Increased blood–brain barrier permeability is not a primary determinant for lethality of West Nile virus infection in rodents

Abstract

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.

Differential Replication of Pathogenic and Nonpathogenic Strains of West Nile Virus within Astrocytes

“…Increasing evidence suggests that WNV entry into the CNS is a multistep process that can occur through one of several routes (17,20,(31)(32)(33)(34)(35). WNV entry into the CNS has been shown to precede disruption of the BBB and leukocyte infiltration (32,33,36,37), suggesting that WNV utilizes a direct mechanism to initially invade the CNS, such as basolateral secretion of virus particles from infected brain endothelial cells or transcytosis. Thus, the brain endothelium likely constitutes a primary barrier to WNV neuroinvasion.…”

Encephalitic Arboviruses: Emergence, Clinical Presentation, and Neuropathogenesis

“…In a model of WNV infection using insect cell-derived WNV, BBB disruption coincided with peripheral infection and preceded CNS entry [152,157]. However, recent studies using mice infected with JEV [151], WNV [158,159], and tick-borne encephalitis virus (TBEV) [160] have demonstrated that CNS entry of virus can occur before BBB disruption. Paracellular entry under these conditions may contribute to a second phase of CNS infection.…”

Usutuvirus

“…Mäuse entwickeln nach intraperitonealer Infektion mit USUV neurologische Symptome, jedoch nur, wenn sie innerhalb einer Woche nach Geburt infiziert werden [26]. WNV hingegen ist in der Lage, auch ältere Mäuse zu infizieren und letale Erkrankungen hervorzurufen [27]. Frucht-fressende afrikanische Fledermäuse ließen sich experimentell nicht mit USUV infizieren [28].…”