**7. Acknowledgement**

The authors thanks the University of la Réunion (Felloship to GVTH), the CPER/FEDER funds (GRII Phase I-III), the ANR, INSERM (Fellowship to PG) the Regional Council of la Reunion (Fellowship to SK), the CRVOI for funds and continuous support. We express or thanks to other members of the laboratory (EA4517) for constructive criticisms and helps.

### **8. References**


Despite the vast genetic diversity among viruses, these pathogens face similar obstacles on the way into the CNS with the dual role of a physical and molecular barriers of the innate immune system to restrict and protect from infection. However, upon entry whether they are hidden in leukocytes or in apoptotic blebs, they will be free to interact with neurons in a rather 'immunopriviliged' environnement allowing viral persistence. However, this paradigm has been reconsidered with the observation that resident cells possess several of the key innate immune receptors involved in the recognition of the intruders and to engage a salutary antiviral response (IFN). It is now clear that other molecular interactions between the viruses and these host cells expressing primary and secondary signaling receptors will determine the outcome of the infection. Some receptors may control apoptosis or cell differentiation which in turn may have an impact on the capacity to resist viral infection and spreading. Our understanding of the molecular mechanisms of CNS diseases is still in its infancy. Increasingly, identification of virulence factors and host receptors will provide solutions for this complex puzzle. Understanding these interactions will increase our ability to control neuroinvasion and encephalitis. Moreover, it will also teach how to use these entry routes for therapeutic benefit, for example, for gene delivery of therapy of cancer and

The authors thanks the University of la Réunion (Felloship to GVTH), the CPER/FEDER funds (GRII Phase I-III), the ANR, INSERM (Fellowship to PG) the Regional Council of la Reunion (Fellowship to SK), the CRVOI for funds and continuous support. We express or thanks to other members of the laboratory (EA4517) for constructive criticisms and helps.

Abbott, N.J., A.A. Patabendige, D.E. Dolman, S.R. Yusof, and D.J. Begley. 2010. Structure

Alexopoulou, L., A.C. Holt, R. Medzhitov, and R.A. Flavell. 2001. Recognition of double-

Alkhatib, G., C. Combadiere, C.C. Broder, Y. Feng, P.E. Kennedy, P.M. Murphy, and E.A.

Areschoug, T., and S. Gordon. 2009. Scavenger receptors: role in innate immunity and

Bagasra, O., E. Lavi, L. Bobroski, K. Khalili, J.P. Pestaner, R. Tawadros, and R.J. Pomerantz.

Balasubramanian, K., and A.J. Schroit. 2003. Aminophospholipid asymmetry: A matter of

stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature.

Berger. 1996. CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion

1996. Cellular reservoirs of HIV-1 in the central nervous system of infected individuals: identification by the combination of in situ polymerase chain reaction

and function of the blood-brain barrier. Neurobiol Dis. 37:13-25.

cofactor for macrophage-tropic HIV-1. Science. 272:1955-1958.

microbial pathogenesis. Cell Microbiol. 11:1160-1169.

and immunohistochemistry. AIDS. 10:573-585.

life and death. Annu Rev Physiol. 65:701-734.

**6. Conclusion** 

neurodegeneration.

**8. References** 

413:732-738.

**7. Acknowledgement** 


Virus-Induced Encephalitis and

161:6250-6257.

272:872-877.

Med. 3:553-564.

84:8021-8032.

Virol. 74:3399-3403.

infection. Trends Microbiol. 7:160-165.

Neuropathol Appl Neurobiol. 32:397-409.

Innate Immune Responses – A Focus on Emerging or Re-Emerging Viruses 79

Everett, H., and G. McFadden. 1999. Apoptosis: an innate immune response to virus

Evlashev, A., E. Moyse, H. Valentin, O. Azocar, M.C. Trescol-Biemont, J.C. Marie, C.

Fadok, V.A., M.L. Warner, D.L. Bratton, and P.M. Henson. 1998. CD36 is required for

Fazakerley, J.K., C.L. Cotterill, G. Lee, and A. Graham. 2006. Virus tropism, distribution,

Feng, Y., C.C. Broder, P.E. Kennedy, and E.A. Berger. 1996. HIV-1 entry cofactor: functional

Fiala, M., D.J. Looney, M. Stins, D.D. Way, L. Zhang, X. Gan, F. Chiappelli, E.S. Schweitzer,

Fujimoto, I., J. Pan, T. Takizawa, and Y. Nakanishi. 2000. Virus clearance through apoptosis-

Fujita, T., K. Onoguchi, K. Onomoto, R. Hirai, and M. Yoneyama. 2007. Triggering antiviral

Furr, S.R., V.S. Chauhan, D. Sterka, Jr., V. Grdzelishvili, and I. Marriott. 2008.

Ganesan, K., A. Diwan, S.K. Shankar, S.B. Desai, G.S. Sainani, and S.M. Katrak. 2008.

