A Novel Conserved Linear Neutralizing Epitope on the Receptor-Binding Domain of the SARS-CoV-2 Spike Protein.

The continuous emergence of new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made it challenging to develop broad-spectrum prophylactic vaccines and therapeutic antibodies. Here, we have identified a broad-spectrum neutralizing antibody and its highly conserved epitope in the receptor-binding domain (RBD) of the spike protein (S) S1 subunit of SARS-CoV-2. First, nine monoclonal antibodies (MAbs) against the RBD or S1 were generated; of these, one RBD-specific MAb, 22.9-1, was selected for its broad RBD-binding abilities and neutralizing activities against SARS-CoV-2 variants. An epitope of 22.9-1 was fine-mapped with overlapping and truncated peptide fusion proteins. The core sequence of the epitope, 405D(N)EVR(S)QIAPGQ414, was identified on the internal surface of the up-state RBD. The epitope was conserved in nearly all variants of concern of SARS-CoV-2. MAb 22.9-1 and its novel epitope could be beneficial for research on broad-spectrum prophylactic vaccines and therapeutic antibody drugs. IMPORTANCE The continuous emergence of new variants of SARS-CoV-2 has caused great challenge in vaccine design and therapeutic antibody development. In this study, we selected a broad-spectrum neutralizing mouse monoclonal antibody which recognized a conserved linear B-cell epitope located on the internal surface of RBD. This MAb could neutralize all variants until now. The epitope was conserved in all variants. This work provides new insights in developing broad-spectrum prophylactic vaccines and therapeutic antibodies.

Cognitive decline among older adults with heart diseases before and during the COVID-19 pandemic: A longitudinal cohort study.

Background: Little is known about the impact induced by the COVID-19 pandemic on the cognitive function of older adults with heart diseases. This study aimed to examine whether older adults with heart diseases suffered larger cognitive deterioration during the COVID-19 pandemic. Methods: This study leveraged longitudinal data from the Health and Retirement Study (HRS), a nationally representative U.S. aging cohort with objective cognitive assessments measured before and during the pandemic. The interval from HRS waves 13 to 14 (April 2016 to June 2019) was defined as the pre-pandemic period to control the pre-existed cognitive difference between participants with and without heart diseases, and the interval from waves 14 to 15 (June 2019 to June 2021) was defined as the pandemic period. The HRS wave 14 survey was considered the baseline. The heart disease status was defined by a self-reported diagnosis. Linear mixed models were performed to evaluate and compare the cognitive differences during different periods. Results: A total of 9,304 participants (women: 5,655, 60.8%; mean age: 65.8 ± 10.8 years) were included, and 2,119 (22.8%) had heart diseases. During the pre-pandemic period, there was no significant difference (-0.03, 95% CI: -0.22 to 0.15, P = 0.716) in the changes in global cognitive scores between participants with and without heart disease. During the pandemic period, a larger decreased change in the global cognitive score was observed in the heart disease group compared with the non-heart disease group (-0.37, 95% CI: -0.55 to -0.19, P < 0.001). An enlarged difference in global cognitive score was observed during the pandemic period (-0.33, 95% CI: -0.65 to -0.02, P = 0.036). Conclusion: The findings demonstrated that the population with heart diseases suffered more cognitive decline related to the pandemic, underscoring the necessity to provide immediate cognitive monitoring and interventions for the population with heart diseases.

Sex differences in changes of depressive symptoms among older adults before and during the COVID-19 pandemic: evidence from two longitudinal cohorts.

