Presence of Virus Neutralizing Antibodies in Cerebral Spinal Fluid Correlates with Non-Lethal Rabies in Dogs

Clement W Gnanadurai,Biao He,Chien-Tsun Huang,Stephen B Harvey,Berhnard Dietzchold,Christina M Leyson,Yang Yang,Zhenhai Chen,Ming Zhou,Gregory Salyards,Wenqi He,D C Hooper,Zhen F Fu,Gerd Pluschke

doi:10.1371/journal.pntd.0002375

Abstract

BackgroundRabies 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 FindingsNon-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/SignificanceNon-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.

Highlights

Rabies is a highly lethal disease caused by the neurotropic rabies virus (RABV)
The striking difference between dogs that survived a wt RABV infection and dogs that succumbed to the infection is that the surviving dogs showed high level of virus neutralizing antibodies (VNA) in the serum and in the cerebral spinal fluids (CSF), as well as mild immune cell accumulation in the central nervous system (CNS), whereas dogs that succumbed to disease showed little or no VNA in the serum or in the CSF and developed severe CNS inflammation
Considering the role of VNA in clearing the virus from the CNS, production of VNA within the CNS or infiltration of VNA from the periphery into the CNS across the blood-brain barrier appears to be important for clearing the virus from CNS thereby preventing a lethal rabies infection

Summary

Introduction

Rabies is a highly lethal disease caused by the neurotropic rabies virus (RABV). It has been estimated that about 55,000 persons died from rabies each year mostly in Africa and Asia [1]. Chronic natural RABV infection in vampire bats [20], recovery from experimental RABV infection in dogs and ferrets, and recovery of humans from rabies has been documented [10,13,21], the mechanism(s) involved in the prevention of lethal rabies are not completely understood. These observations have led to renewed efforts to obtain evidence of underlying mechanisms behind nonfatal rabies infections. Increasing evidence indicates that non-lethal infection as well as recovery from flaccid paralysis and encephalitis occurs in laboratory animals as well as humans

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