Host range and structural analysis of bat-origin RshSTT182/200 coronavirus binding to human ACE2 and its animal orthologs.

Bat-origin RshSTT182 and RshSTT200 coronaviruses (CoV) from Rhinolophus shameli in Southeast Asia (Cambodia) share 92.6% whole-genome identity with SARS-CoV-2 and show identical receptor-binding domains (RBDs). In this study, we determined the structure of the RshSTT182/200 receptor binding domain (RBD) in complex with human angiotensin-converting enzyme 2 (hACE2) and identified the key residues that influence receptor binding. The binding of the RshSTT182/200 RBD to ACE2 orthologs from 39 animal species, including 18 bat species, was used to evaluate its host range. The RshSTT182/200 RBD broadly recognized 21 of 39 ACE2 orthologs, although its binding affinities for the orthologs were weaker than those of the RBD of SARS-CoV-2. Furthermore, RshSTT182 pseudovirus could utilize human, fox, and Rhinolophus affinis ACE2 receptors for cell entry. Moreover, we found that SARS-CoV-2 induces cross-neutralizing antibodies against RshSTT182 pseudovirus. Taken together, these findings indicate that RshSTT182/200 can potentially infect susceptible animals, but requires further evolution to obtain strong interspecies transmission abilities like SARS-CoV-2.

Molecular Basis of Mink ACE2 Binding to SARS-CoV-2 and Its Mink-Derived Variants.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is transmitted between humans and minks, and some mutations in the spike (S) protein, especially in the receptor-binding domain (RBD), have been identified in mink-derived viruses. Here, we examined binding of the mink angiotensin-converting enzyme 2 (ACE2) receptor to mink-derived and important human-originating variants, and we demonstrated that most of the RBD variants increased the binding affinities to mink ACE2 (mkACE2). Cryo-electron microscopy structures of the mkACE2-RBD Y453F (with a Y-to-F change at position 453) and mkACE2-RBD F486L complexes helped identify the key residues that facilitate changes in mkACE2 binding affinity. Additionally, the data indicated that the Y453F and F486L mutations reduced the binding affinities to some human monoclonal antibodies, and human vaccinated sera efficiently prevented infection of human cells by pseudoviruses expressing Y453F, F486L, or N501T RBD. Our findings provide an important molecular mechanism for the rapid adaptation of SARS-CoV-2 in minks and highlight the potential influence of the main mink-originating variants for humans. IMPORTANCE Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a broad range of hosts. Mink-derived SARS-CoV-2 can transmit back to humans. There is an urgent need to understand the binding mechanism of mink-derived SARS-CoV-2 variants to mink receptor. In this study, we identified all mutations in the receptor-binding domain (RBD) of spike (S) protein from mink-derived SARS-CoV-2, and we demonstrated the enhanced binding affinity of mink angiotensin-converting enzyme 2 (ACE2) to most of the mink-derived RBD variants as well as important human-originating RBD variants. Cryo-electron microscopy structures revealed that the Y453F and F486L mutations enhanced the binding forces in the interaction interface. In addition, Y453F and F486L mutations reduced the binding affinities to some human monoclonal antibodies, and the SARS-CoV-2 pseudoviruses with Y453F, F486L, or N501T mutations were neutralized by human vaccinated sera. Therefore, our results provide valuable information for understanding the cross-species transmission mechanism of SARS-CoV-2.

Broader-species receptor binding and structural bases of Omicron SARS-CoV-2 to both mouse and palm-civet ACE2s.

The Omicron variant of SARS-CoV-2 carries multiple unusual mutations, particularly in the receptor-binding domain (RBD) of the spike (S) protein. Moreover, host-adapting mutations, such as residues 493, 498, and 501, were also observed in the Omicron RBD, which indicates that it is necessary to evaluate the interspecies transmission risk of the Omicron variant. Herein, we evaluated the interspecies recognition of the Omicron BA.1 and Delta RBDs by 27 ACE2 orthologs, including humans. We found that Omicron BA.1 expanded its receptor binding spectra to palm-civet, rodents, more bats (least horseshoe bat and greater horseshoe bat) and lesser hedgehog tenrec. Additionally, we determined the cryo-electron microscopy (cryo-EM) structure of the Omicron BA.1 S protein complexed with mouse ACE2 (mACE2) and the crystal structure of Omicron RBD complexed with palm-civet ACE2 (cvACE2). Several key residues for the host range have been identified. These results suggest that surveillance should be enhanced on the Omicron variant for its broader-species receptor binding to prevent spillover and expansion of reservoir hosts for a prolonged pandemic.

Atlas of currently available human neutralizing antibodies against SARS-CoV-2 and escape by Omicron sub-variants BA.1/BA.1.1/BA.2/BA.3.