BACKGROUND: Major concerns about the adverse mental health impact of the rapidly spread COVID-19 pandemic have been raised. Previous studies on changes of depressive symptoms during the COVID-19 pandemic have yielded inconsistent results regarding the sex differences. Since women have higher depressive symptoms even without the pandemic, it is essential to consider the pre-existing change of depressive symptoms of a similar period to discern the effect of the pandemic on depression. This study aimed to evaluate sex differences in depressive symptoms before and during the pandemic. METHODS: Data from the Health and Retirement Study (HRS; waves 13 to 15) and the English Longitudinal Study of Ageing (ELSA; wave 8 to COVID-19 wave 2) were analyzed. Depressive symptoms were assessed by the 8-item Center for Epidemiological Studies Depression (CES-D) scale. According to the time of COVID-19 outbreak in the US and the UK, the intervals from waves 13 to 14 surveys of the HRS and from waves 8 to 9 surveys of the ELSA were employed as pre-pandemic periods to control for the pre-existing depressive symptoms, respectively. Changes of CES-D scores during the pre-pandemic and pandemic periods were assessed by linear mixed models. RESULTS: Nine thousand, seven hundred thirty-seven participants (mean age: 66.7 ± 10.7 years) from the HRS and 5,098 participants (mean age: 68.7 ± 10.0 years) from the ELSA were included. CES-D scores among women were significantly higher than those among men at all waves in both cohorts. During the pre-pandemic period, no significant sex difference on changes of CES-D scores was detected in either the HRS or the ELSA. During the pandemic period, CES-D scores were increased in both men and women and the sex differences in CES-D increments of the two cohorts were both significant. Enlarged sex differences were demonstrated in increments of CES-D scores during the pandemic period. CONCLUSIONS: Our results suggest women suffered from worse depressive symptoms in response to the pandemic, although the changes of depression were similar between men and women before the pandemic. These findings underscore the necessity to support the vulnerable populations, especially women, to manage the distress brought by the pandemic and maintain optimal mental health status.

Cognitive Decline Before and During COVID-19 Pandemic Among Older People With Multimorbidity: A Longitudinal Study.

OBJECTIVE: To investigate whether older people living with multimorbidity would suffer an accelerated decline in cognition during the COVID-19 pandemic, compared with prepandemic data. DESIGN: A 5-year cohort conducting surveys from year 2016 to 2021, with 2016 to 2019 as the control period and 2019 to 2021 the pandemic period. SETTING AND PARTICIPANTS: In total, 9304 cognitively healthy older participants age ≥50 years were included from the Health and Retirement Study (HRS). METHODS: Multimorbidity was defined as the concurrent presence of 2 or more chronic diseases. A global cognition z score was calculated using memory (immediate and delayed word recall tests) and executive function (counting backwards and the serial sevens tests). Incident dementia was defined using either the reported physician diagnosis or an alternative approach based on cognition summary score. Linear mixed models were used to assess longitudinal changes, while modified Poisson regression models were used to analyze the risk of incident dementia. RESULTS: Of the 9304 participants included, 3649 (39.2%) were men, with a mean age of 65.8 ± 10.8 years. Participants with multimorbidity (n = 4375) suffered accelerated declines of 0.08 standard deviation (95% confidence interval 0.03, 0.13, P = .003) in global cognition and an elevated dementia risk (risk ratio 1.66, 95% confidence 1.05 to 2.61, P = .029), compared with individuals without morbidity (n = 1818) during the pandemic period. After further adjusting sociodemographic characteristics and prepandemic cognitive measurements, these differences remained evident. In contrast, no significant differences in cognitive declines were observed during the control period. CONCLUSIONS AND IMPLICATIONS: During the COVID-19 pandemic, older people with multimorbidity suffered an accelerated decline in cognition and elevated incident dementia risk, while no evident differences in cognitive decline rates were observed before the pandemic. Measures targeting vulnerable older people with multimorbidity could be significant for assisting these individuals to tackle neurocognitive challenges during the pandemic.

Impact on Mental Well-Being and Resilience of Patients with Multiple Chronic Conditions in Different Periods during the Coronavirus Disease 2019 Outbreak in Taiwan.

