RESUMO
The current study was initiated when our specific pathogen-free laboratory toms developed unexpectedly high levels of cross-reactive antibodies to human SARS-CoV-2 (SCoV2) receptor binding domain (RBD) upon mating with feline coronavirus (FCoV)-positive queens. Multi-sequence alignment analyses of SCoV2 Wuhan RBD and four strains each from FCoV serotypes 1 and 2 (FCoV1, FCoV2) demonstrated amino acid sequence identity of 11.5% and similarity of 31.8% with FCoV1 RBD, as well as 12.2% identity and 36.5% similarity for FCoV2 RBD. The sera from all three toms and three mated queens cross-reacted with SCoV2 RBD and reacted with FCoV1 RBD and FCoV2 spike-2, nucleocapsid, and membrane proteins of FCoV2 whole-virus, but not with FCoV2 RBD. Additionally, the plasma from all six FCoV2-inoculated laboratory cats reacted with FCoV2 and SCoV2 RBDs, but not with FCoV1 RBD. In another study, eight group-housed laboratory cats from a different lineage had a range of serum cross-reactivity to SCoV2 RBD even 15 months later. Such cross-reactivity was also observed in FCoV1-positive group-housed pet cats. The SCoV2 RBD at a high non-toxic dose and FCoV2 RBD at a 60-400-fold lower dose blocked the in vitro FCoV2 infection of the feline cells, demonstrating their close structural conformations essential as vaccine immunogens. Furthermore, such cross-reactivity to SCoV2 RBD was also detected by the peripheral blood mononuclear cells of both transient and chronically FCoV1-infected cats. Overall, the cross-reactivity with SCoV2 RBD by the sera from both serotypes of FCoV-infected cats also suggests that the cross-reactive epitope(s) on FCoV1 and FCoV2 RBDs may be similar to those of SCoV2 RBD and provides essential insights to developing a pan-CoV vaccine. Author SummaryTo date, there are no reports on the sera from feline coronavirus (FCoV)-infected cats cross-reacting with either SARS-CoV-1 or SARS-CoV2 (SCoV2) receptor binding domains (RBDs). This report describes the presence of cross-reactive antibodies to SCoV2 RBD in the sera of FCoV-infected laboratory cats, even though SCoV2 RBD and each FCoV serotype (FCoV1, FCoV2) RBD had minimal sequence similarity. However, this observation of serum cross-reactivity to SCoV2 RBD was confirmed by more stringent antibody-based assays and viral assays. Furthermore, both serotypes of FCoV-infected cats, including FCoV1-infected pet cats, produced the cross-reactive antibodies, and such cross-reactivity to SCoV2 RBD was also detected, most likely, by the T cells in peripheral blood mononuclear cells of both transient and chronically FCoV1-infected cats. Since SCoV2 RBD is essential component for current vaccines against COVID-19 disease, our findings should provide essential insights to developing a pan-coronavirus vaccine that induces full-scale immunity to completely prevent SCoV2 infection in humans and pet animals.
RESUMO
To elucidate the host genetic loci affecting severity of SARS-CoV-2 infection, or Coronavirus disease 2019 (COVID-19), is an emerging issue in the face of the current devastating pandemic. Here, we report a genome-wide association study (GWAS) of COVID-19 in a Japanese population led by the Japan COVID-19 Task Force, as one of the initial discovery GWAS studies performed on a non-European population. Enrolling a total of 2,393 cases and 3,289 controls, we not only replicated previously reported COVID-19 risk variants (e.g., LZTFL1, FOXP4, ABO, and IFNAR2), but also found a variant on 5q35 (rs60200309-A at DOCK2) that was associated with severe COVID-19 in younger (<65 years of age) patients with a genome-wide significant p-value of 1.2 x 10-8 (odds ratio = 2.01, 95% confidence interval = 1.58-2.55). This risk allele was prevalent in East Asians, including Japanese (minor allele frequency [MAF] = 0.097), but rarely found in Europeans. Cross-population Mendelian randomization analysis made a causal inference of a number of complex human traits on COVID-19. In particular, obesity had a significant impact on severe COVID-19. The presence of the population-specific risk allele underscores the need of non-European studies of COVID-19 host genetics.
RESUMO
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes the disease COVID-19 can lead to serious symptoms, such as severe pneumonia, in the elderly and those with underlying medical conditions. While vaccines are now available, they do not work for everyone and therapeutic drugs are still needed particularly for treating life-threatening conditions. Here, we showed nasal delivery of a new, unmodified camelid single-domain antibody (VHH), termed K-874A, effectively inhibited SARS-CoV-2 titers in infected lungs of Syrian hamsters without causing weight loss and cytokine induction. In vitro studies demonstrated that K-874A neutralized SARS-CoV-2 in both VeroE6/TMPRSS2 and human lung-derived alveolar organoid cells. Unlike other drug candidates, K-874A blocks viral membrane fusion rather than viral attachment. Cryo-electron microscopy revealed K-874A bound between the receptor binding domain and N-terminal domain of the virus S protein. Further, infected cells treated with K-874A produced fewer virus progeny that were less infective. We propose that direct administration of K-874A to the lung via a nebulizer could be a new treatment for preventing the reinfection of amplified virus in COVID-19 patients. Author summaryVaccines for COVID-19 are now available but therapeutic drugs are still needed to treat life-threatening cases and those who cannot be vaccinated. We discovered a new heavy-chain single-domain antibody that can effectively neutralize the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes COVID-19. Unlike other drug candidates, which prevent the virus from attaching to the receptor on the host cell, this new antibody acts by blocking the virus membrane from fusing with the host cell membrane. We studied the behavior of the new antibody in vitro using VeroE6/TMPRSS2 cells and human lung organoids. When delivered through the nose to infected Syrian hamsters, we found that this antibody could prevent the typical symptoms caused by SARS-CoV-2. Our results are significant because delivering simple drugs directly to infected lungs using a nebulizer could increase the potency of the drugs while reducing the risk of immune reaction that could occur if the drugs escape or are delivered through the blood stream.
