 (2009).
92. Salminen A, Kaarniranta K. ER stress and hormetic regulation of the aging process. Ageing Res. Rev. 9(3), 211-217 (2010).
93. Castriotta RJ, Eldadah BA, Foster WM et al. Workshop on idiopathic pulmonary fbrosis in older adults. Chest 138(3), 693-703 (2010).
94. Aw D, Silva AB, Palmer DB. Immunosenescence: emerging challenges for an ageing population. Immunology 120(4), 435-446 (2007).
95. Gardner EM, Murasko DM. Age-related changes in Type 1 and Type 2 cytokine production in humans. Biogerontology 3(5), 271-290 (2002).
96. Goronzy JJ, Lee WW, Weyand CM. Aging and T-cell diversity. Exp. Gerontol. 42(5), 400-406 (2007).
97. Stowe RP, Kozlova EV, Yetman DL, Walling DM, Goodwin JS, Glaser R. Chronic herpesvirus reactivation occurs in aging. Exp Gerontol., 42(6), 563-570 (2007).
98. Goronzy JJ, Fulbright JW, Crowson CS, Poland GA, O'Fallon WM, Weyand CM. Value of immunological markers in predicting responsiveness to infuenza vaccination in elderly individuals. J. Virol. 75(24), 12182-12187 (2001).
99. Khan N, Hislop A, Gudgeon N et al. Herpesvirus-specifc CD8 T cell immunity in old age: cytomegalovirus impairs the response to a coresident EBV infection. J. Immunol. 173(12), 7481-7489 (2004).
100. Tsakiri KD, Cronkhite JT, Kuan PJ et al. Adult-onset pulmonary fbrosis caused by mutations in telomerase. Proc. Natl Acad. Sci. USA 104(18), 7552-7557 (2007).
101. Alder JK, Chen JJ, Lancaster L et al. Short telomeres are a risk factor for idiopathic pulmonary fbrosis. Proc. Natl Acad. Sci. USA 105(35), 13051-13056 (2008).
102. Calado RT, Young NS. Telomere diseases. N. Engl. J. Med. 361(24), 2353-2365 (2009).
103. Naik PK, Wilke CA, Vannella KM, Stoolman JST, Toews GB, Moore BB. Increased pulmonary fbrosis in aged mice infected with murine gammaherpesvirus when compared to young controls. Am. J. Respir. Crit. Care Med. 181, A1996 (2010).
104. Torres-Gonzalez E, Jones DP, Sorescu D, Rojas M, Stecenko AA, Mora AL. Oxidative stress and susceptibility to virus-induced lung fbrosis in aging mice. Am J. Respir. Crit. Care Med. 181, A1997 (2010).
105. Yager EJ, Kim IJ, Freeman ML et al. Differential impact of ageing on cellular and humoral immunity to a persistent murine gamma-herpesvirus. Immun. Ageing 7, 3 (2010).