Concerns over the coronavirus disease 2019 (COVID-19) pandemic and control measures have affected the routine outpatient visits of individuals with comorbidities and their mental well-being. From October 2019 to August 2020, this cross-sectional study enrolled 135 patients who sought medical attention at a medical center in Taiwan. This period covered the early (October to December 2019), peak (January to April 2020), and late (May to August 2020) periods of the COVID-19 outbreak in Taiwan. The demographic data, social support data, activities of daily living (ADL), resilience scale scores, and mental well-being scale scores of the participants were compared. There were no statistically significant differences in the participation rate, demographic data, and social support data between the three periods. The correlation analysis confirmed significant negative relationships between the number of COVID-19 cases and outpatient department visits per month (r = -0.764, p < 0.001), emergency department visits per month (r = -0.023, p < 0.001), ADL (r = -0.257, p = 0.03), resilience scale (r = -0.390, p < 0.001), and mental well-being scale (r = -0.475, p < 0.001). In conclusion, the severity of the COVID-19 outbreak in Taiwan was associated with declines in the ADL, mental well-being, and resilience of patients who sought medical attention.

Both Underweight and Obesity Are Associated With an Increased Risk of Coronavirus Disease 2019 (COVID-19) Severity.

Introduction: As coronavirus Disease 2019 (COVID-19) has evolved into a global pandemic, increasing numbers of reports have linked obesity to more severe COVID-19 illness and death. However, almost all the studies focused on an increased risk of mortality or intensive care unit (ICU) admission among hospitalized obese patients with COVID-19. Is obesity also associated with the incidence of acute lung injury (ALI) in the patients with COVID-19? How about underweight patients? The answer is lacking. Therefore, our following research will answer the above two questions. Methods: We collected and analyzed epidemiologic, demographic, clinical, and laboratory data from 193 confirmed cases of COVID-19 at Union Hospital, Tongji Medical College, Huazhong University of Science and Technology in Wuhan, China, between January 1, 2020, and March 13, 2020. They were followed up until April 15, 2020. Underweight was defined by body mass index (BMI) lower than 18.5 kg/m2, normal weight by 18.5-23.9 kg/m2, overweight by 24.0-27.9 kg/m2, and obesity as ≥28 kg/m2. Results: Among these patients, 5.70% were underweight, 58.03% were normal weight, 27.98% were overweight, and 8.29% were obese. Underweight patients were more likely to have a headache (P = 0.029). Obese patients were more likely than other groups to experience a decline in lymphocyte counts (P = 0.038), an increase in C-reactive protein (CRP; P = 0.023), bilateral multiple mottling, and ground glass opacity in the lungs (P = 0.007). Besides, the proportion of patients receiving human immunoglobulin + systematic corticosteroids treatment is the highest among the obese group compared with other BMI groups. After adjusting for potential confounders, underweight patients had a 6.483-fold higher (P = 0.012), and obese patients showed a 5.965-fold higher odds for developing ALI than normal-weight patients (P = 0.022). In addition, underweight patients were 3.255 times more likely than normal-weight patients to develop secondary infections (P = 0.041). Conclusions: Our study showed that both underweight and obese patients with COVID-19 tend to develop ALI compared with normal-weight patients. Underweight patients were more likely to develop a secondary infection than other patients.

SARS-CoV-2 NSP12 Protein Is Not an Interferon-ß Antagonist.

