An in silico analysis of early SARS-CoV-2 variant B.1.1.529 (Omicron) genomic sequences and their epidemiological correlates

BackgroundA newly emerged SARS-CoV-2 variant B.1.1.529 has worried the health policy makers worldwide due to the presence of a large number of mutations in its genomic sequence, especially in the spike protein region. World Health Organization (WHO) has designated it as a global variant of concern (VOC) and has named as Omicron. A surge in new COVID-19 cases have been reported from certain geographical locations, primarily in South Africa (SA) following the emergence of Omicron. Materials and methodsWe performed an in silico analysis of the complete genomic sequences of Omicron available on GISAID (until 2021-12-10) to predict the functional impact of the mutations present in this variant on virus-host interactions in terms of viral transmissibility, virulence/lethality, and immune escape. The mutations present at the receptor binding domain (RBD) of the variants were assessed using an open analysis pipeline which integrates a yeast-display platform with deep mutational scanning. Further, we performed a correlation analysis of the relative proportion of the genomic sequences of specific SARS-CoV-2 variants (in the period of 01 Oct-10th Dec, 2021) with the current epidemiological data (new COVID-19 cases and deaths) from SA to understand whether the Omicron has an epidemiological advantage over existing variants. ResultsCompared to the current list of global VOCs/VOIs (as per WHO) Omicron bears more sequence variation, specifically in the spike protein and host receptor-binding motif (RBM). Omicron showed the closest nucleotide and protein sequence homology with Alpha variant for the complete sequence as well as for RBM. The mutations were found primarily condensed in spike region (28-48) of the virus. Further, the mutational analysis showed enrichment for the mutations decreasing ACE2-binding affinity and RBD protein expression, in contrast, increasing the propensity of immune escape. An inverse correlation of Omicron with Delta variant was noted (r=-0.99, p< .001, 95% CI: -0.99 to - 0.97) in the sequences reported from SA post-emergence of the new variant, later showing a decrease. There has been a steep rise in the new COVID-19 cases in parallel with increase in the proportion of Omicron since the first case (74-100%), on the contrary, the incidences of new deaths have not been increased (r=-0.04, p>0.05, 95% CI =-0.52 to 0.58). ConclusionsOmicron may have greater immune escape ability than the existing VOCs/VOIs. However, there are no clear indications coming out from the predictive mutational analysis that the Omicron may have higher virulence/lethality than other variants, including Delta. The higher ability for immune escape may be a likely reason for the recent surge in Omicron cases in SA. HighlightsO_LIHigher immune escape ability than the existing VOCs/VOIs C_LIO_LINo clear indications of increased affinity for ACE2 binding C_LIO_LIDriving a new COVID-19 wave in South Africa C_LIO_LIOutcompeting Delta variant C_LIO_LICurrently, no clear evidence for increased virulence/lethality C_LI

Demographic characteristics of SARS-CoV-2 B.1.617.2 (Delta) variant infections in Indian population

ImportanceHigher risks of contracting infection, developing severe illness and mortality are known facts in aged and male sex if exposed to the wild type SARS-CoV-2 strains (Wuhan and B.1 strains). Now, accumulating evidence suggests greater involvement of lower age and narrowing the age and sex based differences for the severity of symptoms in infections with emerging SARS-CoV-2 variants. Delta variant (B.1.617.2) is now a globally dominant SARS-CoV-2 strain, however, current evidence on demographic characteristics for this variant are limited. Recently, delta variant caused a devastating second wave of COVID-19 in India. We performed a demographic characterization of COVID-19 cases in Indian population diagnosed with SARS-CoV-2 genomic sequencing for delta variant. ObjectiveTo determine demographic characteristics of delta variant in terms of age and sex, severity of the illness and mortality rate, and post-vaccination infections. DesignA cross sectional study SettingDemographic characteristics, including vaccination status (for two complete doses) and severity of the illness and mortality rate, of COVID-19 cases caused by wild type strain (B.1) and delta variant (B.1.617.2) of SARS-CoV-2 in Indian population were studied. ParticipantsCOVID-19 cases for which SARS-CoV-2 genomic sequencing was performed and complete demographic details (age, sex, and location) were available, were included. ExposuresSARS-CoV-2 infection with Delta (B.1.617.2) variant and wild type (B.1) strain. Main Outcomes and MeasuresThe patient metadata containing details for demographic and vaccination status (two complete doses) of the COVID-19 patients with confirmed delta variant and WT (B.1) infections were analyzed [total number of cases (N) =9500, Ndelta=6238, NWT=3262]. Further, severity of the illness and mortality were assessed in subsets of patients. Final data were tabulated and statistically analyzed to determine age and sex based differences in chances of getting infection and the severity of illness, and post-vaccination infections were compared between wild type and delta variant strains. Graphs were plotted to visualize the trends. ResultsWith delta variant, in comparison to wild type (B.1) strain, higher proportion of lower age groups, particularly <20 year (0-9 year: 4.47% vs. 2.3%, 10-19 year: 9% vs. 7%) were affected. The proportion of women contracting infection were increased (41% vs. 36%). The higher proportion of total young (0-19 year, 10% vs. 4%) (p=.017) population and young (14% vs. 3%) as well as adult (20-59 year, 75% vs. 55%) women developed symptoms/hospitalized with delta variant in comparison to B.1 infection (p< .00001). The mean age of contracting infection [Delta, men=37.9 ({+/-}17.2) year, women=36.6 ({+/-}17.6) year; B.1, men=39.6 ({+/-}16.9) year and women= 40.1 ({+/-}17.4) year (p< .001)] as well as developing symptoms/hospitalization [Delta, men=39.6({+/-} 17.4) year, women=35.6 ({+/-}16.9) year; B.1, men=47({+/-}18) year and women= 49.5({+/-}20.9) year (p< .001)] was considerably lower. The total mortality was about 1.8 times higher (13% vs. 7%). Risk of death increased irrespective of the sex (Odds ratio: 3.034, 95% Confidence Interval: 1.7-5.2, p<0.001), however, increased proportion of women (32% vs. 25%) were died. Further, multiple incidences of delta infections were noted following complete vaccination. Conclusions and RelevanceThe increased involvement of young (0-19 year) and women, lower mean age for contracting infection and symptomatic illness/hospitalization, higher mortality, and frequent incidences of post-vaccination infections with delta variant compared to wild type strain raises significant epidemiological concerns. Key PointsO_ST_ABSQuestionC_ST_ABSDid SARS-CoV-2 B.1.617.2 (Delta) variant infections show varied demographic characteristics in comparison to wild type strains? FindingsIn this cross sectional study viral genomic sequences of 9500 COVID-19 patients were analyzed. As the key findings, increased involvement of young (0-19 year) and women, lower mean age for contracting infection and symptomatic illness/hospitalization, higher mortality, and frequent incidences of post-vaccination infections with delta variant in comparison to wild type (WT) strain (B.1) were observed. MeaningThe findings of this study suggest that delta variant has varied demographic characteristics reflecting increased involvement of the young and women, and increased lethality in comparison to wild type strains.

