Virological characteristics of the SARS-CoV-2 Omicron BA.2.75

SARS-CoV-2 Omicron BA.2.75 emerged in May 2022. BA.2.75 is a BA.2 descendant but is phylogenetically different from BA.5, the currently predominant BA.2 descendant. Here, we showed that the effective reproduction number of BA.2.75 is greater than that of BA.5. While the sensitivity of BA.2.75 to vaccination- and BA.1/2 breakthrough infection-induced humoral immunity was comparable to that of BA.2, the immunogenicity of BA.2.75 was different from that of BA.2 and BA.5. Three clinically-available antiviral drugs were effective against BA.2.75. BA.2.75 spike exhibited a profound higher affinity to human ACE2 than BA.2 and BA.5 spikes. The fusogenicity, growth efficiency in human alveolar epithelial cells, and intrinsic pathogenicity in hamsters of BA.2.75 were comparable to those of BA.5 but were greater than those of BA.2. Our multiscale investigations suggest that BA.2.75 acquired virological properties independently of BA.5, and the potential risk of BA.2.75 to global health is greater than that of BA.5.

SARS-CoV-2 spike S375F mutation characterizes the Omicron BA.1 variant

Recent studies have revealed the unique virological characteristics of Omicron, the newest SARS-CoV-2 variant of concern, such as pronounced resistance to vaccine-induced neutralizing antibodies, less efficient cleavage of the spike protein, and poor fusogenicity. However, it remains unclear which mutation(s) in the spike protein determine the virological characteristics of Omicron. Here, we show that the representative characteristics of the Omicron spike are determined by its receptor-binding domain. Interestingly, the molecular phylogenetic analysis revealed that the acquisition of the spike S375F mutation was closely associated with the explosive spread of Omicron in the human population. We further elucidate that the F375 residue forms an interprotomer pi-pi interaction with the H505 residue in another protomer in the spike trimer, which confers the attenuated spike cleavage efficiency and fusogenicity of Omicron. Our data shed light on the evolutionary events underlying Omicron emergence at the molecular level. HighlightsO_LIOmicron spike receptor binding domain determines virological characteristics C_LIO_LISpike S375F mutation results in the poor spike cleavage and fusogenicity in Omicron C_LIO_LIAcquisition of the spike S375F mutation triggered the explosive spread of Omicron C_LIO_LIF375-H505-mediated {pi}-{pi} interaction in the spike determines the phenotype of Omicron C_LI

Virological characteristics of SARS-CoV-2 BA.2 variant

Soon after the emergence and global spread of a new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron lineage, BA.1 (ref1, 2), another Omicron lineage, BA.2, has initiated outcompeting BA.1. Statistical analysis shows that the effective reproduction number of BA.2 is 1.4-fold higher than that of BA.1. Neutralisation experiments show that the vaccine-induced humoral immunity fails to function against BA.2 like BA.1, and notably, the antigenicity of BA.2 is different from BA.1. Cell culture experiments show that BA.2 is more replicative in human nasal epithelial cells and more fusogenic than BA.1. Furthermore, infection experiments using hamsters show that BA.2 is more pathogenic than BA.1. Our multiscale investigations suggest that the risk of BA.2 for global health is potentially higher than that of BA.1.

SARS-CoV-2 B.1.617 emergence and sensitivity to vaccine-elicited antibodies

The SARS-CoV-2 B.1.617.2 (Delta) variant was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha). In vitro, B.1.617.2 is 6-fold less sensitive to serum neutralising antibodies from recovered individuals, and 8-fold less sensitive to vaccine-elicited antibodies as compared to wild type Wuhan-1 bearing D614G. Serum neutralising titres against B.1.617.2 were lower in ChAdOx-1 versus BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies against the receptor binding domain (RBD) and N-terminal domain (NTD), in particular to the clinically approved bamlavinimab and imdevimab monoclonal antibodies. B.1.617.2 demonstrated higher replication efficiency in both airway organoid and human airway epithelial systems as compared to B.1.1.7, associated with B.1.617.2 spike being in a predominantly cleaved state compared to B.1.1.7. Additionally we observed that B.1.617.2 had higher replication and spike mediated entry as compared to B.1.617.1, potentially explaining B.1.617.2 dominance. In an analysis of over 130 SARS-CoV-2 infected healthcare workers across three centres in India during a period of mixed lineage circulation, we observed substantially reduced ChAdOx-1 vaccine efficacy against B.1.617.2 relative to non-B.1.617.2. Compromised vaccine efficacy against the highly fit and immune evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era.

SARS-CoV-2 ORF3b is a potent interferon antagonist whose activity is further increased by a naturally occurring elongation variant

One of the features distinguishing SARS-CoV-2 from its more pathogenic counterpart SARS-CoV is the presence of premature stop codons in its ORF3b gene. Here, we show that SARS-CoV-2 ORF3b is a potent interferon antagonist, suppressing the induction of type I interferon more efficiently than its SARS-CoV ortholog. Phylogenetic analyses and functional assays revealed that SARS-CoV-2-related viruses from bats and pangolins also encode truncated ORF3b gene products with strong anti-interferon activity. Furthermore, analyses of more than 15,000 SARS-CoV-2 sequences identified a natural variant, in which a longer ORF3b reading frame was reconstituted. This variant was isolated from two patients with severe disease and further increased the ability of ORF3b to suppress interferon induction. Thus, our findings not only help to explain the poor interferon response in COVID-19 patients, but also describe a possibility of the emergence of natural SARS-CoV-2 quasispecies with extended ORF3b that may exacerbate COVID-19 symptoms. HighlightsO_LIORF3b of SARS-CoV-2 and related bat and pangolin viruses is a potent IFN antagonist C_LIO_LISARS-CoV-2 ORF3b suppresses IFN induction more efficiently than SARS-CoV ortholog C_LIO_LIThe anti-IFN activity of ORF3b depends on the length of its C-terminus C_LIO_LIAn ORF3b with increased IFN antagonism was isolated from two severe COVID-19 cases C_LI