The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is bringing an unprecedented health crisis to the world. To date, our understanding of the interaction between SARS-CoV-2 and host innate immunity is still limited. Previous studies reported that SARS-CoV-2 nonstructural protein 12 (NSP12) was able to suppress interferon-ß (IFN-ß) activation in IFN-ß promoter luciferase reporter assays, which provided insights into the pathogenesis of COVID-19. In this study, we demonstrated that IFN-ß promoter-mediated luciferase activity was reduced during coexpression of NSP12. However, we could show NSP12 did not affect IRF3 or NF-κB activation. Moreover, IFN-ß production induced by Sendai virus (SeV) infection or other stimulus was not affected by NSP12 at mRNA or protein level. Additionally, the type I IFN signaling pathway was not affected by NSP12, as demonstrated by the expression of interferon-stimulated genes (ISGs). Further experiments revealed that different experiment systems, including protein tags and plasmid backbones, could affect the readouts of IFN-ß promoter luciferase assays. In conclusion, unlike as previously reported, our study showed SARS-CoV-2 NSP12 protein is not an IFN-ß antagonist. It also rings the alarm on the general usage of luciferase reporter assays in studying SARS-CoV-2. IMPORTANCE Previous studies investigated the interaction between SARS-CoV-2 viral proteins and interferon signaling and proposed that several SARS-CoV-2 viral proteins, including NSP12, could suppress IFN-ß activation. However, most of these results were generated from IFN-ß promoter luciferase reporter assay and have not been validated functionally. In our study, we found that, although NSP12 could suppress IFN-ß promoter luciferase activity, it showed no inhibitory effect on IFN-ß production or its downstream signaling. Further study revealed that contradictory results could be generated from different experiment systems. On one hand, we demonstrated that SARS-CoV-2 NSP12 could not suppress IFN-ß signaling. On the other hand, our study suggests that caution needs to be taken with the interpretation of SARS-CoV-2-related luciferase assays.

A cohort autopsy study defines COVID-19 systemic pathogenesis.

Severe COVID-19 disease caused by SARS-CoV-2 is frequently accompanied by dysfunction of the lungs and extrapulmonary organs. However, the organotropism of SARS-CoV-2 and the port of virus entry for systemic dissemination remain largely unknown. We profiled 26 COVID-19 autopsy cases from four cohorts in Wuhan, China, and determined the systemic distribution of SARS-CoV-2. SARS-CoV-2 was detected in the lungs and multiple extrapulmonary organs of critically ill COVID-19 patients up to 67 days after symptom onset. Based on organotropism and pathological features of the patients, COVID-19 was divided into viral intrapulmonary and systemic subtypes. In patients with systemic viral distribution, SARS-CoV-2 was detected in monocytes, macrophages, and vascular endothelia at blood-air barrier, blood-testis barrier, and filtration barrier. Critically ill patients with long disease duration showed decreased pulmonary cell proliferation, reduced viral RNA, and marked fibrosis in the lungs. Permanent SARS-CoV-2 presence and tissue injuries in the lungs and extrapulmonary organs suggest direct viral invasion as a mechanism of pathogenicity in critically ill patients. SARS-CoV-2 may hijack monocytes, macrophages, and vascular endothelia at physiological barriers as the ports of entry for systemic dissemination. Our study thus delineates systemic pathological features of SARS-CoV-2 infection, which sheds light on the development of novel COVID-19 treatment.

Structural Basis and Function of the N Terminus of SARS-CoV-2 Nonstructural Protein 1.

Nonstructural protein 1 (Nsp1) of severe acute respiratory syndrome coronaviruses (SARS-CoVs) is an important pathogenic factor that inhibits host protein translation by means of its C terminus. However, its N-terminal function remains elusive. Here, we determined the crystal structure of the N terminus (amino acids [aa] 11 to 125) of SARS-CoV-2 Nsp1 at a 1.25-Å resolution. Further functional assays showed that the N terminus of SARS-CoVs Nsp1 alone loses the ability to colocalize with ribosomes and inhibit protein translation. The C terminus of Nsp1 can colocalize with ribosomes, but its protein translation inhibition ability is significantly weakened. Interestingly, fusing the C terminus of Nsp1 with enhanced green fluorescent protein (EGFP) or other proteins in place of its N terminus restored the protein translation inhibitory ability to a level equivalent to that of full-length Nsp1. Thus, our results suggest that the N terminus of Nsp1 is able to stabilize the binding of the Nsp1 C terminus to ribosomes and act as a nonspecific barrier to block the mRNA channel, thus abrogating host mRNA translation.