1887

Abstract

Cytomegaloviruses (CMVs) establish persistent, systemic infections and cause disease by maternal–foetal transfer, suggesting that their dissemination is a key target for antiviral intervention. Late clinical presentation has meant that human CMV (HCMV) dissemination is not well understood. Murine CMV (MCMV) provides a tractable model. Whole mouse imaging of virus-expressed luciferase has proved a useful way to track systemic infections. MCMV, in which the abundant lytic gene M78 was luciferase-tagged via a self-cleaving peptide (M78-LUC), allowed serial, unbiased imaging of systemic and peripheral infection without significant virus attenuation. Ex vivo luciferase imaging showed greater sensitivity than plaque assay, and revealed both well-known infection sites (the lungs, lymph nodes, salivary glands, liver, spleen and pancreas) and less explored sites (the bone marrow and upper respiratory tract). We applied luciferase imaging to tracking MCMV lacking M33, a chemokine receptor conserved in HCMV and a proposed anti-viral drug target. M33-deficient M78-LUC colonized normally in peripheral sites and local draining lymph nodes but spread poorly to the salivary gland, suggesting a defect in vascular transport consistent with properties of a chemokine receptor.

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2016-12-16
2019-10-17
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References

  1. Amsler L., Malouli D., DeFilippis V..( 2013;). The inflammasome as a target of modulation by DNA viruses. . Future Virol 8: 357–370. [CrossRef] [PubMed]
    [Google Scholar]
  2. Beisser P. S., Vink C., Van Dam J. G., Grauls G., Vanherle S. J., Bruggeman C. A..( 1998;). The R33 G protein-coupled receptor gene of rat cytomegalovirus plays an essential role in the pathogenesis of viral infection. . J Virol 72: 2352–2363.[PubMed]
    [Google Scholar]
  3. Bennett N. J., May J. S., Stevenson P. G..( 2005;). Gamma-herpesvirus latency requires T cell evasion during episome maintenance. . PLoS Biol 3: e120. [CrossRef] [PubMed]
    [Google Scholar]
  4. Bittencourt F. M., Wu S. E., Bridges J. P., Miller W. E..( 2014;). The M33 G protein-coupled receptor encoded by murine cytomegalovirus is dispensable for hematogenous dissemination but is required for growth within the salivary gland. . J Virol 88: 11811–11824. [CrossRef] [PubMed]
    [Google Scholar]
  5. Burke C. W., Mason J. N., Surman S. L., Jones B. G., Dalloneau E., Hurwitz J. L., Russell C. J..( 2011;). Illumination of parainfluenza virus infection and transmission in living animals reveals a tissue-specific dichotomy. . PLoS Pathog 7: e1002134. [CrossRef] [PubMed]
    [Google Scholar]
  6. Cardin R. D., Schaefer G. C., Allen J. R., Davis-Poynter N. J., Farrell H. E..( 2009;). The M33 chemokine receptor homolog of murine cytomegalovirus exhibits a differential tissue-specific role during in vivo replication and latency. . J Virol 83: 7590–7601. [CrossRef] [PubMed]
    [Google Scholar]
  7. Case R., Sharp E., Benned-Jensen T., Rosenkilde M. M., Davis-Poynter N., Farrell H. E..( 2008;). Functional analysis of the murine cytomegalovirus chemokine receptor homologue M33: ablation of constitutive signaling is associated with an attenuated phenotype in vivo. . J Virol 82: 1884–1898. [CrossRef] [PubMed]
    [Google Scholar]