Gautier, I., J. Coppey, and C. Durieux. 2003. Early apoptosis-related changes triggered by

George, C.X., Z. Li, K.M. Okonski, A.M. Toth, Y. Wang, and C.E. Samuel. 2009. Tipping the

Geraghty, R.J., C. Krummenacher, G.H. Cohen, R.J. Eisenberg, and P.G. Spear. 1998. Entry of

1 case with autopsy findings. AJNR Am J Neuroradiol. 29:1636-1637. Gardner, J., I. Anraku, T.T. Le, T. Larcher, L. Major, P. Roques, W.A. Schroder, S. Higgs, and

HSV-1 in individual neuronlike cells. Exp Cell Res. 289:174-183.

products. J Interferon Cytokine Res. 29:477-487.

poliovirus receptor. Science. 280:1618-1620.

glia following exposure to vesicular stomatitis virus. J Neurovirol:1-11. Gamp, A.C., Y. Tanaka, R. Lullmann-Rauch, D. Wittke, R. D'Hooge, P.P. De Deyn, T. Moser,

response by RIG-I-related RNA helicases. Biochimie. 89:754-760.

peripheral neuropathy in mice. Hum Mol Genet. 12:631-646.

and apoptosis in CD46 transgenic mice. J Virol. 74:1373-1382.

Rabourdin-Combe, and B. Horvat. 2000. Productive measles virus brain infection

phagocytosis of apoptotic cells by human macrophages that use either a phosphatidylserine receptor or the vitronectin receptor (alpha v beta 3). J Immunol.

persistence and pathology in the corpus callosum of the Semliki Forest virusinfected mouse brain: a novel system to study virus-oligodendrocyte interactions.

cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science.

P. Shapshak, M. Weinand, M.C. Graves, M. Witte, and K.S. Kim. 1997. TNF-alpha opens a paracellular route for HIV-1 invasion across the blood-brain barrier. Mol

dependent phagocytosis of influenza A virus-infected cells by macrophages. J

Characterization of retinoic acid-inducible gene-I expression in primary murine

H. Maier, D. Hartmann, K. Reiss, A.L. Illert, K. von Figura, and P. Saftig. 2003. LIMP-2/LGP85 deficiency causes ureteric pelvic junction obstruction, deafness and

Chikungunya encephalomyeloradiculitis: report of 2 cases with neuroimaging and

A. Suhrbier. 2010. Chikungunya virus arthritis in adult wild-type mice. J Virol.

balance: antagonism of PKR kinase and ADAR1 deaminase functions by virus gene

alphaherpesviruses mediated by poliovirus receptor-related protein 1 and

young age and inefficient type-I interferon signaling are risk factors for severe disease. PLoS Pathog. 4:e29.


Crimeen-Irwin, B., S. Ellis, D. Christiansen, M.J. Ludford-Menting, J. Milland, M. Lanteri,

Daffis, S., M.A. Samuel, M.S. Suthar, M. Gale, Jr., and M.S. Diamond. 2008. Toll-like receptor 3 has a protective role against West Nile virus infection. J Virol. 82:10349-10358. Dalgleish, A.G., P.C. Beverley, P.R. Clapham, D.H. Crawford, M.F. Greaves, and R.A. Weiss.

Danial, N.N., and S.J. Korsmeyer. 2004. Cell death: critical control points. Cell. 116:205-219. Das, T., M.C. Jaffar-Bandjee, J.J. Hoarau, P. Krejbich Trotot, M. Denizot, G. Lee-Pat-Yuen, R.

Deng, H., R. Liu, W. Ellmeier, S. Choe, D. Unutmaz, M. Burkhart, P. Di Marzio, S. Marmon,

Doranz, B.J., J. Rucker, Y. Yi, R.J. Smyth, M. Samson, S.C. Peiper, M. Parmentier, R.G.

Dorig, R.E., A. Marcil, A. Chopra, and C.D. Richardson. 1993. The human CD46 molecule is

Dragic, T., V. Litwin, G.P. Allaway, S.R. Martin, Y. Huang, K.A. Nagashima, C. Cayanan,

Drickamer, K. 1995. Increasing diversity of animal lectin structures. Curr Opin Struct Biol.

Dropulic, B., and C.L. Masters. 1990. Entry of neurotropic arboviruses into the central

Economopoulou, A., M. Dominguez, B. Helynck, D. Sissoko, O. Wichmann, P. Quenel, P.

Egea, J., and R. Klein. 2007. Bidirectional Eph-ephrin signaling during axon guidance.

Eskelinen, E.L., Y. Tanaka, and P. Saftig. 2003. At the acidic edge: emerging functions for

Esko, J.D., and S.B. Selleck. 2002. Order out of chaos: assembly of ligand binding sites in

a receptor for measles virus (Edmonston strain). Cell. 75:295-305.

into the central nervous system. Microbes Infect. 2:1609-1618.

