Journal of NeuroVirology

, Volume 20, Issue 2, pp 150–156 | Cite as

Innate immune response to La Crosse virus infection

  • Katherine G. Taylor
  • Karin E. Peterson


Viral encephalitis represents a significant, and costly, public health threat particularly for high-risk pediatric populations. An emerging mosquito-borne pathogen endemic to the United States, La Crosse virus (LACV) is one of the most common causes of viral encephalitis in children in the United States. However, no licensed therapeutics or vaccines currently exist for treatment. Hampering development efforts, the host response to LACV and its role in disease pathogenesis has only recently been examined. In this review, we discuss the current understanding of innate immune response in the context of viral pathogenesis and host susceptibility to LACV. In addition, we address the need for a clearer understanding of the early host–virus interactions in LACV infections as it relates to viral pathogenesis in the central nervous system.


La Crosse Encephalitis Innate SARM1 Interferon 


  1. Balfour HH Jr, Siem RA, Bauer H, Quie PG (1973) California Arbovirus (La Crosse) infections I. Clinical and laboratory findings in 66 children with meningoencephalitis. Pediatrics 52:680–691PubMedGoogle Scholar
  2. Bennett RS, Ton DR, Hanson CT, Murphy BR, Whitehead SS (2007) Genome sequence analysis of La Crosse virus and in vitro and in vivo phenotypes. Virol J 4:41PubMedCentralPubMedCrossRefGoogle Scholar
  3. Bennett RS, Cress CM, Ward JM, Firestone CY, Murphy BR, Whitehead SS (2008) La Crosse virus infectivity, pathogenesis, and immunogenicity in mice and monkeys. Virol J 5:25PubMedCentralPubMedCrossRefGoogle Scholar
  4. Bennett RS, Gresko AK, Murphy BR, Whitehead SS (2011) Tahyna virus genetics, infectivity, and immunogenicity in mice and monkeys. Virol J 8:135PubMedCentralPubMedCrossRefGoogle Scholar
  5. Blakqori G, Delhaye S, Habjan M, Blair CD, Sanchez-Vargas I, Olson KE, Attarzadeh-Yazdi G, Fragkoudis R, Kohl A, Kalinke U, Weiss S, Michiels T, Staeheli P, Weber F (2007) La Crosse bunyavirus nonstructural protein NSs serves to suppress the type I interferon system of mammalian hosts. J Virol 81:4991–4999PubMedCentralPubMedCrossRefGoogle Scholar
  6. Calisher CH (1994) Medically important arboviruses of the United States and Canada. Clin Microbiol Rev 7:89–116PubMedCentralPubMedGoogle Scholar
  7. Case KL, West RM, Smith MJ (1993) Histocompatibility antigens and La Crosse encephalitis. J Infect Dis 168:358–360PubMedCrossRefGoogle Scholar
  8. Chen CY, Lin CW, Chang CY, Jiang ST, Hsueh YP (2011) Sarm1, a negative regulator of innate immunity, interacts with syndecan-2 and regulates neuronal morphology. J Cell Biol 193:769–784PubMedCentralPubMedCrossRefGoogle Scholar
  9. Cho H, Diamond MS (2012) Immune responses to West Nile virus infection in the central nervous system. Viruses 4: 3812–30Google Scholar
  10. Delhaye S, Paul S, Blakqori G, Minet M, Weber F, Staeheli P, Michiels T (2006) Neurons produce type I interferon during viral encephalitis. Proc Natl Acad Sci U S A 103:7835–7840PubMedCentralPubMedCrossRefGoogle Scholar
  11. Frese M, Kochs G, Feldmann H, Hertkorn C, Haller O (1996) Inhibition of bunyaviruses, phleboviruses, and hantaviruses by human MxA protein. J Virol 70:915–923PubMedCentralPubMedGoogle Scholar
  12. Gonzalez-Scarano F, Janssen RS, Najjar JA, Pobjecky N, Nathanson N (1985) An avirulent G1 glycoprotein variant of La Crosse bunyavirus with defective fusion function. J Virol 54:757–763PubMedCentralPubMedGoogle Scholar
