Ebola Virus VP35 Interacts Non-Covalently with Ubiquitin Chains to Promote Viral Replication Creating New Therapeutic Opportunities

 Ebolavirus (EBOV) causes severe hemorrhagic fever in humans, relying on the viral polymerase complex with VP35 as a crucial factor. VP35 undergoes covalent ubiquitination, fundamental for regulating its interaction within the complex, aiding virus replication. VP35 also participates in non-covalent interaction with ubiquitin (Ub), the purpose of which was unclear. This research unveils VP35's specific interaction with free K63-linked polyUb chains. Manipulating Isopeptidase T (USP5), responsible for degrading unanchored polyUb chains, reduced VP35's association with Ub. This decrease correlated with diminished polymerase activity, impacting EBOV replication. Through computational modeling, the authors mapped the VP35-Ub non-covalent interaction, validated the interface with mutations, and identified compounds disrupting this interaction. These compounds effectively reduced viral polymerase activity, impeding infectious EBOV replication. This study sheds light on the role of unanchored polyUb chains in regulating Ebola virus polymerase function. Additionally, the discovery of compounds disrupting VP35-Ub interactions holds promise for potential anti-Ebola virus therapies.

(LA)

Ebola virus disease: current vaccine solutions

Ebola Virus Disease (EVD) is a promising zoonotic disease with sporadic outbreaks in Central and West African countries. It has unpredictable high case fatality rate and public health concern. From 2013-2016, in West Africa, a licensed vaccine was used as prophylactic protection in human and non-human primates, and also showed progress rate against to the devastating outbreak of EVD. Recently, two vaccines: Ervebo (rVSV-ZEBOV) and a two-dose combination of Zabdeno (Ad26.ZEBOV) and Mvabea (MVA-BN-Filo) have been authorized and in use. Many reasons are making challenge the licensing of an Ebola vaccine such as the sporadic and limited nature of EVD outbreaks and shortage of resources needed to bring a vaccine to licensure. For reducing the fatality of EVD, not only vaccine solutions are still important but also other strategic interventions are necessary for the prevention and control of EVD.

(RA)

A Point Mutation in the Human Parainfluenza Virus Type 2 Nucleoprotein Leads to Two Separate Effects on Virus Replication

 Human parainfluenza virus type 2 (hPIV2) represents Paramyxovirus genomes strictly following the "rule of six," with each nucleoprotein subunit (NP) binding precisely six nucleotides. Within NP's RNA binding groove, among ten residues, only Q202 directly engages with a nucleotide base, exemplifying the stringent adherence to this genomic principle. NPQ202 mutation leads to two distinct outcomes: facilitating the viral polymerase in replicating defective bipartite promoter minigenomes when NPwt is inactive, while hindering the conventional rescue of rPIV2 carrying this mutation. The absence of rPIV2 NPQ202A initially impeded a comprehensive analysis of the latter phenotype. After extensive cocultivation of transfected cells, researchers successfully recovered an rPIV2 variant with the NPQ202A mutation, found viable due to an additional NP mutation (I35L). This investigation infers separate effects induced by the Q202 mutation, resulting in the observed phenotypes. Additionally, it suggests a plausible link between the challenge in rescuing the virus and the incapacity of transfected cells to assimilate viral nucleocapsids during virus budding. The study highlights a potential secondary role of helical nucleocapsids' (NC) 3' ends in Paramyxovirus genomes. These ends might interact specifically with virus-modified cell membranes, crucial for integrating viral NCs into budding virions, impacting the virus lifecycle.

(LA)

Recombinant DNA technology for producing new rinderpest virus vaccines

Goal of vaccination is to control rather than suspension or abolition disease with few exceptions. In the 1970s, smallpox & two other human diseases like polio and measles were being targeted for eradication by the World Health Organization. Cattle plague caused by rinderpest virus, has put this virus on the verge of global extinction. In Europe, Asia and Africa, for decade, cattle plague disease affected by this virus. The favorable outcome of the Global Rinderpest Eradication Program by vaccination was to change people's lives economically and socially. In this article, researcher illustrated about the history of the development of this vaccine and the new research to produce marker vaccines by recombinant DNA technology and reverse genetics. Furthermore, researcher gave a configuration that marker vaccines can make a valuable contribution in the final stages of the rinderpest eradication program.