2005-2006 outbreak on Reunion. Epidemiol Infect. 137:534-541.

lysosomal membrane proteins. Trends Cell Biol. 13:137-145.

heparan sulfate. Annu Rev Biochem. 71:435-471.

disease. PLoS Pathog. 4:e29.

Chem. 278:46927-46937.

Nature. 381:661-666.

Cell. 85:1149-1158.

5:612-616.

161:685-691.

Trends Cell Biol. 17:230-238.

retrovirus. Nature. 312:763-767.

arbovirus. Prog Neurobiol. 91:121-129.

young age and inefficient type-I interferon signaling are risk factors for severe

B.E. Loveland, D. Gerlier, and S.M. Russell. 2003. Ligand binding determines whether CD46 is internalized by clathrin-coated pits or macropinocytosis. J Biol

1984. The CD4 (T4) antigen is an essential component of the receptor for the AIDS

Sahoo, P. Guiraud, D. Ramful, S. Robin, J.L. Alessandri, B.A. Gauzere, and P. Gasque. 2010. Chikungunya fever: CNS infection and pathologies of a re-emerging

R.E. Sutton, C.M. Hill, C.B. Davis, S.C. Peiper, T.J. Schall, D.R. Littman, and N.R. Landau. 1996. Identification of a major co-receptor for primary isolates of HIV-1.

Collman, and R.W. Doms. 1996. A dual-tropic primary HIV-1 isolate that uses fusin and the beta-chemokine receptors CKR-5, CKR-3, and CKR-2b as fusion cofactors.

P.J. Maddon, R.A. Koup, J.P. Moore, and W.A. Paxton. 1996. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature. 381:667-673. Drevets, D.A., and P.J. Leenen. 2000. Leukocyte-facilitated entry of intracellular pathogens

nervous system: an in vitro study using mouse brain endothelium. J Infect Dis.

Germonneau, and I. Quatresous. 2009. Atypical Chikungunya virus infections: clinical manifestations, mortality and risk factors for severe disease during the


Virus-Induced Encephalitis and

996.

Microbes Infect. 11:1206-1218.

infection. Neurology. 41:778-785.

Rev Immunol. 2:675-687.

106:17916-17920.

FASEB J. 25:314-325.

Science. 286:2333-2337.

in cell death. Physiol Rev. 87:99-163.

Lafon, M. 2005. Rabies virus receptors. J Neurovirol. 11:82-87.

Innate Immune Responses – A Focus on Emerging or Re-Emerging Viruses 81

Jaffar-Bandjee, M.C., T. Das, J.J. Hoarau, P. Krejbich Trotot, M. Denizot, A. Ribera, P.

Jaffar-Bandjee, M.C., D. Ramful, B.A. Gauzere, J.J. Hoarau, P. Krejbich-Trotot, S. Robin, A.

Janssen, R.S., D.R. Cornblath, L.G. Epstein, R.P. Foa, J.C. McArthur, R.W. Price, A.K.K.

Jarvis, M.A., and J.A. Nelson. 2002. Human cytomegalovirus persistence and latency in endothelial cells and macrophages. Curr Opin Microbiol. 5:403-407. Katze, M.G., Y. He, and M. Gale, Jr. 2002. Viruses and interferon: a fight for supremacy. Nat

Klatzmann, D., E. Champagne, S. Chamaret, J. Gruest, D. Guetard, T. Hercend, J.C.

Klionsky, D.J. 2007. Autophagy: from phenomenology to molecular understanding in less

Kopp, S.J., G. Banisadr, K. Glajch, U.E. Maurer, K. Grunewald, R.J. Miller, P. Osten, and P.G.

Krejbich-Trotot, P., M. Denizot, J.J. Hoarau, M.C. Jaffar-Bandjee, T. Das, and P. Gasque. 2011.

Kroemer, G., L. Galluzzi, and C. Brenner. 2007. Mitochondrial membrane permeabilization

Kuronita, T., E.L. Eskelinen, H. Fujita, P. Saftig, M. Himeno, and Y. Tanaka. 2002. A role for

Labadie, K., T. Larcher, C. Joubert, A. Mannioui, B. Delache, P. Brochard, L. Guigand, L.

Lanciotti, R.S., J.T. Roehrig, V. Deubel, J. Smith, M. Parker, K. Steele, B. Crise, K.E. Volpe,

long-term viral persistence in macrophages. J Clin Invest. 120:894-906.

endosomal and lysosomal morphology. J Cell Sci. 115:4117-4131.

receptor for human retrovirus LAV. Nature. 312:767-768.

than a decade. Nat Rev Mol Cell Biol. 8:931-937.

Gluckman, and L. Montagnier. 1984. T-lymphocyte T4 molecule behaves as the

Spear. 2009. Infection of neurons and encephalitis after intracranial inoculation of herpes simplex virus requires the entry receptor nectin-1. Proc Natl Acad Sci U S A.

