1887

Abstract

The role played by resident microglia and by the infiltration of peripheral monocytes/macrophages in the innate immune response during herpes simplex virus type 1 (HSV-1) encephalitis was evaluated in mice deficient for the CCR2 and CX3CR1 receptors. CCR2, CX3CR1 and C57BL/6 wild-type (WT) male mice were infected intranasally with 7×10 p.f.u. of an HSV-1 clinical strain and monitored for signs of encephalitis and survival. In addition, brain viral DNA load and cytokine levels were evaluated by RT-PCR and magnetic bead-based immunoassay, respectively. The cellular response was assessed by fluorescence-activated cell sorting of blood and brain leukocytes. Infected CX3CR1 mice had a significantly lower mean life expectancy than WT mice (<0.05, log-rank test) and demonstrated an increased infiltration of Ly-6C ‘inflammatory’ macrophages in the brain (<0.05). Infected CCR2 mice had fewer monocytes (<0.05), with a lower proportion of Ly-6C ‘inflammatory’ monocytes in the blood than the other groups (<0.05). Brain viral DNA loads were only slightly higher in knockout mice than in WT mice (-value not significant). These data suggest that CCR2 and especially CX3CR1 receptors are necessary to initiate a proper immune response during HSV encephalitis. More precisely, CCR2 is crucial for the emigration of monocytes from the bone marrow to the blood, whereas CX3CR1 is mostly implicated in the regulation of infiltrating cells from the blood to the site of infection and in the control of the immune homeostasis of the brain.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.041046-0
2012-06-01
2024-03-29
Loading full text...

Full text loading...

/deliver/fulltext/jgv/93/6/1294.html?itemId=/content/journal/jgv/10.1099/vir.0.041046-0&mimeType=html&fmt=ahah