The effects of long-term low intensity aerobic training and the cessation of training on the serum lipid and lipoprotein concentrations in older patients / 体力科学

The effects of long-term low intensity aerobic training and detraining on serum lipid and lipoprotein concentrations were examined in 10 older patients suffering from hypertension and coronary heart disease. Training was carried out for 30 minutes 3-6 times a week for a mean of 17.1 months using a treadmill with the intensity level set at the blood lactate threshold (LT) .<BR>Following this training both LT and the serum HDL-c increased significantly (P<0.001, P<0.01, respectively) after 6 months while the TC/HDL-c ratio decreased singificantly (P<0.001) only after 1 month and stabilized at a steady favorable value throughout the remainder of the study. The serum TC, TG and LDL-c did not change significantly by the end of the training period. There was a significant negative correlation between the initial TC/ HDL-c level and the change in the TC/HDL-c level at 1 month after training (r=-0.71, P< 0.02) . Only 1 month after the detraining the HDL-c decreased significantly while the TC/HDL-c increased in comparison with the final training value (P<0.001, P<0.05, respectively) and then returned to the pre-training levels.<BR>In conclusion, these results suggest that long-term low intensity aerobic training could improve the profile of the serum lipid and lipoprotein concentrations in older patients. However, these results might depend on such factors as a low HDL-c level, a high TG level, the length of the exercise period, or the frequency per week and the age of the patient, while the cessation of such training quickly returned the profile to that of pre-training levels.

The effects of long-term mild aerobic training at lactate threshold and its cessation on blood pressure in older hypertensive patients under medication / 体力科学

After a general clinical observation period of 3 months, men and women from 66-82 yr. of age with hypertension (n=10) were studied to assess the effects of long-term mild aerobic training and detraining on their blood pressure. Ten patients agreed to take part in aerobic training using a treadmill with the intensity at the lactate threshold (LT) for 30minutes 3-6 times a week for mean 17.1±9.8 months while the time course of changes in the resting blood pressure was monitored.<BR>Following the training period the LT increased significantly by the end of the training period (P<0.001) . After 3months of training both the systolic and diastolic blood pressure decreased significantly (P<0.05, respectively) and both blood pressures stabilized at a significantly lower level throughout the remainder of the study. The mean blood pressure decreased significantly for 9 months (P<0.05) . Finally, the systolic, mean and diastolic blood pressure were found to have decreased significantly, by 9, 5, 11 mmHg, respectively by the end of the training period. (SBP and MBP: P<0.05, DBP: P<0.01, respectively) . One month after the training ended the systolic, mean and diastolic blood pressure all increased significantly (SBP and MBP: P<0.001, DBP: P<0.01, respectively) and approached the initial pre-training levels.<BR>In conclusion, the antihypertensive effect of mild aerobic training at the LT was confirmed for older patients taking antihypertensive medications. However, the cessation of such training resulted in a quick return to pre-training levels.

Effects of 9 months mild aerobic training on serum lipids and lipoprotein concentrations in older than 65 years men and women with hypertension / 体力科学

In the present study, we instiuted a long-term mild aerobic training program for older patients with hypertension and investigated its effects on serum lipids and lipoprotein concentrations. The intensity of exercise in mild aerobic training was adjusted to the lactate threshold level (LT), i, e., the level at which the blood lactate concentration began to increase nonlinearly with increasing work intensity. The training group (15 patients, 7 men and 8 women) and control group (15 patients, 7 men and 8 women) were 65-83 year-old patients with mean ages of 75.5±5.6 and 73.7±4.4 (mean±S.D), respectively, who had never exercised regularly up to that time. Treadmill training at the LT was carried out for 30min/day 3-6 times/week and continued for 9 months under the supervision of exercise physiology specialists.<BR>In the training group, LT speed significantly increased from 3.43±0.65 km/h to 3.73±0.67 km/h (9.0%) in men, and from 2.75±0.57 km/h to 3.05±0.61 km/h (11.8%) in women (both P<0.05) . HDL-c was significantly increased 9 months after training both in men (19.2%) and women (20.9%) (both P<0.05) . The TC/HDL-c ratio, an atherogenetic index, was significantly (P<0.05) decreased by training in women but not in men. The other serum lipid and lipoprotein profiles were unchanged in both men and women. In the control group, all serum lipid and lipoprotein profiles were unchanged in both men and women.<BR>The HDL-c level in the training group was higher than in the control group after 9 months in both men and women (both P<0.02) . The TC/HDL-c ratio in the training group was lower only in women (P<0.02) . There were no significant differences in other values between the training group and the control group in either men or women.<BR>These results suggest that mild aerobic training at the LT is an effective method of improving the level of serum HDL-c, the TC/HDL-c ratio and aerobic capacity in the older patients with hypertension.