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)