Omicron favors neuropilin1 binding over ACE2: Increased infectivity and available drugs

COVID-19 pandemic is continue with thousands of new cases every day around the world, even then different vaccines have been developed and proven efficacious against SARS-CoV-2. Several know antivirals drugs have been repurposed or tested against SARS-CoV-2 but we still don’t have an effective therapeutic strategy to control this viral infection. Moreover, in the race of finding out an efficient antiviral, excess uses of antiviral drugs developed a selective pressure on the virus that results in the high frequency of mutations and the possible emergence of antiviral drug resistance against SARS-CoV-2. Omicron is a recently emerged, highly mutated variant of SARS-CoV-2, reported for high infectivity. In the present study, we performed molecular docking analysis between available potential antiviral drugs (remdesivir, nirmatrelvir, molnupiravir, EIDD-1931, GS-441524, and favipiravir) and omicron S protein including S protein/ACE2 complex. Our results suggest high infectivity of omicron, however, the known antiviral drugs were found efficacious against omicron variant. Further, to investigate the high infectivity of omicron, we performed a docking experiment between omicron S protein and neuropilin1 (NRP1). Surprisingly, results suggest high affinities with NRP1 than ACE2. Overall, results suggest that omicron favors NRP1 binding over ACE2, the possible reason behind improved infectivity of omicron variant.

Monoclonal antibodies for COVID-19 therapy and SARS-CoV-2 detection

The coronavirus disease 2019 (COVID-19) pandemic is an exceptional public health crisis that demands the timely creation of new therapeutics and viral detection. Owing to their high specificity and reliability, monoclonal antibodies (mAbs) have emerged as powerful tools to treat and detect numerous diseases. Hence, many researchers have begun to urgently develop Ab-based kits for the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Ab drugs for use as COVID-19 therapeutic agents. The detailed structure of the SARS-CoV-2 spike protein is known, and since this protein is key for viral infection, its receptor-binding domain (RBD) has become a major target for therapeutic Ab development. Because SARS-CoV-2 is an RNA virus with a high mutation rate, especially under the selective pressure of aggressively deployed prophylactic vaccines and neutralizing Abs, the use of Ab cocktails is expected to be an important strategy for effective COVID-19 treatment. Moreover, SARS-CoV-2 infection may stimulate an overactive immune response, resulting in a cytokine storm that drives severe disease progression. Abs to combat cytokine storms have also been under intense development as treatments for COVID-19. In addition to their use as drugs, Abs are currently being utilized in SARS-CoV-2 detection tests, including antigen and immunoglobulin tests. Such Ab-based detection tests are crucial surveillance tools that can be used to prevent the spread of COVID-19. Herein, we highlight some key points regarding mAb-based detection tests and treatments for the COVID-19 pandemic.

Evolution of Plant RNA Viruses and Mechanisms in Overcoming Plant Resistance

Plant RNA viruses are one of the most destructive pathogens that cause a significant loss in crop production worldwide. They have evolved with high genetic diversity and adaptability due to the short replication cycle and high mutation rate during genome replication, which are characteristics of RNA viruses. Plant RNA viruses exist as quasispecies with high genetic diversity; thereby, a rapid population transition with new fitness can occur due to selective pressure resulting from environmental changes. Plant resistance can act as selective pressure and affect the fitness of the virus, which may lead to the emergence of resistance-breaking variants. In this paper, we introduced the evolutionary perspectives of plant RNA viruses and the driving forces in their evolution. Based on this, we discussed the mechanism of the emergence of variant viruses that overcome plant resistance. In addition, strategies for deploying plant resistance to viral diseases and improving resistance durability were discussed.

Reversion mutations in phosphoprotein P of a codon-pair-deoptimized human respiratory syncytial virus confer increased transcription, immunogenicity, and genetic stability without loss of attenuation

Recoding viral genomes by introducing numerous synonymous nucleotide substitutions that create suboptimal codon pairs provides new live-attenuated vaccine candidates. Because recoding typically involves a large number of nucleotide substitutions, the risk of de-attenuation is presumed to be low. However, this has not been thoroughly studied. We previously generated human respiratory syncytial virus (RSV) in which the NS1, NS2, N, P, M and SH ORFs were codon-pair deoptimized (CPD) by 695 synonymous nucleotide changes (Min A virus). Min A exhibited a global reduction in transcription and protein synthesis, was restricted for replication in vitro and in vivo, and exhibited moderate temperature sensitivity. Here, we show that under selective pressure by serial passage at progressively increasing temperatures, Min A regained replication fitness and lost its temperature sensitivity. Whole-genome deep sequencing identified numerous missense mutations in several genes, in particular ones accumulating between codons 25 and 34 of the phosphoprotein (P), a polymerase cofactor and chaperone. When re-introduced into Min A, these P mutations restored viral transcription to wt level, resulting in increased protein expression and RNA replication. Molecular dynamic simulations suggested that these P mutations increased the flexibility of the N-terminal domain of P, which might facilitate its interaction with the nucleoprotein N, and increase the functional efficiency of the RSV transcription/replication complex. Finally, we evaluated the effect of the P mutations on Min A replication and immunogenicity in hamsters. Mutation P[F28V] paradoxically reduced Min A replication but not its immunogenicity. The further addition of one missense mutation each in M and L generated a version of Min A with increased genetic stability. Thus, this study provides further insight into the adaptability of large-scale recoded RNA viruses under selective pressure and identified an improved CPD RSV vaccine candidate.

