Abstract
Enhancement of blood–brain barrier (BBB) permeability is necessary for clearing virus in the central nervous system (CNS). It has been reported that only laboratory-attenuated rabies virus (RABV) induces inflammatory response to lead BBB transient breakdown rather than wild-type (wt) strains. As a component of ribonucleoprotein (RNP), phosphoprotein (P) of RABV plays a key role in viral replication and pathogenicity. To our knowledge, the function of RABV P gene during RABV invasion was unclear so far. In order to determine the role of RABV P gene during RABV infection, we evaluated the BBB permeability in vivo after infection with wt RABV strain (GD-SH-01), a lab-attenuated RABV strain (HEP-Flury), and a chimeric RABV strain (rHEP-SH-P) whose P gene cloned from GD-SH-01 was expressed in the genomic backbone of HEP-Flury. We found that rHEP-SH-P caused less enhancement of BBB permeability and was less pathogenic to adult mice than GD-SH-01 and HEP-Flury. In an effort to investigate the mechanism, we found that the replication of rHEP-SH-P has been limited due to the suppressed P protein expression and induced less response to maintain BBB integrity. Our data indicated that the P gene of wt RABV was a potential determinant in hampering viral replication in vivo, which kept BBB integrity. These findings provided an important foundation for understanding the viral invasion and development of novel vaccine.
Highlights
Blood–brain barrier is a physical barrier between the central nervous system (CNS) and peripheral environment, which impedes the entrance of virus-neutralizing antibody (VNA) from peripheral blood into CNS to eliminate virus when the host was infected with lethal rabies virus (RABV)
In an effort to determine the role of RABV P protein during infection, we evaluated the BBB permeability in vivo after infection with wt RABV strain (GD-SH-01), laboratory-attenuated RABV strain (HEP-Flury), and a chimeric RABV strain that was rescued in our laboratory previously (Tian et al, 2017b)
GD-SH-01 is a wt RABV strain that was isolated from the brain tissue of rabid pig in our laboratory and is phylogenetically close to canine RABV (Luo et al, 2012, 2013), HEP-Flury, a laboratory-attenuated high egg passage (HEP) RABV strain, which is preserved in our laboratory, and rHEP-SH-P, which is a chimeric strain whose P gene was adopted from GD-SH-01 and expressed in the backbone of HEP-Flury genome (Tian et al, 2017a)
Summary
Blood–brain barrier is a physical barrier between the CNS and peripheral environment, which impedes the entrance of VNA from peripheral blood into CNS to eliminate virus when the host was infected with lethal RABV. This study demonstrates that the P gene of RABV plays a potential determinant in hampering the viral proliferation to realize immune escape during the infection course, which gives a framework to understand the genetic function better and develop more efficient therapeutic strategies against rabies. Rabies virus (RABV) is a non-segmented negative-stranded RNA virus in genus Lyssavirus within the Rhabdoviridae family (Schnell et al, 2010). It causes an acute and fatal zoonotic disease, where there is no cure once clinical symptoms develop and is responsible for more than 55,000 human deaths every year (Fu, 1997; Jackson, 2003).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
