Autophagy and Apoptosis in Rabies Virus Replication

Rabies virus (RABV), the prototype member of the genus Lyssavirus in the family Rhabdoviridae, is known to induce two evolutionarily conserved and genetically regulated processes called autophagy and apoptosis in target cells; however, the exact mechanisms behind both processes are not clearly understood. Thus, this report analyses and outlined the molecular mechanisms of RABV induced autophagy and apoptosis, and the effects of such cellular events on RABV replication. The report shows the RABV capacity to stimulate and utilize autophagy during replication through different pathways including N/P proteins directed CASP2 downregulation, inhibition of mTOR, and phosphorylation of AMPK and MAPK to initiate the autophagy. Consequently, the viral P protein frequently binds to the host BECN1 protein to facilitate the nucleation of autophagosomes, and the fusion of autophagosomes with lysosomes leading to an incomplete autophagy. Similarly, cell apoptosis can be activated through diverse ways following RABV invasion: as a defense measure to suppress RABV replication, the level of apoptosis correlates positively with the expression level of RABV G-protein. While, the M and P proteins commonly target mitochondria to induce intrinsic apoptosis through both caspase-dependent and independent pathways. In most RABV infections, a crosstalk between autophagy and apoptosis acts to inhibit RABV replication.
(BNU)

Design of universal Ebola virus vaccine candidates via immunofocusing

Ebola virus, a member of the Filoviridae family, is highly pathogenic and threat to public health. Two vaccines were developed for prevention of the infection of ebola virus, however they both must be stored in cold room, and they have possibility of causing mild to moderate side effects in vaccinated individuals. Therefore, they have used to a very limited extent. So, we need to design of new prophylactic vaccines that are suitable for widespread use and confer durable and cross-protective immunity. Ebola virus Glycoprotein (GP) mediates viral infection and serves as the primary target of neutralizing antibodies. Hyperglycosylated GP-Fer with two or three additional glycans indicated consistent cross-neutralizing activity against Bundibugyo virus and Sudan virus. GP-based immunogens that have thermostability and elicit cross-protective responses hold promise as effective universal orthoebolavirus vaccine candidates.

(RN)

Development of a New Reverse Genetics System for Ebola Virus

Ebola virus from the family Filoviridae is very pathogenic and has caused several deaths especially in west Africa. It has a non segmented single stranded RNA genome encoding for seven genes. Reverse genetics are systems that are used to study these pathogenic viruses by production of mutant viruses that are safer and suitable models. For Ebola virus several reverse genetics system have been generated in the past. These systems require studying under biosafety level 4 conditions or subvirals under biosafety level 2 conditions. These earlier systems require multiple plasmids expressing viral proteins and viral genomes that are important for Ebola virus replication to be transfected. This study came up with a novel reverse genetic system for Ebola virus that required only a single viral genome transfection into a helper cell line. This cell line expresses nucleoprotein (NP), viral protein 35 and VP30 and the large protein (L) which have been fine tuned for Ebola replication. Compared to other systems this novel reverse genetic system has advantages. One is that it only requires single viral RNA genome to be transfected, the second advantage is that the helper cell lines can also be used to rescue infectious virions as well as subviral particles. Disadvantage is that the rescue of the virions is restricted to only the helper cells.

(BEC)

Structural insights into RNA polymerases of negative-sense RNA viruses

The genomes of negative-sense RNA viruses (NSVs) consist of a single or multiple RNA segments encapsidated by oligomeric viral nucleoproteins into helical viral ribonucleoprotein complexes. The replication and transcription of such viral genome is performed mainly by a ~250–450kDa viral encoded RNA-dependent RNA polymerases (RdRP) containing capping or cap-snatching activity. This study has comprehensively compiled the molecular structures of the RdRP from different NSVs including their domain organization and conformational rearrangements as described by recent high-resolution X-rays and cryoelectron microscopy. In addition, the study unraveled the two globular domains of the oligomeric NSVs nucleoproteins including the head, and body domains of the Influenza A virus; the N-terminal, and CT lobes of Hantaan virus; and the C-terminal, and NT domains of Measles virus. Moreover, the complex relationships between the RdRP ultrastructure, molecular mechanisms of viral transcription and replication, and novel antiviral drug targets for therapeutic applications were highlighted. 

(BNU)

Feline Morbillivirus: Clinical Relevance of a Widespread Endemic Viral Infection of Cats

Feline morbillivirus (FeMV) was isolated in 2012 from stray cats from Hong Kong. FeMV has two type Genotype (GT), GT1 and GT2. GT1 was first identified in 2012 in Hong Kong and is found worldwide in Asia, Europe, and America. GT2 was identified in Germany in 2018. FeMV can be cultivated many kinds of cells of cat, so it is suggested that systemic infections can occur with FeMV and that clinically relevant genotype differences in tropism may exist. The host of FeMV is not only domestic cats, but also wild fields, so FeMV could be a threat for susceptible endangered host species. According to the information from experimental infection studies, FeMV infection shows few clinical signs. However, FeMV was detected from the urine of FeMV infection cats for a long time. Histopathological changes were found in kidney, liver, and spleen. Regarding FeMV pathogenicity, a wide spectrum of clinical outcomes appears to be possible, from subclinical infections to acute and/or chronic disease and lethal outcomes.

(RN)

A Point Mutation in the RNA-Binding Domain of Human Parainfluenza Virus Type 2 Nucleoprotein Elicits Abnormally Enhanced Polymerase Activity

Human parainfluenza virus type 2 (HPIV2) from the family paramyxoviridae contains six genes (NP, P/V, M, F, HN and L) which are firmly covered by the nucleoprotein (NP) forming a helical nucleocapsid. This nucleocapsid is the template for synthesis of viral RNA. Transcription and replication are the functions of Phosphoprotein (P) and large protein (L) which together form the viral RNA-dependent RNA polymerase (RdRp). This virus has several amino acids. For optimum replication to take place the RNA genome length must be a multiple of six nucleotides. This is a rule that is followed by all the paramyxoviruses and is known as the ‘rule of six’. In this study ten amino acids in NP that contacts RNA and are conserved in the HPIV2 and PIV5 viruses were examined for polymerase activity. They found out that when there is substitution mutation of HPIV2 Q202 to different amino acids, the polymerase activity increases but the affinity of RNA binding is not changed. This means genome replication is increased. Another interesting finding is that with the mutation, minigenomes without leader sequence and not multiple of six were used by the polymerase. However, this mutation does not affect the functions of NP such as signal editing and junctional recognition.

(BEC)