There is insufficient data about the mechanism of cell exposure to ER stress caused by wild-type rabies species. We decided to affect the SRABV on the mouse nervous system cells and observe the results. Since our work was the first study of SRABV, we had to compare the results of our research with the research that scientists have done on other viruses.
It is accepted that patients with hepatitis B e antigen (HBeAg)-positive have chronic HBV infection. The two types of large HBV surface antigens (LHBs) mutant, pre-S1, and pre-S2 can remain in the ER and escape immune system invasion. Pre-S mutants can start ER stress to enforce oxidative DNA injury and genomic inconstancy, leading to hepatocellular carcinoma(HCC). Also, the hepatitis C virus is one of the leading causes of chronic liver disease, cirrhosis, and HCC. Expression of HCV and HBV proteins in hepatocytes induces ER stress and causes the release of calcium from the ER. Calcium can either activate caspase and apoptosis via the calpain pathway or lead to autophagy by activating AMPK (5’adenosine monophosphate-activated protein kinase) and Mammalian Target of rapamycin (mTOR). Several documents have suggested that during viral infection, the interferon response is triggered by double-stranded RNA of the virus, and then synthesized polypeptides of the virus arouse the ER. They have stated that during viral infection, the released proteins bind to the BiP (Binding immunoglobulin protein) and release ER stress transducers such as Protein kinase RNA like ER-localized kinase (PERK), ATF-6, and Inositol-requiring enzyme 1α (IRE1α). Dengue virus can escape the host immune system by managing the UPR, simplifying its replication, and activating autophagy. Dengue virus regulates host pathways to activate ataxia telangiectasia mutated (ATM) signaling which is the first response to infection and then lead to production of ROS following stress in the endoplasmic reticulum (ER). Inhibition of ER stress response diminishes autophagosome efficiency, decreases virus titers, and produces less ROS. Limiting ATM activation, only reduces transcription of ER stress response proteins . Yang et al. found that the expression of glucose-regulated protein 78 (GRP78, the ER stress marker) was enhanced in Pseudorabies virus (PVR) infection, demonstrating that PRV infection corrupted the ER hemostasis, activated the CHOP-Bcl2 pathway, and induced apoptosis in the last phases of PVR infection. Liu et al.  observed that in HEP-Flury and CVS-11 strains, phosphoproteins of rabies virus could attach to beclin1 and evolved defective autophagy via the caspase2-mediated signaling pathways to increase viral infection genome replication. It should be noted that both strains are attenuated, and their use is limited to vaccine production and research, so they differ from the circulating wild type strain.
Our research showed high expression of ASK-1 gene mRNA in group D. This result was quite predictable because SRABV, a pathogenic virus, activates autophagy to preserve neurons and thus increases virus replication. Therefore the SRABV activates the path of IRE1α, and then ASK-1increase causes autophagy. Also, we observed a significant increase in mRNA expression of the ATF-6 gene in group D. The presence of abnormal proteins leads to the production of GRP78, which activates ATF- 6, then stimulates the UPR for response to ER stress. Previous or simultaneous injections of pIRES-EGFP-beclin1 and the SRABV did not make a difference in response to ER stress, injections of both of them increased Casp3, and we found significant changes only in the A and B groups. As we expected, the increase of Casp3 got to lead to apoptosis. When we looked at changes in the CHOP gene, we found that it was significant only in group D. This might be due to activation of the eukaryotic initiation factor 2α (eIf2α) and IRE1α pathways or abnormal proteins' production during the SRABV infection process, which lead to increased expression of ATF-6.
In general, comparing the results of our research with the published articles of other scientists, it can be concluded that SRABV infection may have increased abnormal proteins and ER stress, which ultimately led to the activation of the UPR or ERAD pathway. Activation of this pathway initially prolongs cell survival through autophagy, but it leads to apoptosis and cell death as the infection progresses. The authors believe that more detailed research is needed to investigate the mechanism of ER stress during the wild-type rabies infection process.