Chikungunya virus mobilizes the apoptotic machinery to invade host cell defenses.

the lysosomal membrane protein LGP85 in the biogenesis and maintenance of

Dubreil, P. Lebon, B. Verrier, X. de Lamballerie, A. Suhrbier, Y. Cherel, R. Le Grand, and P. Roques. 2010. Chikungunya disease in nonhuman primates involves

M.B. Crabtree, J.H. Scherret, R.A. Hall, J.S. MacKenzie, C.B. Cropp, B. Panigrahy, E. Ostlund, B. Schmitt, M. Malkinson, C. Banet, J. Weissman, N. Komar, H.M. Savage, W. Stone, T. McNamara, and D.J. Gubler. 1999. Origin of the West Nile virus responsible for an outbreak of encephalitis in the northeastern United States.

Roques, and P. Gasque. 2009. Chikungunya virus takes centre stage in virally induced arthritis: possible cellular and molecular mechanisms to pathogenesis.

Ribera, J. Selambarom, and P. Gasque. 2011. Emergence and clinical insights into the pathology of Chikungunya virus infection. Expert Rev Anti Infect Ther. 8:987-

Asbury, A. Beckett, D.F. Benson, T.P. Bridge, C.M. Leventhal, P. Satz, A.J. Saykin, J.J. Sidtis, and S. Tross. 1991. Nomenclature and research case definitions for neurological manifestations of human immunodeficiency virus type 1 (HIV-1)


Goldstein, J.L., Y.K. Ho, S.K. Basu, and M.S. Brown. 1979. Binding site on macrophages that

Granwehr, B.P., K.M. Lillibridge, S. Higgs, P.W. Mason, J.F. Aronson, G.A. Campbell, and

Griffin, D.E. 2003. Immune responses to RNA-virus infections of the CNS. Nat Rev

Griffin, D.E. 2010. Emergence and re-emergence of viral diseases of the central nervous

Griffin, D.E., and J.M. Hardwick. 1997. Regulators of apoptosis on the road to persistent

Griffiths, M.R., P. Gasque, and J.W. Neal. 2009. The multiple roles of the innate immune

Hashimoto, Y., T. Moki, T. Takizawa, A. Shiratsuchi, and Y. Nakanishi. 2007. Evidence for

Hauwel, M., E. Furon, C. Canova, M. Griffiths, J. Neal, and P. Gasque. 2005. Innate

Henson, P.M., D.L. Bratton, and V.A. Fadok. 2001. Apoptotic cell removal. Curr Biol.

Herndon, R.M., R.T. Johnson, L.E. Davis, and L.R. Descalzi. 1974. Ependymitis in mumps

Himanen, J.P., N. Saha, and D.B. Nikolov. 2007. Cell-cell signaling via Eph receptors and

Hoarau, J.J., M.C. Jaffar Bandjee, P. Krejbich Trotot, T. Das, G. Li-Pat-Yuen, B. Dassa, M.

Husemann, J., J.D. Loike, R. Anankov, M. Febbraio, and S.C. Silverstein. 2002. Scavenger

regulators (NIReg). CNS Neurol Disord Drug Targets. 10:25-43.

Jackson, A.C. 2003. Rabies virus infection: an update. J Neurovirol. 9:253-258.

massive cholesterol deposition. Proc Natl Acad Sci U S A. 76:333-337. Goodbourn, S., L. Didcock, and R.E. Randall. 2000. Interferons: cell signalling, immune

2364.

Immunol. 3:493-502.

Exp Neurol. 68:217-226.

11:R795-805.

Neurol. 30:475-479.

system. Prog Neurobiol. 91:95-101.

Brain Res Brain Res Rev. 48:220-233.

ephrins. Curr Opin Cell Biol. 19:534-542.

cells of the nervous system. Glia. 40:195-205.

alphavirus infection. Annu Rev Microbiol. 51:565-592.

macrophages in mice. J Immunol. 178:2448-2457.

mediates uptake and degradation of acetylated low density lipoprotein, producing

modulation, antiviral response and virus countermeasures. J Gen Virol. 81:2341-

A.D. Barrett. 2004. West Nile virus: where are we now? Lancet Infect Dis. 4:547-556.

system in the regulation of apoptosis and inflammation in the brain. J Neuropathol

phagocytosis of influenza virus-infected, apoptotic cells by neutrophils and

(inherent) control of brain infection, brain inflammation and brain repair: the role of microglia, astrocytes, "protective" glial stem cells and stromal ependymal cells.

virus meningitis. Electron microscopical studies of cerebrospinal fluid. Arch

Denizot, E. Guichard, A. Ribera, T. Henni, F. Tallet, M.P. Moiton, B.A. Gauzere, S. Bruniquet, Z. Jaffar Bandjee, P. Morbidelli, G. Martigny, M. Jolivet, F. Gay, M. Grandadam, H. Tolou, V. Vieillard, P. Debre, B. Autran, and P. Gasque. 2010. Persistent chronic inflammation and infection by Chikungunya arthritogenic alphavirus in spite of a robust host immune response. J Immunol. 184:5914-5927. Hoarau, J.J., P. Krejbich-Trotot, M.C. Jaffar-Bandjee, T. Das, G.V. Thon-Hon, S. Kumar, J.W.

