A Murine Model of Post-acute Neurological Sequelae Following SARS-CoV-2 Variant Infection (preprint)

Viral variant is one known risk factor associated with post-acute sequelae of COVID-19 (PASC), yet the pathogenesis is largely unknown. Here, we studied SARS-CoV-2 Delta variant-induced PASC in K18-hACE2 mice. The virus replicated productively, induced robust inflammatory responses in lung and brain tissues, and caused weight loss and mortality during the acute infection. Longitudinal behavior studies in surviving mice up to 4 months post-acute infection revealed persistent abnormalities in neuropsychiatric state and motor behaviors, while reflex and sensory functions recovered over time. Surviving mice showed no detectable viral RNA in the brain and minimal neuroinflammation post-acute infection. Transcriptome analysis revealed persistent activation of immune pathways, including humoral responses, complement, and phagocytosis, and reduced levels of genes associated with ataxia telangiectasia, impaired cognitive function and memory recall, and neuronal dysfunction and degeneration. Furthermore, surviving mice maintained potent T helper 1 prone cellular immune responses and high neutralizing antibodies against Delta and Omicron variants in the periphery for months post-acute infection. Overall, infection in K18-hACE2 mice recapitulates the persistent clinical symptoms reported in long COVID patients and may be useful for future assessment of the efficacy of vaccines and therapeutics against SARS-CoV-2 variants.

A single-dose of intranasal vaccination with a live-attenuated SARS-CoV-2 vaccine candidate promotes protective mucosal and systemic immunity (preprint)

An attenuated SARS-CoV-2 virus with modified viral transcriptional regulatory sequences and deletion of open-reading frames 3, 6, 7 and 8 ({triangleup}3678) was previously reported to protect hamsters from SARS-CoV-2 infection and transmission. Here we report that a single-dose intranasal vaccination of {triangleup}3678 protects K18-hACE2 mice from wild-type or variant SARS-CoV-2 challenge. Compared with wild-type virus infection, the {triangleup}3678 vaccination induces equivalent or higher levels of lung and systemic T cell, B cell, IgA, and IgG responses. The results suggest {triangleup}3678 as an attractive mucosal vaccine candidate to boost pulmonary immunity against SARS-CoV-2.

Molecular docking, DFT analysis, and dynamics simulation of natural bioactive compounds targeting ACE2 and TMPRSS2 dual binding sites of spike protein of SARS CoV-2.

The scientific community is continuously working to discover drug candidates against potential targets of SARS-CoV-2, but effective treatment has not been discovered yet. The virus enters the host cell through molecular interaction with its enzymatic receptors i.e., ACE2 and TMPRSS2, which, if, synergistically blocked can lead to the development of novel drug candidates. In this study, 1503 natural bioactive compounds were screened by HTVS, followed by SP and XP docking using Schrodinger Maestro software. Bio-0357 (protozide) and Bio-597 (chrysin) were selected for dynamics simulation based on synergistic binding affinity on S1 (docking score -9.642 and -8.78 kcal/mol) and S2 domains (-5.83 and -5.3 kcal/mol), and the RMSD, RMSF and Rg analyses showed stable interaction. The DFT analysis showed that the adsorption of protozide/chrysin, the band gap of protozide/chrysin-F/G reduced significantly. From SERS, results, it can be concluded that QDs nanocluster will act as a sensor for the detection of drugs. The docking study showed Bio-0357 and Bio-0597 bind to both S1 and S2 domains through stable molecular interactions, which can lead to the discovery of new drug candidates to prevent the entry of SARS-CoV-2. This in-silico study may be helpful to researchers for further in vitro experimental validation and development of new therapy for COVID-19.