SARS-CoV-2 variants of concern (VOC) B.1.1.7 (alpha) and B.1.351 (beta) show increased transmissibility and enhanced antibody neutralization resistance. Here we demonstrate in K18-hACE2 transgenic mice that B.1.1.7 and B.1.351 are 100-fold more lethal than the original SARS-CoV-2 bearing 614D. B.1.1.7 and B.1.351 cause more severe organ lesions in K18-hACE2 mice than early SARS-CoV-2 strains bearing 614D or 614G, with B.1.1.7 and B.1.351 infection resulting in distinct tissue-specific cytokine signatures, significant D-dimer depositions in vital organs and less pulmonary hypoxia signaling before death. However, K18-hACE2 mice with prior infection of early SARS-CoV-2 strains or intramuscular immunization of viral spike or receptor binding domain are resistant to the lethal reinfection of B.1.1.7 or B.1.351, despite having reduced neutralization titers against these VOC than early strains. Our results thus distinguish pathogenic patterns in K18-hACE2 mice caused by B.1.1.7 and B.1.351 infection from those induced by early SARS-CoV-2 strains, and help inform potential medical interventions for combating COVID-19.

Our results suggest that repeated H3 exposures imprinted not only antibody quantity but also antibody quality. The "naive" ferret model currently used for vaccine strain selection does not recapitulate the complexity of human preexisting immunity. Vaccine strains identified hereby may not provide coverage sufficient for those who were frequently infected and/or vaccinated, leading to the reduced VE observed.

No abstract

Spike-mediated entry of SARS-CoV-2 into human airway epithelial cells is an attractive therapeutic target for COVID-19. In addition to protein receptors, the SARS-CoV-2 spike (S) protein also interacts with heparan sulfate, a negatively charged glycosaminoglycan (GAG) attached to certain membrane proteins on the cell surface. This interaction facilitates the engagement of spike with a downstream receptor to promote viral entry. Here, we show that Mitoxantrone, an FDA-approved topoisomerase inhibitor, targets a heparan sulfate-spike complex to compromise the fusogenic function of spike in viral entry. As a single agent, Mitoxantrone inhibits the infection of an authentic SARS-CoV-2 strain in a cell-based model and in human lung EpiAirway 3D tissues. Gene expression profiling supports the plasma membrane as a major target of Mitoxantrone but also underscores an undesired activity targeting nucleosome dynamics. We propose that Mitoxantrone analogs bearing similar heparan sulfate-binding activities but with reduced affinity for DNA topoisomerases may offer an alternative therapy to overcome breakthrough infections in the post-vaccine era.

SARS-CoV-2 continues to circulate globally resulting in emergence of several variants of concern (VOC), including B.1.1.7 and B.1.351 that show increased transmissibility and enhanced resistance to antibody neutralization. In a K18-hACE2 transgenic mouse model, we demonstrate that Both B.1.1.7 and B.1.351 are 100 times more lethal than the original SARS-CoV-2 bearing 614D. Mice infected with B.1.1.7 and B.1.351 exhibited more severe lesions in internal organs than those infected with early SARS-CoV-2 strains bearing 614D or 614G. Infection of B.1.1.7 and B.1.351 also results in distinct tissue-specific cytokine signatures, significant D-dimer depositions in vital organs and less pulmonary hypoxia signaling before death as compared to the mice infected with early SARS-CoV-2 strains. However, K18-hACE2 mice with the pre-existing immunity from prior infection or immunization were resistant to the lethal reinfection of B.1.1.7 or B.1.351, despite having reduced neutralization titers against these VOC. Our study reveals distinguishing pathogenic patterns of B.1.1.7 and B.1.351 variants from those early SARS-CoV-2 strains in K18-hACE2 mice, which will help to inform potential medical interventions for combating COVID-19.

No abstract

Background The influenza activity of the 2019/20 season remained high and widespread in the US with type B viruses predominating the early season. The majority of B viruses characterized belonged to B/Victoria (B/Vic) lineage and contained a triple deletion of amino acid (aa) 162-164 in hemagglutinin (3DEL). These 3DEL viruses are antigenically distinct from B/Colorado/06/2017 (CO/06) – the B/Vic vaccine component of the 2018/19 and 2019/20 seasons representing the viruses with a double deletion of aa 162-163 in hemagglutinin (2DEL). Methods We performed molecular characterization and phylogenetic analysis of circulating B/Vic viruses. We also conducted hemagglutination inhibition (HAI) assay using archived human post-vaccination sera collected from healthy subjects administered with different types of 2018/19 or 2019/20 seasonal vaccines. Their HAI cross-reactivity to representative 3DEL viruses were analyzed. Results The CO/06-specific human post-vaccination sera, after being adjusted for vaccine type, had significantly reduced HAI cross-reactivity toward representative 3DEL viruses, especially the 136E+150K subgroup. The geometric mean titers against 3DEL viruses containing 136E+150K mutations were 1.6-fold lower in all population (p=0.051) and 1.9-fold lower in adults (p=0.016) as compared to those against the 136E+150N viruses. Conclusions Our results indicate that post-vaccination antibodies induced by the B/Vic vaccine component of the 2019/20 influenza season had reduced HAI cross-reactivity toward predominant 3DEL viruses in the US. A close monitoring of 3DEL 136E+150K subgroup is warranted should this subgroup return and predominate the 2020/21 influenza season.

A rodent-transmitted enveloped lymphocytic choriomeningitis virus (LCMV) is an RNA virus causing persistent infection. During persistent infection, a unique strain MX of LCMV does not yield infectious virions, therefore it is not able to use a receptor for its dissemination, and spreads by cell-to-cell contacts. Virus can be transported to the neighboring cell by di erent cellular structures such as tunneling nanotubes or cytonemes. Using q-PCR, immuno uorescence, siRNA and western blot, we show that keratin 1 (K1) is essential for the persistent infection caused by LCMV strain MX, and its absence very e ectively slows down the course of infection. In contrast, other LCMV strains, namely Clone 13 and Armstrong, which produce expression of K1, desmosomes in cells expressing K1 (42-MG-BA) but not in cells without K1 expression (NIH/3T3). We conclude that the presence of the virus enhances the K1 expression, while the presence of K1 protein potentiates the viral spread in persistently infected cells.