  13. Gonzalez-Scarano F, Beaty B, Sundin D, Janssen R, Endres MJ, Nathanson N (1988) Genetic determinants of the virulence and infectivity of La Crosse virus. Microb Pathog 4:1–7PubMedCrossRefGoogle Scholar
  14. Gray KK, Worthy MN, Juelich TL, Agar SL, Poussard A, Ragland D, Freiberg AN, Holbrook MR (2012) Chemotactic and inflammatory responses in the liver and brain are associated with pathogenesis of Rift Valley fever virus infection in the mouse. PLoS Negl Trop Dis 6:e1529PubMedCentralPubMedCrossRefGoogle Scholar
  15. Grimstad PR, Barrett CL, Humphrey RL, Sinsko MJ (1984) Serologic evidence for widespread infection with La Crosse and St. Louis encephalitis viruses in the Indiana human population. Am J Epidemiol 119:913–930PubMedGoogle Scholar
  16. Griot C, Pekosz A, Davidson R, Stillmock K, Hoek M, Lukac D, Schmeidler D, Cobbinah I, Gonzalez-Scarano F, Nathanson N (1994) Replication in cultured C2C12 muscle cells correlates with the neuroinvasiveness of California serogroup bunyaviruses. Virology 201:399–403PubMedCrossRefGoogle Scholar
  17. Haddow AD, Odoi A (2009) The incidence risk, clustering, and clinical presentation of La Crosse virus infections in the eastern United States, 2003–2007. PLoS One 4:e6145PubMedCentralPubMedCrossRefGoogle Scholar
  18. Haddow AD, Jones CJ, Odoi A (2009) Assessing risk in focal arboviral infections: are we missing the big or little picture? PLoS One 4:e6954PubMedCentralPubMedCrossRefGoogle Scholar
  19. Hammon WM, Reeves WC (1952) California Encephalitis. Calif Med 77:303–309PubMedCentralPubMedGoogle Scholar
  20. Hammon WM, Reeves WC, Sather G (1952) California encephalitis virus, a newly described agent. II. Isolations and attempts to identify and characterize the agent. J Immunol 69:493–510Google Scholar
  21. Hefti HP, Frese M, Landis H, Di PC, Aguzzi A, Haller O, Pavlovic J (1999) Human MxA protein protects mice lacking a functional alpha/beta interferon system against La crosse virus and other lethal viral infections. J Virol 73:6984–6991PubMedCentralPubMedGoogle Scholar
  22. Hollidge BS, Nedelsky NB, Salzano MV, Fraser JW, Gonzalez-Scarano F, Soldan SS (2012) Orthobunyavirus entry into neurons and other mammalian cells occurs via clathrin-mediated endocytosis and requires trafficking into early endosomes. J Virol 86:7988–8001PubMedCentralPubMedCrossRefGoogle Scholar
  23. Janssen R, Gonzalez-Scarano F, Nathanson N (1984a) Mechanisms of bunyavirus virulence. Lab Investig 50:447–455PubMedGoogle Scholar
  24. Janssen R, Gonzalez-Scarano F, Nathanson N (1984b) Mechanisms of bunyavirus virulence. Lab Investig 50:447–455PubMedGoogle Scholar
  25. Johnson RT (1983) Pathogenesis of La Crosse virus in mice. Prog Clin Biol Res 123:139–144PubMedGoogle Scholar
  26. Johnson KP, Johnson RT (1968) California encephalitis. II. Studies of experimental infection in the mouse. J Neuropath Exp Neurol 27:390–400Google Scholar
  27. Jones TF, Craig AS, Nasci RS, Patterson LE, Erwin PC, Gerhardt RR, Ussery XT, Schaffner W (1999) Newly recognized focus of La Crosse encephalitis in Tennessee. Clin Infect Dis 28:93–97PubMedCrossRefGoogle Scholar
  28. Jortner BS, Shope RE, Manuelidis EE (1971) Neuropathologic and virus assay studies of experimental California virus encephalitis in the mouse. J Neuropathol Exp Neurol 30:91–98PubMedCrossRefGoogle Scholar
  29. Kalfayan B (1983) Pathology of La Crosse virus infection in humans. Prog Clin Biol Res 123:179–186PubMedGoogle Scholar
  30. Kallfass C, Ackerman A, Lienenklaus S, Weiss S, Heimrich B, Staeheli P (2012) Visualizing production of beta interferon by astrocytes and microglia in brain of La Crosse virus-infected mice. J Virol 86:11223–11230PubMedCentralPubMedCrossRefGoogle Scholar