  8. Chong K. T., Mims C. A..( 1981;). Murine cytomegalovirus particle types in relation to sources of virus and pathogenicity. . J Gen Virol 57: 415–419. [CrossRef] [PubMed]
    [Google Scholar]
  9. Coleman S. M., McGregor A..( 2015;). A bright future for bioluminescent imaging in viral research. . Future Virol 10: 169–183. [CrossRef] [PubMed]
    [Google Scholar]
  10. Cook S. H., Griffin D. E..( 2003;). Luciferase imaging of a neurotropic viral infection in intact animals. . J Virol 77: 5333–5338. [CrossRef] [PubMed]
    [Google Scholar]
  11. Daley-Bauer L. P., Roback L. J., Wynn G. M., Mocarski E. S..( 2014;). Cytomegalovirus hijacks CX3CR1(hi) patrolling monocytes as immune-privileged vehicles for dissemination in mice. . Cell Host Microbe 15: 351–362. [CrossRef] [PubMed]
    [Google Scholar]
  12. Davis-Poynter N. J., Lynch D. M., Vally H., Shellam G. R., Rawlinson W. D., Barrell B. G., Farrell H. E..( 1997;). Identification and characterization of a G protein-coupled receptor homolog encoded by murine cytomegalovirus. . J Virol 71: 1521–1529.[PubMed]
    [Google Scholar]
  13. El-Gogo S., Flach B., Staib C., Sutter G., Adler H..( 2008;). In vivo attenuation of recombinant murine gammaherpesvirus 68 (MHV-68) is due to the expression and immunogenicity but not to the insertion of foreign sequences. . Virology 380: 322–327. [CrossRef] [PubMed]
    [Google Scholar]
  14. Epelman S., Lavine K. J., Randolph G. J..( 2014;). Origin and functions of tissue macrophages. . Immunity 41: 21–35. [CrossRef] [PubMed]
    [Google Scholar]
  15. Farrell H. E., Abraham A. M., Cardin R. D., Sparre-Ulrich A. H., Rosenkilde M. M., Spiess K., Jensen T. H., Kledal T. N., Davis-Poynter N..( 2011;). Partial functional complementation between human and mouse cytomegalovirus chemokine receptor homologues. . J Virol 85: 6091–6095. [CrossRef] [PubMed]
    [Google Scholar]
  16. Farrell H. E., Abraham A. M., Cardin R. D., Mølleskov-Jensen A. S., Rosenkilde M. M., Davis-Poynter N..( 2013;). Identification of common mechanisms by which human and mouse cytomegalovirus seven-transmembrane receptor homologues contribute to in vivo phenotypes in a mouse model. . J Virol 87: 4112–4117. [CrossRef] [PubMed]
    [Google Scholar]
  17. Farrell H. E., Davis-Poynter N., Bruce K., Lawler C., Dolken L., Mach M., Stevenson P. G..( 2015;). Lymph node macrophages restrict murine cytomegalovirus dissemination. . J Virol 89: 7147–7158. [CrossRef] [PubMed]
    [Google Scholar]
  18. Farrell H. E., Lawler C., Tan C. S., MacDonald K., Bruce K., Mach M., Davis-Poynter N., Stevenson P. G..( 2016;). Murine cytomegalovirus exploits olfaction to enter new hosts. . MBio 7: e00251-16. [CrossRef] [PubMed]
    [Google Scholar]
  19. Fenner F..( 1948;). The pathogenesis of the acute exanthems. An interpretation based on experimental investigations with mousepox (infectious ectromelia of mice). . Lancet 2: 915–920.[PubMed] [CrossRef]
    [Google Scholar]
  20. Frederico B., Chao B., May J. S., Belz G. T., Stevenson P. G..( 2014;). A murid gamma-herpesviruses exploits normal splenic immune communication routes for systemic spread. . Cell Host Microbe 15: 457–470. [CrossRef] [PubMed]
    [Google Scholar]
  21. Heaton N. S., Leyva-Grado V. H., Tan G. S., Eggink D., Hai R., Palese P..( 2013;). In vivo bioluminescent imaging of influenza a virus infection and characterization of novel cross-protective monoclonal antibodies. . J Virol 87: 8272–8281. [CrossRef] [PubMed]
    [Google Scholar]