Bacterial Mixology: Combining Pharmacodynamic Models to Predict In Vitro Competition of MCR-1-Harboring E. coli

The emergence of mobile colistin resistance (mcr)-mediated polymyxin resistance has resulted in a significant detriment to the utility of the polymyxins in the clinical setting. Though the risk for horizontal transfer of an mcr-containing plasmid is a major component of the transmissibility, selection of polymyxin resistant subpopulations is still a major risk factor for developing polymyxin-resistant infections. Using static time-kills over 24 h (h), we performed competition studies by mixing known inocula of isogenic Escherichia coli strains (wildtype [WT] and mcr-1-harboring) and treating with a concentration array of polymyxin B. These results were then compared to a priori predictions of bacterial-killing effects by polymyxin B on a mixed population of E. coli cells using a previously published mechanism-based model. The data showed that both selective pressure between WT and mcr-1-harboring strains as well as underlying polymyxin B heteroresistance within each of the two strains contributed to bacterial regrowth despite treatment with high concentration polymyxin B. Moreover, the simulations showed that when mcr-1-harboring cells were 1% or 10% of the total population, regrowth by 24 h was still observed in ≥50% of the simulated subjects for both a 106 and 108 inoculum. These results indicate that at lower inoculums with a low proportion of mcr-1-harboring cells, selective pressure from a pharmacokinetic-optimized regimen of polymyxin B still results in regrowth and selection of polymyxin-resistant cells.

Early Response of Antimicrobial Resistance and Virulence Genes Expression in Classical, Hypervirulent, and Hybrid hvKp-MDR Klebsiella pneumoniae on Antimicrobial Stress

Klebsiella pneumoniae is an increasingly important hospital pathogen. Classical K. pneumoniae (cKp) and hypervirulent K. pneumoniae (hvKp) are two distinct evolutionary genetic lines. The recently ongoing evolution of K. pneumoniae resulted in the generation of hybrid hvKP-MDR strains. K. pneumoniae distinct isolates (n = 70) belonged to 20 sequence types with the prevalence of ST395 (27.1%), ST23 (18.6%), ST147 (15.7%), and ST86 (7.1%), and 17 capsular types with the predominance of K2 (31.4%), K57 (18.6%), K64 (10.0%), K1 (5.7%) were isolated from patients of the Moscow neurosurgery ICU in 2014–2019. The rate of multi-drug resistant (MDR) and carbapenem-resistant phenotypes were 84.3% and 45.7%, respectively. Whole-genome sequencing of five selected strains belonging to cKp (ST395K47 and ST147K64), hvKp (ST86K2), and hvKp-MDR (ST23K1 and ST23K57) revealed blaSHV, blaTEM, blaCTX, blaOXA-48, and blaNDM beta-lactamase genes; acr, oqx, kpn, kde, and kex efflux genes; and K. pneumoniae virulence genes. Selective pressure of 100 mg/L ampicillin or 10 mg/L ceftriaxone induced changes of expression levels for named genes in the strains belonging to cKp, hvKp, and hybrid hvKp-MDR. Obtained results seem to be important for epidemiologists and clinicians for enhancing knowledge about hospital pathogens.

Analysis of Immune Escape Variants from Antibody-Based Therapeutics against COVID-19: A Systematic Review

The accelerated SARS-CoV-2 evolution under selective pressure by massive deployment of neutralizing antibody-based therapeutics is a concern with potentially severe implications for public health. We review here reports of documented immune escape after treatment with monoclonal antibodies and COVID-19-convalescent plasma (CCP). While the former is mainly associated with specific single amino acid mutations at residues within the receptor-binding domain (e.g., E484K/Q, Q493R, and S494P), a few cases of immune evasion after CCP were associated with recurrent deletions within the N-terminal domain of the spike protein (e.g., ΔHV69-70, ∆LGVY141-144 and ΔAL243-244). The continuous genomic monitoring of non-responders is needed to better understand immune escape frequencies and the fitness of emerging variants.