  31. Kim Y, Zhou P, Qian L, Chuang JZ, Lee J, Li C, Iadecola C, Nathan C, Ding A (2007) MyD88-5 links mitochondria, microtubules, and JNK3 in neurons and regulates neuronal survival. J Exp Med 204:2063–2074PubMedCentralPubMedCrossRefGoogle Scholar
  32. Kochs G, Janzen C, Hohenberg H, Haller O (2002) Antivirally active MxA protein sequesters La Crosse virus nucleocapsid protein into perinuclear complexes. Proc Natl Acad Sci U S A 99:3153–3158PubMedCentralPubMedCrossRefGoogle Scholar
  33. Lambert AJ, Blair CD, D’Anton M, Ewing W, Harborth M, Seiferth R, Xiang J, Lanciotti RS (2010) La Crosse virus in Aedes albopictus mosquitoes, Texas, USA, 2009. Emerg Infect Dis 16:856–858PubMedCentralPubMedCrossRefGoogle Scholar
  34. Lehnardt S, Massillon L, Follett P, Jensen FE, Ratan R, Rosenberg PA, Volpe JJ, Vartanian T (2003) Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proc Natl Acad Sci U S A 100:8514–8519PubMedCentralPubMedCrossRefGoogle Scholar
  35. Leisnham PT, Juliano SA (2012) Impacts of climate, land use, and biological invasion on the ecology of immature Aedes mosquitoes: implications for La Crosse emergence. EcoHealth 9:217–228PubMedCentralPubMedCrossRefGoogle Scholar
  36. Lienenklaus S, Cornitescu M, Zietara N, Lyszkiewicz M, Gekara N, Jablonska J, Edenhofer F, Rajewsky K, Bruder D, Hafner M, Staeheli P, Weiss S (2009) Novel reporter mouse reveals constitutive and inflammatory expression of IFN-beta in vivo. J Immunol 183:3229–3236PubMedCrossRefGoogle Scholar
  37. Luby JP (1975) Sensitivities of neurotropic arboviruses to human interferon. J Infect Dis 132:361–367PubMedCrossRefGoogle Scholar
  38. Ma Y, Li J, Chiu I, Wang Y, Sloane JA, Lu J, Kosaras B, Sidman RL, Volpe JJ, Vartanian T (2006) Toll-like receptor 8 functions as a negative regulator of neurite outgrowth and inducer of neuronal apoptosis. J Cell Biol 175:209–215PubMedCentralPubMedCrossRefGoogle Scholar
  39. Miura TA, Carlson JO, Beaty BJ, Bowen RA, Olson KE (2001) Expression of human MxA protein in mosquito cells interferes with LaCrosse virus replication. J Virol 75:3001–3003PubMedCentralPubMedCrossRefGoogle Scholar
  40. Mukherjee P, Woods TA, Moore RA, Peterson KE (2013). Activation of the Innate Signaling Molecule MAVS by Bunyavirus Infection Upregulates the Adaptor Protein SARM1, Leading to Neuronal Death. Immunity.Google Scholar
  41. Operschall E, Schuh T, Heinzerling L, Pavlovic J, Moelling K (1999) Enhanced protection against viral infection by co-administration of plasmid DNA coding for viral antigen and cytokines in mice. J Clin Virol 13:17–27PubMedCrossRefGoogle Scholar
  42. Osterloh JM, Yang J, Rooney TM, Fox AN, Adalbert R, Powell EH, Sheehan AE, Avery MA, Hackett R, Logan MA, MacDonald JM, Ziegenfuss JS, Milde S, Hou YJ, Nathan C, Ding A, Brown RH Jr, Conforti L, Coleman M, Tessier-Lavigne M, Zuchner S, Freeman MR (2012) dSarm/Sarm1 is required for activation of an injury-induced axon death pathway. Science 337:481–484PubMedCrossRefGoogle Scholar
  43. Pavlovic J, Schultz J, Hefti HP, Schuh T, Molling K (2000) DNA vaccination against La Crosse virus. Intervirology 43:312–321PubMedCrossRefGoogle Scholar
  44. Pekosz A, Gonzalez-Scarano F (1996) The extracellular domain of La Crosse virus G1 forms oligomers and undergoes pH-dependent conformational changes. Virology 225:243–247PubMedCrossRefGoogle Scholar
  45. Pekosz A, Griot C, Stillmock K, Nathanson N, Gonzalez-Scarano F (1995) Protection from La Crosse virus encephalitis with recombinant glycoproteins: role of neutralizing anti-G1 antibodies. J Virol 69:3475–81Google Scholar