  22. Hertel L..( 2014;). Human cytomegalovirus tropism for mucosal myeloid dendritic cells. . Rev Med Virol 24: 379–395. [CrossRef] [PubMed]
    [Google Scholar]
  23. Jarvis M. A., Nelson J. A..( 2002;). Mechanisms of human cytomegalovirus persistence and latency. . Front Biosci 7: d1575–1582. [CrossRef]
    [Google Scholar]
  24. Krmpotic A., Bubic I., Polic B., Lucin P., Jonjic S..( 2003;). Pathogenesis of murine cytomegalovirus infection. . Microbes Infect 5: 1263–1277. [CrossRef] [PubMed]
    [Google Scholar]
  25. Luker G. D., Bardill J. P., Prior J. L., Pica C. M., Piwnica-Worms D., Leib D. A..( 2002;). Noninvasive bioluminescence imaging of herpes simplex virus type 1 infection and therapy in living mice. . J Virol 76: 12149–12161. [CrossRef] [PubMed]
    [Google Scholar]
  26. Luker K. E., Hutchens M., Schultz T., Pekosz A., Luker G. D..( 2005;). Bioluminescence imaging of vaccinia virus: effects of interferon on viral replication and spread. . Virology 341: 284–300. [CrossRef] [PubMed]
    [Google Scholar]
  27. Milho R., Smith C. M., Marques S., Alenquer M., May J. S., Gillet L., Gaspar M., Efstathiou S., Simas J. P., Stevenson P. G..( 2009;). In vivo imaging of murid herpesvirus-4 infection. . J Gen Virol 90: 21–32. [CrossRef] [PubMed]
    [Google Scholar]
  28. Misra V., Hudson J. B..( 1980;). Minor base sequence differences between the genomes of two strains of murine cytomegalovirus differing in virulence. . Arch Virol 64: 1–8. [CrossRef] [PubMed]
    [Google Scholar]
  29. Mocarski E. S., Shenk T., Pass R. F..( 2007;). Cytomegaloviruses. . In Fields’ Virology, pp. 2702–2772. Edited by Knipe D. M., Howley P. M.. Philadelphia:: Lippincott Williams and Wilkins;.
    [Google Scholar]
  30. Noriega V. M., Gardner T. J., Redmann V., Bongers G., Lira S. A., Tortorella D..( 2014;). Human cytomegalovirus US28 facilitates cell-to-cell viral dissemination. . Viruses 6: 1202–1218. [CrossRef] [PubMed]
    [Google Scholar]
  31. O'Connor C. M., Shenk T..( 2012;). Human cytomegalovirus pUL78 G protein-coupled receptor homologue is required for timely cell entry in epithelial cells but not fibroblasts. . J Virol 86: 11425–11433. [CrossRef] [PubMed]
    [Google Scholar]
  32. Oliveira S. A., Shenk T. E..( 2001;). Murine cytomegalovirus M78 protein, a G protein-coupled receptor homologue, is a constituent of the virion and facilitates accumulation of immediate-early viral mRNA. . Proc Natl Acad Sci U S A 98: 3237–3242. [CrossRef] [PubMed]
    [Google Scholar]
  33. Papadimitriou J. M., Shellam G. R., Robertson T. A..( 1984;). An ultrastructural investigation of cytomegalovirus replication in murine hepatocytes. . J Gen Virol 65: 1979–1990. [CrossRef] [PubMed]
    [Google Scholar]
  34. Poole E., Reeves M., Sinclair J. H..( 2014;). The use of primary human cells (fibroblasts, monocytes, and others) to assess human cytomegalovirus function. . Methods Mol Biol 1119: 81–98. [CrossRef] [PubMed]
    [Google Scholar]
  35. Raaben M., Prins H. J., Martens A. C., Rottier P. J., De Haan C. A..( 2009;). Non-invasive imaging of mouse hepatitis coronavirus infection reveals determinants of viral replication and spread in vivo. . Cell Microbiol 11: 825–841. [CrossRef] [PubMed]
    [Google Scholar]
  36. Rawlinson W. D., Farrell H. E., Barrell B. G..( 1996;). Analysis of the complete DNA sequence of murine cytomegalovirus. . J Virol 70: 8833–8849.[PubMed]
