Presence of virus neutralizing antibodies in cerebral spinal fluid correlates with non-lethal rabies in dogs.

BACKGROUND: Rabies is traditionally considered a uniformly fatal disease after onset of clinical manifestations. However, increasing evidence indicates that non-lethal infection as well as recovery from flaccid paralysis and encephalitis occurs in laboratory animals as well as humans. METHODOLOGY/PRINCIPAL FINDINGS: Non-lethal rabies infection in dogs experimentally infected with wild type dog rabies virus (RABV, wt DRV-Mexico) correlates with the presence of high level of virus neutralizing antibodies (VNA) in the cerebral spinal fluid (CSF) and mild immune cell accumulation in the central nervous system (CNS). By contrast, dogs that succumbed to rabies showed only little or no VNA in the serum or in the CSF and severe inflammation in the CNS. Dogs vaccinated with a rabies vaccine showed no clinical signs of rabies and survived challenge with a lethal dose of wild-type DRV. VNA was detected in the serum, but not in the CSF of immunized dogs. Thus the presence of VNA is critical for inhibiting virus spread within the CNS and eventually clearing the virus from the CNS. CONCLUSIONS/SIGNIFICANCE: Non-lethal infection with wt RABV correlates with the presence of VNA in the CNS. Therefore production of VNA within the CNS or invasion of VNA from the periphery into the CNS via compromised blood-brain barrier is important for clearing the virus infection from CNS, thereby preventing an otherwise lethal rabies virus infection

Detection of viral antigens in dog brain.

<p>Paraffin sections obtained from DRV Mexico infected dog brains were subjected to immunohistochemistry for the detection of RABV glycoprotein (A) and nucleoprotein (B) in the hippocampus, hypothalamus and cerebellum.</p

Detection of VNA in the serum and CSF.

<p>CSF and serum samples were subjected to RFFIT for the analysis of virus neutralizing antibodies (VNA). Statistical analysis was performed by student T test and the symbol *** indicates a p value <0.0001, ** indicates a p value <0.001 and * indicates a p value <0.05.</p

Measurement of WBC and total protein in the CSF.

<p>CSF samples obtained from DRV Mexico infected dogs were subjected to clinical pathological analysis. Statistical analysis was performed by student T test and the symbol *** indicates a p value <0.0001, ** indicates a p value <0.001 and * indicates a p value <0.05.</p

Infiltration of inflammatory cells into the CNS of dogs.

<p>Paraffin sections obtained from DRV Mexico infected dog brains were subjected to HE staining (A) or immunohistochemistry for detecting CD3-positive cells (B). Three serial sections and two vessels were selected from each dog for quantification, and the average numbers of CD3-positive cells, degenerated neurons and perivascular infiltrated cells obtained were used for statistical analysis (C). Statistical analysis was performed by student T test and the symbol *** indicates a p value <0.0001, ** indicates a p value <0.001 and * indicates a p value <0.05.</p