SARS-CoV-2 Omicron variant has presented significant challenges to current antibodies and vaccines. Herein, we systematically compared the efficacy of 50 human monoclonal antibodies (mAbs), covering the seven identified epitope classes of the SARS-CoV-2 RBD, against Omicron sub-variants BA.1, BA.1.1, BA.2, and BA.3. Binding and pseudovirus-based neutralizing assays revealed that 37 of the 50 mAbs lost neutralizing activities, whereas the others displayed variably decreased activities against the four Omicron sub-variants. BA.2 was found to be more sensitive to RBD-5 antibodies than the other sub-variants. Furthermore, a quaternary complex structure of BA.1 RBD with three mAbs showing different neutralizing potencies against Omicron provided a basis for understanding the immune evasion of Omicron sub-variants and revealed the lack of G446S mutation accounting for the sensitivity of BA.2 to RBD-5 mAbs. Our results may guide the application of the available mAbs and facilitate the development of universal therapeutic antibodies and vaccines against COVID-19.

Efficacy Analysis of DSA-Guided Bronchial Arterial Chemoembolization Interventional Therapy in Patients with Middle-Advanced Primary Bronchial Lung Cancer.

Objective: To investigate the clinical efficacy of digital subtraction angiography- (DSA-) guided bronchial arterial chemoembolization (BACE) in patients with primary bronchial lung cancer. Methods: A total of 178 patients with primary intermediate and advanced bronchial lung cancer admitted to our hospital from February 2019 to March 2020 were selected as the subjects, and they were divided into control group (84 cases) and observation group (94 cases) according to the different chemotherapy regimens adopted by the patients. The control group was treated with traditional perfusion chemotherapy, and the observation group was treated with DSA-guided BACE interventional therapy, treated for 4 cycles, and followed up until the end of June 2021. The short-term clinical efficacy, hemoptysis remission, and incidence of adverse reactions were compared between the two groups. The mortality and recurrence rates between the two groups from treatment to the end of follow-up were counted, and the quality of life after treatment and 1 year after treatment were compared. Results: The short-term remission rate (73.40% vs. 58.33%), disease control rate (93.62% vs. 84.52%), hemoptysis remission rate (75.00% vs. 41.51%), the quality of life after chemotherapy cycle (90.86 ± 2.55 vs. 78.04 ± 2.21), and the quality of life after 1 year of follow-up (85.68 ± 2.23 vs. 70.27 ± 1.72) in the observation group were significantly higher than those in the control group, and the difference was statistically significant (P < 0.05). The incidence of adverse reactions (9.57% vs. 20.24%), mortality (10.64% vs. 21.43%), and recurrence rate (11.70% vs. 27.38%) during the follow-up period in the observation group were significantly lower than those in control group, and the differences were statistically significant (P < 0.05). Conclusion: DSA-guided BACE interventional therapy for patients with primary middle-advanced bronchial lung cancer has significant efficacy, which can not only reduce the mortality and recurrence rate of patients but also improve the quality of life of patients, with fewer adverse reactions and high safety, which is worthy of promotion.

Molecular basis of cross-species ACE2 interactions with SARS-CoV-2-like viruses of pangolin origin.

Pangolins have been suggested as potential reservoir of zoonotic viruses, including SARS-CoV-2 causing the global COVID-19 outbreak. Here, we study the binding of two SARS-CoV-2-like viruses isolated from pangolins, GX/P2V/2017 and GD/1/2019, to human angiotensin-converting enzyme 2 (hACE2), the receptor of SARS-CoV-2. We find that the spike protein receptor-binding domain (RBD) of pangolin CoVs binds to hACE2 as efficiently as the SARS-CoV-2 RBD in vitro. Furthermore, incorporation of pangolin CoV RBDs allows entry of pseudotyped VSV particles into hACE2-expressing cells. A screen for binding of pangolin CoV RBDs to ACE2 orthologs from various species suggests a broader host range than that of SARS-CoV-2. Additionally, cryo-EM structures of GX/P2V/2017 and GD/1/2019 RBDs in complex with hACE2 show their molecular binding in modes similar to SARS-CoV-2 RBD. Introducing the Q498H substitution found in pangolin CoVs into the SARS-CoV-2 RBD expands its binding capacity to ACE2 homologs of mouse, rat, and European hedgehog. These findings suggest that these two pangolin CoVs may infect humans, highlighting the necessity of further surveillance of pangolin CoVs.

Global Significant Changes in Formaldehyde (HCHO) Columns Observed From Space at the Early Stage of the COVID-19 Pandemic.

Satellite HCHO data are widely used as a reliable proxy of non-methane volatile organic compounds (NMVOCs) to constrain underlying emissions and chemistry. Here, we examine global significant changes in HCHO columns at the early stage of the COVID-19 pandemic (January-April 2020) compared with the same period in 2019 with observations from the TROPOspheric Monitoring Instrument (TROPOMI). HCHO columns decline (11.0%) in the Northern China Plain (NCP) because of a combination of meteorological impacts, lower HCHO yields as NO x emission plunges (by 36.0%), and reduced NMVOC emissions (by 15.0%) resulting from the lockdown. HCHO columns change near Beijing (+8.4%) due mainly to elevated hydroxyl radical as NO x emission decreases in a NO x -saturated regime. HCHO columns change in Australia (+17.5%), Northeastern Myanmar of Southeast Asia (+14.9%), Central Africa (+7.8%), and Central America (+18.9%), consistent with fire activities. Our work also points to other changes related to temperature and meteorological variations.