A comparative genomic approach to decipher the mutations associated with Nipah viral human isolates from southeast Asia.

Background and Objectives: Multiple outbreaks over two decades and a high mortality rate have emphasized the Nipah virus (NiV) as a priority research area. The study focuses on identifying the mutational landscape in sequences from NiV human isolates from different geographical regions. Materials and Methods: Thirty-seven NiV genomes of human samples from Malaysia, Bangladesh, and India were subjected to phylogeny and metagenomic analysis to decipher the genome variability using MEGA11 software and the meta-CATS web server. Using the Single-Likelihood Ancestor Counting method, the synonymous and nonsynonymous mutations among NiV genes were identified. Further, the nonsynonymous variations were used to identify mutations in all the NiV proteins. Results: The NiV isolates were categorized into NiV-M, NiV-B, and NiV-I clades based on phylogenetic analysis. Metagenomic analysis revealed 1636 variations in the noncoding and coding regions of the genomes of the three clades of NiV. Further analysis of nonsynonymous mutations showed the phosphoprotein to be highly mutating, whereas the matrix protein was stable. Conclusion: Deciphering the mutation pattern using a comparative genomics approach for human isolates provided valuable insight into the stability of NiV proteins which can be further used for understanding variations in host-pathogen interaction and developing effective therapeutic measures.

Bitter taste receptors establish a stable binding affinity with the SARS-CoV-2-spike 1 protein akin to ACE2.

COVID-19 is caused by the highly contagious SARS-CoV-2 virus, which originated in Wuhan, China, resulting in the highest worldwide mortality rate. Gustatory dysfunction is common among individuals infected with the Wild-type Wuhan strain. However, there are no reported cases of gustatory dysfunction among patients infected with the mutant delta variant. The reason behind this remains elusive to date. This in-silico-based study aims to unravel this clinical factor by evaluating the overall binding affinity of predominant bitter taste receptors associated with gustatory function (T2R-4, 10, 14, 19, 31, 38, 43, and 46) with the Receptor Binding Domain (RBD) of spike 1 (S1) protein of Wuhan (Wild)/delta-SARS-CoV-2 (mut1-T478K; mut2-E484K) variants. Based on docking and MM/PBSA free binding energy scores, the Wild RBD showed a stronger interaction with T2R-46 compared to the ACE2 protein. However, both delta variant mutants (mut1 and mut2) could not establish a stronger binding affinity with bitter taste receptor proteins, except for T2R-43 against mut1. In conclusion, the delta variants could not establish a better binding affinity with bitter taste receptors, contradicting the Wild variant that determines the severity of gustatory dysfunction among patients exposed to the delta and Wild SARS-CoV-2 variants. The study's inference also proposes T2R-46 as an alternate binding receptor target for RBD-S1 of Wild SARS-CoV-2, augmenting its virulence in all functional organs with compromised α-gustducin interaction and bitter sensitization. This in-silico-based study needs further wet-lab-based validation for a better understanding of the role of T2R-46-based viral entry in the human host.Communicated by Ramaswamy H. Sarma.

Predicting the changes in neutralizing antibody interaction with G protein derived from Bangladesh isolates of Nipah virus: molecular dynamics based approach.

The infectious Nipah virus (NiV) is categorized into NiV-M (Malaysia) and NiV-B (Bangladesh) groups based on its genome comparison, pathogenicity, and mortality rate. The development of therapeutic molecules has used NiV-M-derived data in multiple studies than NiV-B. In continuation with this, the protein level investigation is also less explored to understand the interaction with therapeutic neutralizing antibodies for NiV-B. So, this study focuses on understanding the impact of NiV-B-specific mutations on the interaction of therapeutic neutralizing antibodies with the G protein. The population-based comparative analysis of NiV-B G protein sequences with NiV-M sequence identified twenty-six mutations. These predominantly polar mutations were then used to model the mutant protein (G_MT). In a comparative study, the G protein G_MT and reference protein G_WT (Malaysian origin) were subjected to a protein docking with neutralizing human monoclonal antibody HENV26. The binding affinity and the free binding energy of the glycoprotein in complex with G-WT and G_MT were calculated using PRODIGY and MM/PBSA tools respectively. Based on the PRODIGY report, G-WT showed stronger binding (-13.8 kcal/mol) compared to that of the G_MT (-9.0 kcal/mol) with the HENV26 antibody. The stability of the complexes was evaluated using MM/PBSA which showed higher binding energy with HENV26 for G_WT (-75.11 kcal/mol) in contrast to G_MT (-41.66 kcal/mol). The results indicate that the mutant G protein has a reduced ability to bind to neutralizing antibodies, resulting in a decreased effectiveness against strains carrying these mutations.Communicated by Ramaswamy H. Sarma.