Neal, and P. Gasque. 2011. Activation and control of CNS innate immune responses in health and diseases: a balancing act finely tuned by neuroimmune

receptors in neurobiology and neuropathology: their role on microglia and other


Virus-Induced Encephalitis and

90:10474-10478.

264:1918-1921.

SIGN. Virology. 297:78-88.

features. Ann Neurol. 19:517-524.

Immunol. 156:1284-1295.

Cell Biol. 6:462-475.

133:38-52.

79:12893-12904.

Science. 239:586-592.

paramyxovirus. Nature. 436:401-405.

Innate Immune Responses – A Focus on Emerging or Re-Emerging Viruses 83

Mori, I., Y. Nishiyama, T. Yokochi, and Y. Kimura. 2005. Olfactory transmission of

Morrison, L.A., and B.N. Fields. 1991. Parallel mechanisms in neuropathogenesis of enteric

Moses, A.V., F.E. Bloom, C.D. Pauza, and J.A. Nelson. 1993. Human immunodeficiency

Mukhopadhyay, S., and S. Gordon. 2004. The role of scavenger receptors in pathogen

Mukhtar, M., S. Harley, P. Chen, M. BouHamdan, C. Patel, E. Acheampong, and R.J.

Muller, U., U. Steinhoff, L.F. Reis, S. Hemmi, J. Pavlovic, R.M. Zinkernagel, and M. Aguet.

Nakhaei, P., P. Genin, A. Civas, and J. Hiscott. 2009. RIG-I-like receptors: sensing and

Navia, B.A., B.D. Jordan, and R.W. Price. 1986. The AIDS dementia complex: I. Clinical

Negrete, O.A., E.L. Levroney, H.C. Aguilar, A. Bertolotti-Ciarlet, R. Nazarian, S. Tajyar, and

Negrete, O.A., M.C. Wolf, H.C. Aguilar, S. Enterlein, W. Wang, E. Muhlberger, S.V. Su, A.

Pasquale, E.B. 2005. Eph receptor signalling casts a wide net on cell behaviour. Nat Rev Mol

Pasquale, E.B. 2008. Eph-ephrin bidirectional signaling in physiology and disease. Cell.

Paul, S., C. Ricour, C. Sommereyns, F. Sorgeloos, and T. Michiels. 2007. Type I interferon

Persidsky, Y., M. Stins, D. Way, M.H. Witte, M. Weinand, K.S. Kim, P. Bock, H.E.

blood-brain barrier during HIV-1 encephalitis. J Immunol. 158:3499-3510. Prehaud, C., F. Megret, M. Lafage, and M. Lafon. 2005. Virus infection switches TLR-3-

Price, R.W., B. Brew, J. Sidtis, M. Rosenblum, A.C. Scheck, and P. Cleary. 1988. The brain in

Gendelman, and M. Fiala. 1997. A model for monocyte migration through the

positive human neurons to become strong producers of beta interferon. J Virol.

AIDS: central nervous system HIV-1 infection and AIDS dementia complex.

response in the central nervous system. Biochimie. 89:770-778.

responding to RNA virus infection. Semin Immunol. 21:215-222.

recognition and innate immunity. Immunobiology. 209:39-49.

virus infection of human brain capillary endothelial cells occurs via a CD4/galactosylceramide-independent mechanism. Proc Natl Acad Sci U S A.

Pomerantz. 2002. Primary isolated human brain microvascular endothelial cells express diverse HIV/SIV-associated chemokine coreceptors and DC-SIGN and L-

1994. Functional role of type I and type II interferons in antiviral defense. Science.

B. Lee. 2005. EphrinB2 is the entry receptor for Nipah virus, an emergent deadly

Bertolotti-Ciarlet, R. Flick, and B. Lee. 2006. Two key residues in ephrinB3 are critical for its use as an alternative receptor for Nipah virus. PLoS Pathog. 2:e7. Nottet, H.S., Y. Persidsky, V.G. Sasseville, A.N. Nukuna, P. Bock, Q.H. Zhai, L.R. Sharer,

R.D. McComb, S. Swindells, C. Soderland, and H.E. Gendelman. 1996. Mechanisms for the transendothelial migration of HIV-1-infected monocytes into brain. J

neurotropic viruses. J Neurovirol. 11:129-137.

virus infections. J Virol. 65:2767-2772.


Lemant, J., V. Boisson, A. Winer, L. Thibault, H. Andre, F. Tixier, M. Lemercier, E. Antok,

Levine, B., Q. Huang, J.T. Isaacs, J.C. Reed, D.E. Griffin, and J.M. Hardwick. 1993.

