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Abstract

Human cytomegalovirus (HCMV) primary infections are typically asymptomatic in healthy individuals yet can cause increased morbidity and mortality in organ transplant recipients, AIDS patients, neonates, and the elderly. The successful, widespread dissemination of this virus among the population can be attributed in part to its wide cellular tropism and ability to establish life-long latency. HCMV infection is a multi-step process that requires numerous cellular and viral factors. The viral envelope consists of envelope protein complexes that interact with cellular factors; such interactions dictate virus recognition and attachment to different cell types, followed by fusion either at the cell membrane or within an endocytic vesicle. Several HCMV entry factors, including neuropilin-2 (Nrp2), THBD, CD147, OR14I1, and CD46, are characterized as participating in HCMV pentamer-specific entry of non-fibroblast cells such as epithelial, trophoblast, and endothelial cells, respectively. This study focuses on characterizing the structural elements of CD46 that impact HCMV infection. Infectivity studies of wild-type and CD46 knockout epithelial cells demonstrated that levels of CD46 expressed on the cell surface were directly related to HCMV infectivity. Overexpression of CD46 isomers BC1, BC2, and C2 enhanced infection. Further, CD46 knockout epithelial cells expressing CD46 deletion and chimeric molecules identified that the intact ectodomain was critical for rescue of HCMV infection in CD46 knockout cells. Collectively, these data support a model that the extracellular domain of CD46 participates in HCMV infection due to its surface expression.

Funding
This study was supported by the:
  • National Institute of Allergy and Infectious Diseases (Award 1R56AI174062-01A1)
    • Principle Award Recipient: DomenicoTortorella
  • National Institute on Aging (Award RF1AG059319)
    • Principle Award Recipient: NotApplicable
  • Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (Award R21AI147632)
    • Principle Award Recipient: DomenicoTortorella
  • Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (Award R01AI139258)
    • Principle Award Recipient: DomenicoTortorella
  • Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (Award T32AI007647)
    • Principle Award Recipient: AndreaJ Parsons
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/content/journal/jgv/10.1099/jgv.0.001892
2023-09-05
2025-02-07
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References

  1. Griffiths P, Reeves M. Pathogenesis of human cytomegalovirus in the immunocompromised host. Nat Rev Microbiol 2021; 19:759–773 [View Article] [PubMed]
    [Google Scholar]
  2. Söderberg-Nauclér C. Does cytomegalovirus play a causative role in the development of various inflammatory diseases and cancer?. J Intern Med 2006; 259:219–246 [View Article] [PubMed]
    [Google Scholar]
  3. Boeckh M, Geballe AP. Cytomegalovirus: pathogen, paradigm, and puzzle. J Clin Invest 2011; 121:1673–1680 [View Article] [PubMed]
    [Google Scholar]
  4. Goodrum F. Human cytomegalovirus latency: approaching the gordian knot. Annu Rev Virol 2016; 3:333–357 [View Article] [PubMed]
    [Google Scholar]
  5. Benditt EP, Benditt JM. Evidence for a monoclonal origin of human atherosclerotic plaques. Proc Natl Acad Sci 1973; 70:1753–1756 [View Article] [PubMed]
    [Google Scholar]
  6. Fabricant CG, Fabricant J, Minick CR, Litrenta MM. Herpesvirus-induced atherosclerosis in chickens. Fed Proc 1983; 42:2476–2479 [PubMed]
    [Google Scholar]
  7. Gattone M, Iacoviello L, Colombo M, Castelnuovo AD, Soffiantino F et al. Chlamydia pneumoniae and cytomegalovirus seropositivity, inflammatory markers, and the risk of myocardial infarction at a young age. Am Heart J 2001; 142:633–640 [View Article] [PubMed]
    [Google Scholar]
  8. Epstein SE, Zhou YF, Zhu J. Infection and atherosclerosis: emerging mechanistic paradigms. Circulation 1999; 100:e20–8 [View Article] [PubMed]
    [Google Scholar]