References

  1. Auffray C., Fogg D., Garfa M., Elain G., Join-Lambert O., Kayal S., Sarnacki S., Cumano A., Lauvau G., Geissmann F. 2007; Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 317:666–670 [View Article][PubMed]
    [Google Scholar]
  2. Auffray C., Sieweke M. H., Geissmann F. 2009; Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu Rev Immunol 27:669–692 [View Article][PubMed]
    [Google Scholar]
  3. Boivin G., Coulombe Z., Rivest S. 2002; Intranasal herpes simplex virus type 2 inoculation causes a profound thymidine kinase dependent cerebral inflammatory response in the mouse hindbrain. Eur J Neurosci 16:29–43 [View Article][PubMed]
    [Google Scholar]
  4. Boivin G., Goyette N., Sergerie Y., Keays S., Booth T. 2006; Longitudinal evaluation of herpes simplex virus DNA load during episodes of herpes labialis. J Clin Virol 37:248–251 [View Article][PubMed]
    [Google Scholar]
  5. Boring L., Gosling J., Chensue S. W., Kunkel S. L., Farese R. V. Jr, Broxmeyer H. E., Charo I. F. 1997; Impaired monocyte migration and reduced type 1 (Th1) cytokine responses in C-C chemokine receptor 2 knockout mice. J Clin Invest 100:2552–2561 [View Article][PubMed]
    [Google Scholar]
  6. Campbell J. J., Qin S., Unutmaz D., Soler D., Murphy K. E., Hodge M. R., Wu L., Butcher E. C. 2001; Unique subpopulations of CD56+ NK and NK-T peripheral blood lymphocytes identified by chemokine receptor expression repertoire. J Immunol 166:6477–6482[PubMed] [CrossRef]
    [Google Scholar]
  7. Candelario-Jalil E., Taheri S., Yang Y., Sood R., Grossetete M., Estrada E. Y., Fiebich B. L., Rosenberg G. A. 2007; Cyclooxygenase inhibition limits blood–brain barrier disruption following intracerebral injection of tumor necrosis factor-α in the rat. J Pharmacol Exp Ther 323:488–498 [View Article][PubMed]
    [Google Scholar]
  8. Cardona A. E., Pioro E. P., Sasse M. E., Kostenko V., Cardona S. M., Dijkstra I. M., Huang D., Kidd G., Dombrowski S. other authors 2006; Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 9:917–924 [View Article][PubMed]
    [Google Scholar]
  9. Corona A. W., Huang Y., O’Connor J. C., Dantzer R., Kelley K. W., Popovich P. G., Godbout J. P. 2010; Fractalkine receptor (CX3CR1) deficiency sensitizes mice to the behavioral changes induced by lipopolysaccharide. J Neuroinflammation 7:93 [View Article][PubMed]
    [Google Scholar]
  10. Davoust N., Vuaillat C., Androdias G., Nataf S. 2008; From bone marrow to microglia: barriers and avenues. Trends Immunol 29:227–234 [View Article][PubMed]
    [Google Scholar]
  11. Ellermann-Eriksen S. 2005; Macrophages and cytokines in the early defence against herpes simplex virus. Virol J 2:59 [View Article][PubMed]
    [Google Scholar]
  12. Getts D. R., Terry R. L., Getts M. T., Müller M., Rana S., Shrestha B., Radford J., Van Rooijen N., Campbell I. L., King N. J. 2008; Ly6c+ “inflammatory monocytes” are microglial precursors recruited in a pathogenic manner in West Nile virus encephalitis. J Exp Med 205:2319–2337 [View Article][PubMed]
    [Google Scholar]
  13. Glass W. G., Lim J. K., Cholera R., Pletnev A. G., Gao J. L., Murphy P. M. 2005; Chemokine receptor CCR5 promotes leukocyte trafficking to the brain and survival in West Nile virus infection. J Exp Med 202:1087–1098 [View Article][PubMed]
    [Google Scholar]
  14. Harrison J. K., Jiang Y., Chen S., Xia Y., Maciejewski D., McNamara R. K., Streit W. J., Salafranca M. N., Adhikari S. other authors 1998; Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc Natl Acad Sci U S A 95:10896–10901 [View Article][PubMed]
    [Google Scholar]
  15. Huang D., Shi F. D., Jung S., Pien G. C., Wang J., Salazar-Mather T. P., He T. T., Weaver J. T., Ljunggren H. G. other authors 2006; The neuronal chemokine CX3CL1/fractalkine selectively recruits NK cells that modify experimental autoimmune encephalomyelitis within the central nervous system. FASEB J 20:896–905 [View Article][PubMed]
    [Google Scholar]
  16. Iijima N., Mattei L. M., Iwasaki A. 2011; Recruited inflammatory monocytes stimulate antiviral Th1 immunity in infected tissue. Proc Natl Acad Sci U S A 108:284–289 [View Article][PubMed]
    [Google Scholar]
  17. Ishida Y., Hayashi T., Goto T., Kimura A., Akimoto S., Mukaida N., Kondo T. 2008; Essential involvement of CX3CR1-mediated signals in the bactericidal host defense during septic peritonitis. J Immunol 181:4208–4218[PubMed] [CrossRef]
    [Google Scholar]
  18. Jia T., Serbina N. V., Brandl K., Zhong M. X., Leiner I. M., Charo I. F., Pamer E. G. 2008; Additive roles for MCP-1 and MCP-3 in CCR2-mediated recruitment of inflammatory monocytes during Listeria monocytogenes infection. J Immunol 180:6846–6853[PubMed] [CrossRef]
    [Google Scholar]
  19. Jung S., Aliberti J., Graemmel P., Sunshine M. J., Kreutzberg G. W., Sher A., Littman D. R. 2000; Analysis of fractalkine receptor CX3CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol Cell Biol 20:4106–4114 [View Article][PubMed]
    [Google Scholar]