Liang, X.H., L.K. Kleeman, H.H. Jiang, G. Gordon, J.E. Goldman, G. Berry, B. Herman, and

Linehan, S.A., L. Martinez-Pomares, P.D. Stahl, and S. Gordon. 1999. Mannose receptor and

Liszewski, M.K., T.W. Post, and J.P. Atkinson. 1991. Membrane cofactor protein (MCP or

Loetscher, M., T. Geiser, T. O'Reilly, R. Zwahlen, M. Baggiolini, and B. Moser. 1994. Cloning

Lopez, M., F. Cocchi, L. Menotti, E. Avitabile, P. Dubreuil, and G. Campadelli-Fiume. 2000.

Lublin, D.M., M.K. Liszewski, T.W. Post, M.A. Arce, M.M. Le Beau, M.B. Rebentisch, L.S.

Martina, B.E., P. Koraka, P. van den Doel, G.F. Rimmelzwaan, B.L. Haagmans, and A.D.

McDougal, J.S., M.S. Kennedy, J.M. Sligh, S.P. Cort, A. Mawle, and J.K. Nicholson. 1986.

McMinn, P.C. 2002. An overview of the evolution of enterovirus 71 and its clinical and

Mock, D.J., J.M. Powers, A.D. Goodman, S.R. Blumenthal, N. Ergin, J.V. Baker, D.H.

progressive multifocal leukoencephalopathy. J Neurovirol. 5:363-373.

36:2536-2541.

189:1961-1972.

Annu Rev Immunol. 9:431-455.

glycoprotein D. J Virol. 74:1267-1274.

Nature. 361:739-742.

Bcl-2-interacting protein. J Virol. 72:8586-8596.

expressed in leukocytes. J Biol Chem. 269:232-237.

genes. Proc Natl Acad Sci U S A. 84:9155-9159.

IFN-alpha and TNF-alpha. Virus Res. 135:64-71.

public health significance. FEMS Microbiol Rev. 26:91-107.

the T4 molecule. Science. 231:382-385.

M.P. Cresta, P. Grivard, M. Besnard, O. Rollot, F. Favier, M. Huerre, J.L. Campinos, and A. Michault. 2008. Serious acute chikungunya virus infection requiring intensive care during the Reunion Island outbreak in 2005-2006. Crit Care Med.

Conversion of lytic to persistent alphavirus infection by the bcl-2 cellular oncogene.

B. Levine. 1998. Protection against fatal Sindbis virus encephalitis by beclin, a novel

its putative ligands in normal murine lymphoid and nonlymphoid organs: In situ expression of mannose receptor by selected macrophages, endothelial cells, perivascular microglia, and mesangial cells, but not dendritic cells. J Exp Med.

CD46): newest member of the regulators of complement activation gene cluster.

of a human seven-transmembrane domain receptor, LESTR, that is highly

Nectin2alpha (PRR2alpha or HveB) and nectin2delta are low-efficiency mediators for entry of herpes simplex virus mutants carrying the Leu25Pro substitution in

Lemons, T. Seya, and J.P. Atkinson. 1988. Molecular cloning and chromosomal localization of human membrane cofactor protein (MCP). Evidence for inclusion in the multigene family of complement-regulatory proteins. J Exp Med. 168:181-194. Maddon, P.J., S.M. Molineaux, D.E. Maddon, K.A. Zimmerman, M. Godfrey, F.W. Alt, L.

Chess, and R. Axel. 1987. Structure and expression of the human and mouse T4

Osterhaus. 2008. DC-SIGN enhances infection of cells with glycosylated West Nile virus in vitro and virus replication in human dendritic cells induces production of

Binding of HTLV-III/LAV to T4+ T cells by a complex of the 110K viral protein and

Mattson, J.G. Assouline, E.J. Bergey, B. Chen, L.G. Epstein, and B.M. Blumberg. 1999. Association of human herpesvirus 6 with the demyelinative lesions of


Virus-Induced Encephalitis and

116:1273-1281.

6:e1000757.

9:603-615.

3:e201.

1660.

2:e1168.

Immunol. 176:4520-4524.

Virol. 71:1739-1746.

Biobehav Rev. 22:709-720.

Rev Immunol. 3:697-709.

kinase PKR. J Biol Chem. 284:29350-29356.

Top Microbiol Immunol. 336:63-81.

Innate Immune Responses – A Focus on Emerging or Re-Emerging Viruses 85

Shieh, M.T., D. WuDunn, R.I. Montgomery, J.D. Esko, and P.G. Spear. 1992. Cell surface

Solignat, M., B. Gay, S. Higgs, L. Briant, and C. Devaux. 2009. Replication cycle of

Suh, H.S., C.F. Brosnan, and S.C. Lee. 2009. Toll-like receptors in CNS viral infections. Curr

Suthar, M.S., D.Y. Ma, S. Thomas, J.M. Lund, N. Zhang, S. Daffis, A.Y. Rudensky, M.J.