  9. Epstein SE, Zhu J, Burnett MS, Zhou YF, Vercellotti G et al. Infection and atherosclerosis: potential roles of pathogen burden and molecular mimicry. Arterioscler Thromb Vasc Biol 2000; 20:1417–1420 [View Article] [PubMed]
    [Google Scholar]
  10. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005; 352:1685–1695 [View Article] [PubMed]
    [Google Scholar]
  11. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002; 105:1135–1143 [View Article] [PubMed]
    [Google Scholar]
  12. Ross R. Atherosclerosis is an inflammatory disease. Am Heart J 1999; 138:S419–20 [View Article] [PubMed]
    [Google Scholar]
  13. Compton T, Feire A. Early events in human cytomegalovirus infection. In Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis 2007 [View Article]
    [Google Scholar]
  14. Ryckman BJ, Jarvis MA, Drummond DD, Nelson JA, Johnson DC. Human cytomegalovirus entry into epithelial and endothelial cells depends on genes UL128 to UL150 and occurs by endocytosis and low-pH fusion. J Virol 2006; 80:710–722 [View Article] [PubMed]
    [Google Scholar]
  15. Compton T, Nepomuceno RR, Nowlin DM. Human cytomegalovirus penetrates host cells by pH-independent fusion at the cell surface. Virology 1992; 191:387–395 [View Article] [PubMed]
    [Google Scholar]
  16. Kari B, Gehrz R. A human cytomegalovirus glycoprotein complex designated gC-II is a major heparin-binding component of the envelope. J Virol 1992; 66:1761–1764 [View Article] [PubMed]
    [Google Scholar]
  17. Kari B, Gehrz R. Structure, composition and heparin binding properties of a human cytomegalovirus glycoprotein complex designated gC-II. J Gen Virol 1993; 74 (Pt 2):255–264 [View Article] [PubMed]
    [Google Scholar]
  18. Wang X, Huang DY, Huong SM, Huang ES. Integrin alphavbeta3 is a coreceptor for human cytomegalovirus. Nat Med 2005; 11:515–521 [View Article] [PubMed]
    [Google Scholar]
  19. Wang X, Huong SM, Chiu ML, Raab-Traub N, Huang ES. Epidermal growth factor receptor is a cellular receptor for human cytomegalovirus. Nature 2003; 424:456–461 [View Article] [PubMed]
    [Google Scholar]
  20. Li Q, Wilkie AR, Weller M, Liu X, Cohen JI. THY-1 cell surface antigen (CD90) has an important role in the initial stage of human cytomegalovirus infection. PLoS Pathog 2015; 11:e1004999 [View Article] [PubMed]
    [Google Scholar]
  21. Wu K, Oberstein A, Wang W, Shenk T. Role of PDGF receptor-α during human cytomegalovirus entry into fibroblasts. Proc Natl Acad Sci 2018; 115:E9889–E9898 [View Article] [PubMed]
    [Google Scholar]
  22. E X, Meraner P, Lu P, Perreira JM, Aker AM et al. OR14I1 is a receptor for the human cytomegalovirus pentameric complex and defines viral epithelial cell tropism. Proc Natl Acad Sci 2019; 116:7043–7052 [View Article]
    [Google Scholar]
  23. Martinez-Martin N, Marcandalli J, Huang CS, Arthur CP, Perotti M et al. An unbiased screen for human cytomegalovirus identifies neuropilin-2 as a central viral receptor. Cell 2018; 174:1158–1171 [View Article] [PubMed]
    [Google Scholar]
  24. Vanarsdall AL, Pritchard SR, Wisner TW, Liu J, Jardetzky TS et al. CD147 promotes entry of pentamer-expressing human cytomegalovirus into epithelial and endothelial cells. mBio 2018; 9: [View Article]
    [Google Scholar]
  25. Stein KR, Gardner TJ, Hernandez RE, Kraus TA, Duty JA et al. CD46 facilitates entry and dissemination of human cytomegalovirus. Nat Commun 2019; 10:2699 [View Article] [PubMed]
    [Google Scholar]
  26. Kschonsak M, Rougé L, Arthur CP, Hoangdung H, Patel N et al. Structures of HCMV trimer reveal the basis for receptor recognition and cell entry. Cell 2021; 184:1232–1244 [View Article] [PubMed]
    [Google Scholar]
  27. Yamamoto H, Fara AF, Dasgupta P, Kemper C. CD46: the “multitasker” of complement proteins. Int J Biochem Cell Biol 2013; 45:2808–2820 [View Article] [PubMed]
    [Google Scholar]
  28. Cattaneo R. Four viruses, two bacteria, and one receptor: membrane cofactor protein (CD46) as pathogens’ magnet. J Virol 2004; 78:4385–4388 [View Article] [PubMed]
    [Google Scholar]
  29. Liszewski MK, Kemper C, Price JD, Atkinson JP. Emerging roles and new functions of CD46. Springer Semin Immunopathol 2005; 27:345–358 [View Article] [PubMed]
    [Google Scholar]