  20. Karlmark K. R., Zimmermann H. W., Roderburg C., Gassler N., Wasmuth H. E., Luedde T., Trautwein C., Tacke F. 2010; The fractalkine receptor CX3CR1 protects against liver fibrosis by controlling differentiation and survival of infiltrating hepatic monocytes. Hepatology 52:1769–1782 [View Article][PubMed]
    [Google Scholar]
  21. Kastrukoff L. F., Lau A. S., Takei F., Smyth M. J., Jones C. M., Clarke S. R., Carbone F. R. 2010; Redundancy in the immune system restricts the spread of HSV-1 in the central nervous system (CNS) of C57BL/6 mice. Virology 400:248–258 [View Article][PubMed]
    [Google Scholar]
  22. Lee S., Varvel N. H., Konerth M. E., Xu G., Cardona A. E., Ransohoff R. M., Lamb B. T. 2010; CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer’s disease mouse models. Am J Pathol 177:2549–2562 [View Article][PubMed]
    [Google Scholar]
  23. Lim J. K., Obara C. J., Rivollier A., Pletnev A. G., Kelsall B. L., Murphy P. M. 2011; Chemokine receptor Ccr2 is critical for monocyte accumulation and survival in West Nile virus encephalitis. J Immunol 186:471–478 [View Article][PubMed]
    [Google Scholar]
  24. Lokensgard J. R., Hu S., Sheng W., vanOijen M., Cox D., Cheeran M. C., Peterson P. K. 2001; Robust expression of TNFα, IL-1β, RANTES, and IP-10 by human microglial cells during nonproductive infection with herpes simplex virus. J Neurovirol 7:208–219 [View Article][PubMed]
    [Google Scholar]
  25. Lundberg P., Openshaw H., Wang M., Yang H. J., Cantin E. 2007; Effects of CXCR3 signaling on development of fatal encephalitis and corneal and periocular skin disease in HSV-infected mice are mouse-strain dependent. Invest Ophthalmol Vis Sci 48:4162–4170 [View Article][PubMed]
    [Google Scholar]
  26. Marques C. P., Hu S., Sheng W., Lokensgard J. R. 2006; Microglial cells initiate vigorous yet non-protective immune responses during HSV-1 brain infection. Virus Res 121:1–10 [View Article][PubMed]
    [Google Scholar]
  27. Marques C. P., Cheeran M. C., Palmquist J. M., Hu S., Urban S. L., Lokensgard J. R. 2008; Prolonged microglial cell activation and lymphocyte infiltration following experimental herpes encephalitis. J Immunol 181:6417–6426[PubMed] [CrossRef]
    [Google Scholar]
  28. Mildner A., Schmidt H., Nitsche M., Merkler D., Hanisch U. K., Mack M., Heikenwalder M., Brück W., Priller J., Prinz M. 2007; Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nat Neurosci 10:1544–1553 [View Article][PubMed]
    [Google Scholar]
  29. Mildner A., Mack M., Schmidt H., Brück W., Djukic M., Zabel M. D., Hille A., Priller J., Prinz M. 2009; CCR2+Ly-6Chi monocytes are crucial for the effector phase of autoimmunity in the central nervous system. Brain 132:2487–2500 [View Article][PubMed]
    [Google Scholar]
  30. Osterholzer J. J., Chen G. H., Olszewski M. A., Curtis J. L., Huffnagle G. B., Toews G. B. 2009; Accumulation of CD11b+ lung dendritic cells in response to fungal infection results from the CCR2-mediated recruitment and differentiation of Ly-6Chigh monocytes. J Immunol 183:8044–8053 [View Article][PubMed]
    [Google Scholar]
  31. Peters W., Scott H. M., Chambers H. F., Flynn J. L., Charo I. F., Ernst J. D. 2001; Chemokine receptor 2 serves an early and essential role in resistance to Mycobacterium tuberculosis . Proc Natl Acad Sci U S A 98:7958–7963 [View Article][PubMed]
    [Google Scholar]
  32. Prinz M., Priller J. 2010; Tickets to the brain: role of CCR2 and CX3CR1 in myeloid cell entry in the CNS. J Neuroimmunol 224:80–84 [View Article][PubMed]
    [Google Scholar]
  33. Scott H. M., Flynn J. L. 2002; Mycobacterium tuberculosis in chemokine receptor 2-deficient mice: influence of dose on disease progression. Infect Immun 70:5946–5954 [View Article][PubMed]
    [Google Scholar]
  34. Serbina N. V., Pamer E. G. 2006; Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat Immunol 7:311–317 [View Article][PubMed]
    [Google Scholar]
  35. Sergerie Y., Rivest S., Boivin G. 2007; Tumor necrosis factor-alpha and interleukin-1β play a critical role in the resistance against lethal herpes simplex virus encephalitis. J Infect Dis 196:853–860 [View Article][PubMed]
    [Google Scholar]
  36. Simard A. R., Rivest S. 2004; Bone marrow stem cells have the ability to populate the entire central nervous system into fully differentiated parenchymal microglia. FASEB J 18:998–1000[PubMed]
    [Google Scholar]
  37. Tsou C. L., Peters W., Si Y., Slaymaker S., Aslanian A. M., Weisberg S. P., Mack M., Charo I. F. 2007; Critical roles for CCR2 and MCP-3 in monocyte mobilization from bone marrow and recruitment to inflammatory sites. J Clin Invest 117:902–909 [View Article][PubMed]
    [Google Scholar]
  38. Tyler K. L. 2004; Update on herpes simplex encephalitis. Rev Neurol Dis 1:169–178[PubMed]
    [Google Scholar]
  39. Whitley R. J., Kimberlin D. W. 2005; Herpes simplex encephalitis: children and adolescents. Semin Pediatr Infect Dis 16:17–23 [View Article][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.041046-0
Loading
/content/journal/jgv/10.1099/vir.0.041046-0
Loading

Data & Media loading...

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