  46. Pekosz A, Phillips J, Pleasure D, Merry D, Gonzalez-Scarano F (1996) Induction of apoptosis by La Crosse virus infection and role of neuronal differentiation and human bcl-2 expression in its prevention. J Virol 70:5329–5335PubMedCentralPubMedGoogle Scholar
  47. Reese SM, Mossel EC, Beaty MK, Beck ET, Geske D, Blair CD, Beaty BJ, Black WC (2010) Identification of super-infected Aedes triseriatus mosquitoes collected as eggs from the field and partial characterization of the infecting La Crosse viruses. Virol J 7:76PubMedCentralPubMedCrossRefGoogle Scholar
  48. Reichelt M, Stertz S, Krijnse-Locker J, Haller O, Kochs G (2004) Missorting of LaCrosse virus nucleocapsid protein by the interferon-induced MxA GTPase involves smooth ER membranes. Traffic 5:772–784PubMedCrossRefGoogle Scholar
  49. Scheidler LC, Dunphy-Daly MM, White BJ, Andrew DR, Mans NZ, Garvin MC (2006) Survey of Aedes triseriatus (Diptera: Culicidae) for Lacrosse encephalitis virus and West Nile virus in Lorain County, Ohio. J Med Entomol 43:589–593PubMedCrossRefGoogle Scholar
  50. Schmaljohn C, Nichol S (2007) Bunyaviridae. In fields virology. Lippencott, Williams, and Wilkins, Philidelphia, pp. 1741–1788Google Scholar
  51. Schuh T, Schultz J, Moelling K, Pavlovic J (1999) DNA-based vaccine against La Crosse virus: protective immune response mediated by neutralizing antibodies and CD4+ T cells. Hum Gene Ther 10:1649–1658PubMedCrossRefGoogle Scholar
  52. Shrestha B, Diamond MS (2004) Role of CD8+ T cells in control of West Nile virus infection. J Virol 78:8312–8321PubMedCentralPubMedCrossRefGoogle Scholar
  53. Sitati EM, Diamond MS (2006) CD4+ T-cell responses are required for clearance of West Nile virus from the central nervous system. J Virol 80:12060–12069PubMedCentralPubMedCrossRefGoogle Scholar
  54. Szumlas DE, Apperson CS, Hartig PC, Francy DB, Karabatsos N (1996a) Seroepidemiology of La Crosse virus infection in humans in western North Carolina. AmJTrop Med Hyg 54:332–337Google Scholar
  55. Szumlas DE, Apperson CS, Powell EE (1996b) Seasonal occurrence and abundance of Aedes triseriatus and other mosquitoes in a La Crosse virus-endemic area in western North Carolina. J Am Mosq Control Assoc 12:184–193PubMedGoogle Scholar
  56. Taylor K, Kolokoltsova O, Patterson M, Poussard A, Smith J, Estes DM, Paessler S (2012) Natural killer cell mediated pathogenesis determines outcome of central nervous system infection with Venezuelan equine encephalitis virus in C3H/HeN mice. Vaccine 30:4095–4105Google Scholar
  57. Thompson WH, Evans A (1965) California encephalitis virus studies in Wisconsin. Am J Epidemiol 81:230–244PubMedGoogle Scholar
  58. Thompson WH, Kalfayan B, Anslow RO (1965) Isolation of California encephalitis group virus from a fatal human illness. Am J Epidemiol 81:245–253PubMedGoogle Scholar
  59. Verbruggen P, Ruf M, Blakqori G, Overby AK, Heidemann M, Eick D, Weber F (2011) Interferon antagonist NSs of La Crosse virus triggers a DNA damage response-like degradation of transcribing RNA polymerase II. J Biol Chem 286:3681–3692PubMedCentralPubMedCrossRefGoogle Scholar
  60. Watts DM, Thompson WH, Yuill TM, Defoliart GR, Hanson RP (1974) Overwintering of La Crosse virus in Aedes triseriatus. AmJTrop Med Hyg 23:694–700Google Scholar

Copyright information

© Journal of NeuroVirology, Inc. (outside the USA) 2013

Authors and Affiliations

  1. 1.Rocky Mountain Laboratories, National Institutes of Allergy and Infectious DiseasesNational Institutes of HealthHamiltonUSA

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