Blood–brain barrier (BBB) permeability was evaluated in mice and hamsters infected with West Nile virus (WNV, flavivirus) as compared to those infected with Semliki Forest (alphavirus) and Banzi (flavivirus) viruses. BBB permeability was determined by measurement of fluorescence in brain homogenates or cerebrospinal fluid (CSF) after intraperitoneal (i.p.) injection of sodium fluorescein, by macroscopic examination of brains after i.p. injection of Evans blue, or by measurement of total protein in CSF compared to serum. Lethal infection of BALB/c mice with Semliki Forest virus and Banzi virus caused the brain : serum fluorescence ratios to increase from a baseline of 2–4 % to as high as 11 and 15 %, respectively. Lethal infection of BALB/c mice with WNV did not increase BBB permeability. When C57BL/6 mice were used, BBB permeability was increased in some, but not all, of the WNV-infected animals. A procedure was developed to measure BBB permeability in live WNV-infected hamsters by comparing the fluorescence in the CSF, aspirated from the cisterna magnum, with the fluorescence in the serum. Despite a time-dependent tendency towards increased BBB permeability in some WNV-infected hamsters, the highest BBB permeability values did not correlate with mortality. These data indicated that a measurable increase in BBB permeability was not a primary determinant for lethality of WNV infection in rodents. The lack of a consistent increase in BBB permeability in WNV-infected rodents has implications for the understanding of viral entry, viral pathogenesis and accessibility of the CNS of rodents to drugs or effector molecules.
DallastaL. M.,
PisarovL. A.,
EsplenJ. E.,
WerleyJ. V.,
MosesA. V.,
NelsonJ. A.,
AchimC. L.1999; Blood–brain barrier tight junction disruption in human immunodeficiency virus-1 encephalitis. Am J Pathol 155:1915–1927[CrossRef]
de VriesH. E.,
Blom-RoosemalenM. C.,
van OostenM.,
de BoerA. G.,
van BerkelT. J.,
BreimerD. D.,
KuiperJ.1996; The influence of cytokines on the integrity of the blood–brain barrier in vitro . J Neuroimmunol 64:37–43[CrossRef]
FialaM.,
LooneyD. J.,
StinsM.,
WayD. D.,
ZhangL.,
GanX.,
ChiappelliF.,
SchweitzerE. S.,
ShapshakP.other authors1997; TNF-alpha opens a paracellular route for HIV-1 invasion across the blood–brain barrier. Mol Med 3:553–564
KleinR. S.,
LinE.,
ZhangB.,
LusterA. D.,
TollettJ.,
SamuelM. A.,
EngleM.,
DiamondM. S.2005; Neuronal CXCL10 directs CD8+ T-cell recruitment and control of West Nile virus encephalitis. J Virol 79:11457–11466[CrossRef]
KleineT. O.,
BenesL.2006; Immune surveillance of the human central nervous system (CNS): different migration pathways of immune cells through the blood–brain barrier and blood–cerebrospinal fluid barrier in healthy persons. Cytometry A 69:147–151
LustigS.,
DanenbergH. D.,
KafriY.,
KobilerD.,
Ben-NathanD.1992; Viral neuroinvasion and encephalitis induced by lipopolysaccharide and its mediators. J Exp Med 176:707–712[CrossRef]
MorreyJ. D.,
SmeeD. F.,
SidwellR. W.,
TsengC. K.2002; Identification of active compounds against a New York isolate of West Nile virus. Antiviral Res 55:107–116[CrossRef]
MorreyJ. D.,
DayC. W.,
JulanderJ. G.,
OlsenA. L.,
SidwellR. W.,
CheneyC. D.,
BlattL. M.2004; Modeling hamsters for evaluating West Nile virus therapies. Antiviral Res 63:41–50[CrossRef]
MorreyJ. D.,
SiddharthanV.,
OlsenA. L.,
RoperG. Y.,
WangH. C.,
BaldwinT. J.,
KoenigS.,
JohnsonS.,
NordstromJ. L.,
DiamondM. S.2006; Humanized monoclonal antibody against West Nile virus E protein administered after neuronal infection protects against lethal encephalitis in hamsters. J Infect Dis 194:1300–1308[CrossRef]
OliphantT.,
EngleM.,
NybakkenG. E.,
DoaneC.,
JohnsonS.,
HuangL.,
GorlatovS.,
MehlhopE.,
MarriA.other authors2005; Development of a humanized monoclonal antibody with therapeutic potential against West Nile virus. Nat Med 11:522–530[CrossRef]
OlsenA. L.,
MorreyJ. D.,
SmeeD. F.,
SidwellR. W.2007; Correlation between breakdown of the blood–brain barrier and disease outcome of viral encephalitis in mice. Antiviral Res 75:104–112[CrossRef]
RansohoffR. M.,
KivisakkP.,
KiddG.2003; Three or more routes for leukocyte migration into the central nervous system. Nat Rev Immunol 3:569–581[CrossRef]
SamuelM. A.,
MorreyJ. D.,
DiamondM. S.2006; Caspase-3 dependent cell death of neurons contributes to the pathogenesis of West Nile virus encephalitis. J Virol 81:2614–2623
SitatiE. M.,
DiamondM. S.2006; CD4+ T-cell responses are required for clearance of West Nile virus from the central nervous system. J Virol 80:12060–12069[CrossRef]
WangT.,
TownT.,
AlexopoulouL.,
AndersonJ. F.,
FikrigE.,
FlavellR. A.2004; Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. Nat Med 10:1366–1373[CrossRef]
XiaoS. Y.,
GuzmanH.,
ZhangH.,
Travassos da RosaA. P.,
TeshR. B.2001; West Nile virus infection in the golden hamster ( Mesocricetus auratus ): a model for West Nile encephalitis. Emerg Infect Dis 7:714–721[CrossRef]
YangJ. S.,
RamanathanM. P.,
MuthumaniK.,
ChooA. Y.,
JinS. H.,
YuQ. C.,
HwangD. S.,
ChooD. K.,
LeeM. D.other authors2002; Induction of inflammation by West Nile virus capsid through the caspase-9 apoptotic pathway. Emerg Infect Dis 8:1379–1384[CrossRef]