Sutherland, M.R., C.M. Raynor, H. Leenknegt, J.F. Wright, and E.L. Pryzdial. 1997. Coagulation initiated on herpesviruses. Proc Natl Acad Sci U S A. 94:13510-13514. Szretter, K.J., S. Daffis, J. Patel, M.S. Suthar, R.S. Klein, M. Gale, Jr., and M.S. Diamond. 2010.

Takai, Y., J. Miyoshi, W. Ikeda, and H. Ogita. 2008. Nectins and nectin-like molecules: roles

Teodoro, J.G., and P.E. Branton. 1997. Regulation of apoptosis by viral gene products. J

Tirabassi, R.S., R.A. Townley, M.G. Eldridge, and L.W. Enquist. 1998. Molecular

Toth, A.M., Z. Li, R. Cattaneo, and C.E. Samuel. 2009. RNA-specific adenosine deaminase

Tsetsarkin, K.A., D.L. Vanlandingham, C.E. McGee, and S. Higgs. 2007. A single mutation in

Van Gorp, H., P.L. Delputte, and H.J. Nauwynck. 2010. Scavenger receptor CD163, a Jack-of-

van Kooyk, Y., and T.B. Geijtenbeek. 2003. DC-SIGN: escape mechanism for pathogens. Nat

Vazeille, M., S. Moutailler, D. Coudrier, C. Rousseaux, H. Khun, M. Huerre, J. Thiria, J.S.

Wang, E., E. Volkova, A.P. Adams, N. Forrester, S.Y. Xiao, I. Frolov, and S.C. Weaver. 2008. Chimeric alphavirus vaccine candidates for chikungunya. Vaccine. 26:5030-5039.

chikungunya: a re-emerging arbovirus. Virology. 393:183-197.

receptors for herpes simplex virus are heparan sulfate proteoglycans. J Cell Biol.

Bevan, E.A. Clark, M.K. Kaja, M.S. Diamond, and M. Gale, Jr. 2010. IPS-1 is essential for the control of West Nile virus infection and immunity. PLoS Pathog.

The innate immune adaptor molecule MyD88 restricts West Nile virus replication and spread in neurons of the central nervous system. J Virol. 84:12125-12138. Takahashi, K., T. Kawai, H. Kumar, S. Sato, S. Yonehara, and S. Akira. 2006. Roles of

caspase-8 and caspase-10 in innate immune responses to double-stranded RNA. J

in contact inhibition of cell movement and proliferation. Nat Rev Mol Cell Biol.

mechanisms of neurotropic herpesvirus invasion and spread in the CNS. Neurosci

ADAR1 suppresses measles virus-induced apoptosis and activation of protein

chikungunya virus affects vector specificity and epidemic potential. PLoS Pathog.

all-trades and potential target for cell-directed therapy. Mol Immunol. 47:1650-

Dehecq, D. Fontenille, I. Schuffenecker, P. Despres, and A.B. Failloux. 2007. Two Chikungunya isolates from the outbreak of La Reunion (Indian Ocean) exhibit different patterns of infection in the mosquito, Aedes albopictus. PLoS One.


Pryzdial, E.L., and J.F. Wright. 1994. Prothrombinase assembly on an enveloped virus:

Raport, C.J., J. Gosling, V.L. Schweickart, P.W. Gray, and I.F. Charo. 1996. Molecular cloning

Sallusto, F., M. Cella, C. Danieli, and A. Lanzavecchia. 1995. Dendritic cells use

Santoro, F., P.E. Kennedy, G. Locatelli, M.S. Malnati, E.A. Berger, and P. Lusso. 1999. CD46

Sato, A., M.M. Linehan, and A. Iwasaki. 2006. Dual recognition of herpes simplex viruses by TLR2 and TLR9 in dendritic cells. Proc Natl Acad Sci U S A. 103:17343-17348. Savarin, C., and C.C. Bergmann. 2008. Neuroimmunology of central nervous system viral

Savill, J., I. Dransfield, C. Gregory, and C. Haslett. 2002. A blast from the past: clearance of apoptotic cells regulates immune responses. Nat Rev Immunol. 2:965-975. Schilte, C., T. Couderc, F. Chretien, M. Sourisseau, N. Gangneux, F. Guivel-Benhassine, A.

Schmidt, N.J., E.H. Lennette, and H.H. Ho. 1974. An apparently new enterovirus isolated from patients with disease of the central nervous system. J Infect Dis. 129:304-309. Schmidtmayerova, H., H.S. Nottet, G. Nuovo, T. Raabe, C.R. Flanagan, L. Dubrovsky, H.E.

Schwartz, A.J., X. Alvarez, and A.A. Lackner. 2002. Distribution and immunophenotype of

Seya, T., A. Hirano, M. Matsumoto, M. Nomura, and S. Ueda. 1999. Human membrane

Seya, T., J.R. Turner, and J.P. Atkinson. 1986. Purification and characterization of a

Sharer, L.R., E.S. Cho, and L.G. Epstein. 1985. Multinucleated giant cells and HTLV-III in

lymph nodes. Proc Natl Acad Sci U S A. 93:700-704.