    [Google Scholar]
  37. Scalzo A. A., Corbett A. J., Rawlinson W. D., Scott G. M., Degli-Esposti M. A..( 2007;). The interplay between host and viral factors in shaping the outcome of cytomegalovirus infection. . Immunol Cell Biol 85: 46–54. [CrossRef] [PubMed]
    [Google Scholar]
  38. Sell S., Dietz M., Schneider A., Holtappels R., Mach M., Winkler T. H..( 2015;). Control of murine cytomegalovirus infection by γδ T cells. . PLoS Pathog 11: e1004481. [CrossRef] [PubMed]
    [Google Scholar]
  39. Shellam G. R., Redwood A. J., Smith L. M., Gorman S..( 2007;). Murine cytomegalovirus and other herpesviruses. . In The Mouse in Biomedical Research, , 2nd edn.,Vol. II, Diseases pp. 1–48. Edited by Fox J. G., Davisson M. T., Quimby F. W., Barthold S. W., Newcomer C. E., Smith A. L.. Amsterdam:: Elsevier:.[CrossRef]
    [Google Scholar]
  40. Sherrill J. D., Stropes M. P., Schneider O. D., Koch D. E., Bittencourt F. M., Miller J. L., Miller W. E..( 2009;). Activation of intracellular signaling pathways by the murine cytomegalovirus G protein-coupled receptor M33 occurs via PLC-{beta}/PKC-dependent and -independent mechanisms. . J Virol 83: 8141–8152. [CrossRef] [PubMed]
    [Google Scholar]
  41. Sinzger C., Digel M., Jahn G..( 2008;). Cytomegalovirus cell tropism. . Curr Top Microbiol Immunol 325: 63–83.[PubMed]
    [Google Scholar]
  42. Smith M. S., Bentz G. L., Alexander J. S., Yurochko A. D..( 2004;). Human cytomegalovirus induces monocyte differentiation and migration as a strategy for dissemination and persistence. . J Virol 78: 4444–4453. [CrossRef] [PubMed]
    [Google Scholar]
  43. Stevenson E. V., Collins-McMillen D., Kim J. H., Cieply S. J., Bentz G. L., Yurochko A. D..( 2014;). HCMV reprogramming of infected monocyte survival and differentiation: a Goldilocks phenomenon. . Viruses 6: 782–807. [CrossRef] [PubMed]
    [Google Scholar]
  44. Stoddart C. A., Cardin R. D., Boname J. M., Manning W. C., Abenes G. B., Mocarski E. S..( 1994;). Peripheral blood mononuclear phagocytes mediate dissemination of murine cytomegalovirus. . J Virol 68: 6243–6253.[PubMed]
    [Google Scholar]
  45. Szymczak A. L., Workman C. J., Wang Y., Vignali K. M., Dilioglou S., Vanin E. F., Vignali D. A..( 2004;). Correction of multi-gene deficiency in vivo using a single ‘self-cleaving’ 2A peptide-based retroviral vector. . Nat Biotechnol 22: 589–594. [CrossRef] [PubMed]
    [Google Scholar]
  46. Tan C. S., Frederico B., Stevenson P. G..( 2014;). Herpesvirus delivery to the murine respiratory tract. . J Virol Methods 206: 105–114. [CrossRef] [PubMed]
    [Google Scholar]
  47. Waldhoer M., Kledal T. N., Farrell H., Schwartz T. W..( 2002;). Murine cytomegalovirus (CMV) M33 and human CMV US28 receptors exhibit similar constitutive signaling activities. . J Virol 76: 8161–8168. [CrossRef] [PubMed]
    [Google Scholar]
  48. Wang X., Messerle M., Sapinoro R., Santos K., Hocknell P. K., Jin X., Dewhurst S..( 2003;). Murine cytomegalovirus abortively infects human dendritic cells, leading to expression and presentation of virally vectored genes. . J Virol 77: 7182–7392. [CrossRef] [PubMed]
    [Google Scholar]
  49. Zhang S., Xiang J., Desmarets L. M. B., Nauwynck H. J..( 2016;). Pattern of circulation of MCMV mimicking natural infection upon oronasal inoculation. . Virus Res 215: 114–120. [CrossRef]
    [Google Scholar]
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