Protection Induced By Attenuated Rabies Virus SRV9and Pirmary Immune Mechanism After Infection With Street Rabies Virus

Rabies is a fatal viral zoonosis caused by viruses of the Lyssavirus genus of theRhabdoviridae family, The WHO-recommended post-exposure prophylaxis (PEP)protocol for rabies includes inactivated human diploid cell vaccine (HDCV) andhuman rabies immune globulin (HRIG). However, resource poor countries wherelife-saving HDCV and HRIG are not always available or affordable, there wasuseless until rabies virus spread to the CNS or sickness, and the levels of anti-rabiesvirus neutralizing antibody in HIV-infected adults and children after post-exposurevaccination with rabies cell culture vaccines correlates directly with the severity oftheir disease. It was demonstrated that the safe and efficient live attenuated rabiesvaccine has the potential for rabies PEP. China has the second highest number ofhuman cases in the world, each year many people accept the routine PEP protocol.However, there are remained a high death rate and no reported about live attenuatedrabies vaccine for rabies PEP in china. SRV9(G protein Arg333â†'Ser333) as anattenuated rabies vaccine strains has been systematic studied in china, it is safe for avariety animals, especially macaque. Therefore, it is necessary to study chineseattenuated vaccine strain SRV9, which was whether used for the rabiespost-exposure prophylaxis or not, even the immune mechanism.The live attenuated rabies SRV9has been studied by two steps. First, the safetyof SRV9was evaluated. After one dose of live SRV9was administered byintracerebral (i.c.) injection to three weeks old ICR mice, no mortality was observedin those mice. Therefore, prophylaxis with one dose of SRV9was administeredeither by i.c. or intramuscular (i.m.) at1,2,3,4,5and6days after rabiespost-exposure (p.e.). The control mice received five dose HDCV in combination with HRIG by Essen routine. There was a difference (p<0.05) in the total survival ofthe mice treated with one dose SRV9(i.m.) compared with the mice treated with fivedose HDCV in combination with HRIG, and significant differnce (p<0.05) was alsoshowed in the total survival of the mice treated with one dose SRV9(i.m.) with themice treated with SRV9(i.c.). Neutralizing antibody titers in mice which treated withone dose SRV9were higher than0.5IU/ml in a short time, especially i.c..Secondly, we studied the immune protective mechanism of SRV9by comparison the changes between SRV9(i.c.) inoculated mice or no inoculated control afterstreet rabies virus HuNPN01infection(i.m.) genes about some cytokines andchemokines in the brain were detected by quantitative real time PCR, we foundTNF-alpha, IL-6, IFN-gamma, IP-10, MCP-1, MIP-1α, MIP-1β, RANTES DOCK,SDF-1and BCA-1were significantly increased SRV9treated mice. Then, sodiumfluorescein and quantitative real time PCR were explored to detect blood-brainbarrier permeability and microvascular endothelial cells of blood-brain barrier tightjunction protein gene ZO-1and Occdludin, we found the SRV9can open blood-brainbarrier and significantly down-regulated the ZO-1and Occdludin; genes related toCD4,CD8,CD19, κ-L chain,GFAP and CD11were detected,that the attenuatedSRV9could significantly upregulated those genes was also showed,same resultswere also confirmed on purified mouse glial cells in vitro.In summary, our studies clearly demonstrated that the chinese attenuated vaccinestrains SRV9may have potential as a PEP agent in the future, and the SRV9couldenhance blood-brain barrier permeability and down-regulated some tight junctiongenes of microvascular endothelial cells, and up-regulated genes associated withchemokines and cytokines, those evidence will highlight the forehead of SRV9inPEP.