Hum Retroviruses. 18:1021-1029.

AIDS encephalopathy. Hum Pathol. 16:760.

Biol. 31:1255-1260.

Med. 163:837-855.

for RANTES, MIP-1beta, and MIP-1alpha. J Biol Chem. 271:17161-17166. Rosen, A., L. Casciola-Rosen, and J. Ahearn. 1995. Novel packages of viral and self-antigens

are generated during apoptosis. J Exp Med. 181:1557-1561.

cytokines and bacterial products. J Exp Med. 182:389-400.

is a cellular receptor for human herpesvirus 6. Cell. 99:817-827.

Blood. 84:3749-3757.

8:472-479.

442.

evidence that the cytomegalovirus surface contains procoagulant phospholipid.

and functional characterization of a novel human CC chemokine receptor (CCR5)

macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: downregulation by

infections: the cells, molecules and mechanisms involved. Curr Opin Pharmacol.

Kraxner, J. Tschopp, S. Higgs, A. Michault, F. Arenzana-Seisdedos, M. Colonna, L. Peduto, O. Schwartz, M. Lecuit, and M.L. Albert. 2010. Type I IFN controls chikungunya virus via its action on nonhematopoietic cells. J Exp Med. 207:429-

Gendelman, A. Cerami, M. Bukrinsky, and B. Sherry. 1996. Human immunodeficiency virus type 1 infection alters chemokine beta peptide expression in human monocytes: implications for recruitment of leukocytes into brain and

DC-SIGN-expressing cells in SIV-infected and uninfected macaques. AIDS Res

cofactor protein (MCP, CD46): multiple isoforms and functions. Int J Biochem Cell

membrane protein (gp45-70) that is a cofactor for cleavage of C3b and C4b. J Exp


**4** 

*USA* 

**Blood-Brain Barrier Disruption and** 

**Encephalitis in Animal Models of AIDS** 

Nicole A. Renner, Andrew A. Lackner and Andrew G. MacLean *Tulane National Primate Research Center, Program in Neuroscience, Covington* 

The pathogenesis of HIV/SIV encephalitis (HIVE/SIVE) remains incompletely understood, but is associated with alterations in the blood brain barrier. In animals infected with pathogenic strains of simian immunodeficiency virus (SIV), such as SIVmac239 and SIVmac251, the virus can be consistently found in the central nervous system (CNS) within 10 to 14 days of infection: at the time of peak viremia (Lackner et al., 1994). This also appears to be true in human immunodeficiency virus (HIV)-infected humans, but the number of cases examined during peak viremia is very small (Davis et al., 1992). In SIV-infected macaques at this early time point, endothelial cells of the blood-brain barrier (BBB) are activated and integrity of the BBB is compromised (Stephens et al., 2003). As viral loads decline toward set point at roughly two months post infection the endothelial activation subsides and BBB integrity is largely restored (Sasseville et al., 1995, Lackner et al., 1994, Annunziata, 2003, Zink et al., 1998). However, in the terminal phases of disease, viral loads rise and approximately one third of animals develop SIV encephalitis (SIVE), which is

The exact mechanisms of BBB disruption are unclear, but it is known that numerous resident and transitory cell populations in the CNS can be infected, with CD14-positive perivascular macrophages being the primary productively-infected cell type (Little et al., 1999, Gorry et al., 2003, Bissel and Wiley, 2004, Ryzhova et al., 2002, Liu et al., 2004, Brack-Werner, 1999, Trillo-Pazos et al., 2003, Williams et al., 2001, Fischer-Smith et al., 2001). Nervous system manifestations associated with HIV infection of humans or SIV infection of rhesus macaques include an encephalitis (SIV or HIV encephalitis, SIVE/HIVE) characterized by astrocytic and microglial activation and scattered perivascular aggregates of mononuclear cells and multinucleated giant cells. These perivascular lesions contain large numbers of HIV/SIV-infected cells, the majority of which are monocyte/macrophages. The presence of cells productively-infected with SIV/HIV in the parenchyma has been shown to induce a response in astrocytes (Nath, 1999, Tyor et al., 1992, Persidsky et al., 1999, Persidsky et al., 2000) which in turn may lead to decreased tight junction protein expression and a leaky BBB (Dallasta et al., 1999, Persidsky et al., 1997, Moses and Nelson, 1994, Boven et al., 2000, Luabeya et al., 2000, Andras et al., 2003, Annunziata, 2003, Kanmogne et al.,

Astrocytes, along with microglia, are resident cells in the brain involved in inflammation. Their role during inflammation is not well understood; it is believed that both cell types are

2005, Kanmogne et al., 2007, MacLean et al., 2004b, Persidsky, 1999).

**1. Introduction** 

associated with breakdown of the BBB.

