Single amino acid change at position 255 in rabies virus glycoprotein decreases viral pathogenicity.

Previous studies have indicated that the amino acid at position 333 in the glycoprotein (G) is closely related to rabies virus (RABV) pathogenicity. However, whether there are other amino acid residues in G that relate to pathogenicity remain unclear. The aim of this study is to find new amino acid residues in G that could strongly reduce RABV pathogenicity. The present study found that the pathogenicity of a virulent strain was strongly attenuated when the amino acid glycine (Gly) replaced the aspartic acid (Asp) at position 255 in G (D255G) as intracranial (i.c.) infection with this D255G mutant virus did not cause death in adult mice. The indexes of neurotropism of the D255G mutant strain and the parent GD-SH-01 are 0.72 and 10.0, respectively, which indicate that the D255G mutation decreased the neurotropism of RABV. In addition, the D255G mutation significantly decreased RABV replication in the mouse brain. Furthermore, the D255G mutation enhanced the immune response in mice, which contributed to the clearance of RABV after infection. The Asp255 â†’ Gly255 mutation was genetically stable in vitro and in vivo. In this study, we describe a new referenced amino acid site in G that relates to the pathogenicity of RABV.

Recombinant rabies virus expressing interleukin-6 enhances the immune response in mouse brain.

Rabies, which is caused by the rabies virus (RABV), is an ancient zoonosis that has a high mortality rate. Previous studies have indicated that recombinant RABV expressing canine interleukin-6 (rHEP-CaIL6), induced more virus-neutralizing antibodies than parental RABV in mice following intramuscular immunization. To investigate the immune response induced in the CNS by rHEP-CaIL6 after intranasal or intracranial administration in mice, the permeability of the blood-brain barrier (BBB), the infiltration of CD3 T cells, and innate immune response-related effector molecules in the CNS were examined. It was observed that infection of rHEP-CaIL6 led to enhanced BBB permeability following intranasal infection. More CD3 T cells infiltrated into the central nervous system (CNS) in mice infected with rHEP-CaIL6 than in those infected with the HEP-Flury strain. Furthermore, rHEP-CaIL6 induced an increased expression of innate immune response-related effector molecules, compared with the parental HEP-Flury strain, within the CNS. Taken together, these findings suggest that rHEP-CaIL6 induced stronger immune responses in mice brains, which is more beneficial for virus clearance. These results may also partly illustrate the role of IL6 in RABV infection.

Hierarchical fusion of common sense knowledge and classifier decisions for answer selection in community question answering.

The goal of answer selection is to select the most applicable answers from an answer candidate pool. It plays an essential role in numerous applications in information retrieval (IR) and natural language processing (NLP). In this paper, we introduce a novel Knowledge-enhanced Hierarchical Attention mechanism for Answer Selection (KHAAS), which fully exploits the common sense knowledge from knowledge bases (KBs) and input textual information. Specifically, we first devise a three-stage knowledge-enhanced hierarchical attention mechanism, including the word-level attention, the phrase-level attention, and the document-level attention to learn the fact-aware intra-document features within questions and answers by fusing the knowledge from both the question/answer and KB. Hence, we can leverage the semantic compositionality of the question/answer and learn more holistic knowledge-enhanced intra-document features of the question/answer at three levels of granularity. Second, after obtaining the knowledge-enhanced question and answer representations, we employ a multi-perspective co-attention network to learn the complex inter-document relationships between the question and answer representations from different representation subspaces, which can capture the interactive semantics of the question and answer representations at three levels. Finally, we propose an adaptive decision fusion method to learn a more effective and robust ensemble answer selection model by adaptively combining multiple classifiers learned with different levels of features. Experimental results on three large-scale answer selection datasets demonstrate that KHAAS consistently outperforms the compared methods.

Expression of interleukin-6 by a recombinant rabies virus enhances its immunogenicity as a potential vaccine.

Several studies have confirmed that interleukin-6 (IL6) mediates multiple biological effects that enhance immune responses when used as an adjuvant. In the present study, recombinant rabies virus (RABV) expressing canine IL6 (rHEP-CaIL6) was rescued and its pathogenicity and immunogenicity were investigated in mice. We demonstrated that mice received a single intramuscular immunization with rHEP-CaIL6 showed an earlier increase and higher maximum titres of virus-neutralizing antibody (VNA) as well as anti-RABV antibodies compared with mice immunized with the parent strain. Moreover, survival rates of mice immunized with rHEP-CaIL6 were higher compared with mice immunized with parent HEP-Flury according to the challenge assay. Flow cytometry further confirmed that immunization with rHEP-CaIL6 induced the strong recruitment of mature B cells and CD8+ T cells to lymph nodes, which may partially explain the high levels of VNA and enhanced cellular immunity. Quantitative real-time PCR indicated that rHEP-CaIL6 induced stronger inflammatory and immune responses in the central nervous system, which might have allowed virus clearance in the early infection phase. Furthermore, mice infected intranasally with rHEP-CaIL6 developed no clinical symptoms while mice infected with HEP-Flury showed piloerection. In summary, these data indicate that rHEP-CaIL6 induces a strong, protective immune response with a good safety profile. Therefore, a recombinant RABV strain expressing canine IL6 may aid the development of an effective, safe attenuated rabies vaccine.