(RA)

Canine Distemper Virus Infection in the Free-Living Wild Canines, the Red Fox (Vulpes vulpes) and Jackal (Canis aureus moreoticus), in Croatia

Canine distemper virus (CDV) is a single stranded negative-sense RNA virus, morbillivirus usually affecting carnivores. The disease is highly contagious, posing a threat to both wild and domestic canids. Like other members of the family Paramyxoviridae, the virus encodes six proteins: nucleocapsid, phospho-, matrix, fusion, hemagglutinin and polymerase proteins. This study investigated the prevalence of this disease in Croatia, in which 176 red foxes and 24 jackal brain samples were collected during a Rabies surveillance in 2021-2022. Only four red foxes (2.27%) tested positive using real-time RT-PCR. All the jackals tested negative for the canine distemper. The CDVs confirmed here belong to the Europa 1 genotype; genetically similar to the CDV sequences obtained from Croatian, Italian and German red foxes, and German barger, Hungarian polecats and Hungarian and German dogs.

(WWN)

GDP polyribonucleotidyltransferase domain of vesicular stomatitis virus polymerase regulates leader-promoter escape and polyadenylation-coupled termination during stop-start transcription

 The unconventional mRNA capping enzyme, the GDP polyribonucleotidyltransferase (PRNTase) domain within the vesicular stomatitis virus (VSV) L protein, possesses a crucial "priming-capping loop." This loop governs both the initiation of leader RNA synthesis and the capping of monocistronic mRNAs during VSV's unique stop-start transcription cycle. The authors’ investigation focused on specific basic amino acid residues within a helix structure directly linked to this loop. Through identifying single-point mutations, they unveiled previously undocumented defective traits in various stages of stop-start transcription. Mutations at residue R1183 (R1183A and R1183K) notably decreased leader RNA synthesis by impeding early elongation, but not de novo initiation or productive elongation. Conversely, mutations at residue R1178 (R1178A and R1178K) reduced the efficiency of mRNA synthesis termination at gene junctions, leading to increased abnormal polycistronic mRNA levels. Remarkably, both residues R1183 and R1178 were found to be nonessential for cap-forming activities. The lethal impact of the R1183K mutation on VSV contrasted with the attenuation caused by the R1178K mutation, which generated polycistronic mRNAs during infection. These findings underscore the multifaceted role of the PRNTase domain, extending beyond pre-mRNA capping, in ensuring precise stop-start transcription in VSV. 

(LA)

Recombinant vesicular stomatitis virus-vectored vaccine induces long-lasting immunity against Nipah virus disease

Novel henipavirus, Langya virus got worldwide concern after infecting over three dozen people in China. Henipaviruses as respiratory pathogen could trace another pandemic like deadly Nipah Virus (NiV). It produces highly fatal respiratory disease & encephalitis in humans in Bangladesh & India. No authorized remedy exists against NiV. Only ideal NiV vaccine would award to both fast-acting & long-lived protection. Researcher reported that a recombinant vesicular stomatitis virus-based (rVSV-based) vaccine expressing the NiV glycoprotein (rVSV-ΔG-NiVBG) that protected 100% NiV-associated lethality in nonhuman primates within a week. Objective of research is to assess the longevity of rVSV-ΔG-NiVBG. Researchers vaccinated African green monkeys (AGMs) in one year before challenging with a lethal dose of NiV. All vaccinated AGMs (whether receiving a single dose or prime-boosted) survived with no detectable clinical signs or NiV replication by producing humoral responses. Transcriptomic analyses showed that sign of adaptive immune correspond with vaccine-mediated protection. While vaccines for COVID-19 have given a durable protection, the research results suggest that rVSV-ΔG-NiVBG bring out a long-lasting immunity.

(AR)