  30. Källström H, Blackmer Gill D, Albiger B, Liszewski MK, Atkinson JP et al. Attachment of Neisseria gonorrhoeae to the cellular pilus receptor CD46: identification of domains important for bacterial adherence. Cell Microbiol 2001; 3:133–143 [View Article] [PubMed]
    [Google Scholar]
  31. Giannakis E, Jokiranta TS, Ormsby RJ, Duthy TG, Male DA et al. Identification of the streptococcal M protein binding site on membrane cofactor protein (CD46). J Immunol 2002; 168:4585–4592 [View Article] [PubMed]
    [Google Scholar]
  32. Wang D, Shenk T. Human cytomegalovirus virion protein complex required for epithelial and endothelial cell tropism. Proc Natl Acad Sci 2005; 102:18153–18158 [View Article]
    [Google Scholar]
  33. Gardner TJ, Bolovan-Fritts C, Teng MW, Redmann V, Kraus TA et al. Development of a high-throughput assay to measure the neutralization capability of anti-cytomegalovirus antibodies. Clin Vaccine Immunol 2013; 20:540–550 [View Article] [PubMed]
    [Google Scholar]
  34. Parsons AJ, Ophir SI, Duty JA, Kraus TA, Stein KR et al. Development of broadly neutralizing antibodies targeting the cytomegalovirus subdominant antigen gH. Commun Biol 2022; 5:387 [View Article] [PubMed]
    [Google Scholar]
  35. Hsi B-L, Yeh C-JG, Fénichel P, Samson M, Grivaux C. Monoclonal antibody GB24 recognizes a trophoblast-lymphocyte cross-reactive antigen. Am J Reprod Immunol Microbiol 1988; 18:21–27 [View Article]
    [Google Scholar]
  36. Oresic K, Noriega V, Andrews L, Tortorella D. A structural determinant of human cytomegalovirus US2 dictates the down-regulation of class I major histocompatibility molecules. J Biol Chem 2006; 281:19395–19406 [View Article] [PubMed]
    [Google Scholar]
  37. Liszewski MK, Post TW, Atkinson JP. Membrane cofactor protein (MCP or CD46): newest member of the regulators of complement activation gene cluster. Annu Rev Immunol 1991; 9:431–455 [View Article] [PubMed]
    [Google Scholar]
  38. Post TW, Liszewski MK, Adams EM, Tedja I, Miller EA et al. Membrane cofactor protein of the complement system: alternative splicing of serine/threonine/proline-rich exons and cytoplasmic tails produces multiple isoforms that correlate with protein phenotype. J Exp Med 1991; 174:93–102 [View Article] [PubMed]
    [Google Scholar]
  39. Wang G, Liszewski MK, Chan AC, Atkinson JP. Membrane cofactor protein (MCP; CD46): isoform-specific tyrosine phosphorylation. J Immunol 2000; 164:1839–1846 [View Article] [PubMed]
    [Google Scholar]
  40. Hansen AS, Bundgaard BB, Møller BK, Höllsberg P. Non-random pairing of CD46 isoforms with skewing towards BC2 and C2 in activated and memory/effector T cells. Sci Rep 2016; 6:35406 [View Article] [PubMed]
    [Google Scholar]
  41. Johnstone RW, Russell SM, Loveland BE, McKenzie IF. Polymorphic expression of CD46 protein isoforms due to tissue-specific RNA splicing. Mol Immunol 1993; 30:1231–1241 [View Article] [PubMed]
    [Google Scholar]
  42. Liszewski MK, Atkinson JP. Membrane cofactor protein (MCP; CD46): deficiency states and pathogen connections. Curr Opin Immunol 2021; 72:126–134 [View Article] [PubMed]
    [Google Scholar]
  43. Persson BD, John L, Rafie K, Strebl M, Frängsmyr L et al. Human species D adenovirus hexon capsid protein mediates cell entry through a direct interaction with CD46. Proc Natl Acad Sci 2021; 118:e2020732118 [View Article] [PubMed]
    [Google Scholar]
  44. Buchholz CJ, Koller D, Devaux P, Mumenthaler C, Schneider-Schaulies J et al. Mapping of the primary binding site of measles virus to its receptor CD46. J Biol Chem 1997; 272:22072–22079 [View Article] [PubMed]
    [Google Scholar]
  45. Greenstone HL, Santoro F, Lusso P, Berger EA. Human herpesvirus 6 and measles virus employ distinct CD46 domains for receptor function. J Biol Chem 2002; 277:39112–39118 [View Article] [PubMed]
    [Google Scholar]
  46. Wrapp D, Ye X, Ku Z, Su H, Jones HG et al. Structural basis for HCMV pentamer recognition by neuropilin 2 and neutralizing antibodies. Sci Adv 2022; 8:eabm2546 [View Article] [PubMed]
    [Google Scholar]
  47. Protein Atlas: CD46 and Nrp2 2023
    [Google Scholar]
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