Second wave of COVID-19 in India could be predicted with genomic surveillance of SARS-CoV-2 variants coupled with epidemiological data: A tool for future

India recently witnessed a devastating second wave of COVID-19, which peaked by the end of the first week of May 2021. We aimed to understand formation and spread of the second wave in the country. We analyzed time series distribution of the genomic sequence data for SARS-CoV-2 and correlated that with the epidemiological data for new cases and deaths, for the corresponding period of the second wave. Further we analyzed the phylodynamics of the circulating SARS-CoV-2 variants in the Indian population in the period of study. Our analysis shows that the first indications of arrival of the second wave were observable by the end of January 2021, and by the end of March, 2021 it was clearly indicated. B.1.617 lineage variants drove the wave, particularly B.1.617.2 (a.k.a. delta variant). Based on the observations of this study, we propose that genomic surveillance of the SARS-CoV-2 variants augmented with epidemiological data can be a promising tool for forecasting imminent COVID-19 waves.

Glucodynamics and glucocracy in type 2 diabetes mellitus: clinical evidence and practice-based opinion on modern sulfonylurea use, from an International Expert Group (South Asia, Middle East & Africa) via modified Delphi method.

Type 2 diabetes mellitus (T2DM) is a global epidemic. According to international guidelines, the management protocol of T2DM includes lowering of blood glucose, along with preventing disease-related complications and maintaining optimal quality of life. Further, the guidelines recommend the use of a patient-centric approaches for the management of T2DM; however, Asian population is underrepresented in landmark cardiovascular outcome trials (CVOTs). There are several guidelines available today for the diagnosis and management of T2DM, and hence there is much confusion among practitioners about which guidelines to follow. A group of thirty international clinical experts comprising of endocrinologists, diabetologists and cardiologist from South Asia, Middle East and Africa met at New Delhi, India on February 8 and 9, 2020 and developed an international expert opinion statements via a structured modified Delphi method on the glucodynamic properties of OADs and the glucocratic treatment approach for the management of T2DM. In this modified Delphi consensus report, we document the glucodynamic properties of Modern SUs in terms of glucoconfidence, glucosafety, and gluconomics. According to glucodynamics theory, an ideal antidiabetic drug should be efficacious, safe, and affordable. Modern SUs as a class of OADs that have demonstrated optimal glucodynamics in terms of glucoconfidence, glucosafety, and gluconomics. Hence, modern SUs are most suitable second line drug after metformin for developing countries. Based on the current evidence, we recommend a glucocratic approach for the treatment of T2DM, where an individualized treatment plan with phenotype, lifestyle, environmental, social, and cultural factors should be considered for persons with T2DM in the South Asian, Middle Eastern and African regions.

Relevance of enriched expression of SARS-CoV-2 binding receptor ACE2 in gastrointestinal tissue with pathogenesis of digestive symptoms, diabetes-associated mortality, and disease recurrence in COVID-19 patients

IntroductionCOVID-19 is caused by a new strain of coronavirus called SARS-coronavirus-2 (SARS-CoV-2), which is a positive sense single strand RNA virus. In humans, it binds to angiotensin converting enzyme 2 (ACE2) with the help a structural protein on its surface called the S-spike. Further, cleavage of the viral spike protein (S) by the proteases like transmembrane serine protease 2 (TMPRSS2) or Cathepsin L (CTSL) is essential to effectuate host cell membrane fusion and virus infectivity. COVID-19 poses intriguing issues with imperative relevance to clinicians. The pathogenesis of GI symptoms, diabetes-associated mortality, and disease recurrence in COVID-19 are of particular relevance because they cannot be sufficiently explained from the existing knowledge of the viral diseases. Tissue specific variations of SARS-CoV-2 cell entry related receptors expression in healthy individuals can help in understanding the pathophysiological basis the aforementioned collection of symptoms. Materials and MethodsThe data were downloaded from the Human Protein Atlas available at (https://www.proteinatlas.org/humanproteome/sars-cov-2) and the tissue specific expressions (both mRNA and protein) of ACE2 and TMPRSS2 as yielded from the studies with RNA sequencing and immunohistochemistry (IHC) were analyzed as a function of the various components of the digestive tract. A digestive system specific functional enrichment map of ACE2 gene was created using g:profiler (https://biit.cs.ut.ee/gprofiler/gost) utility and the data were visualized using Cytoscape software, version 3.7.2 (https://cytoscape.org/). ResultsThe correlated expression (transcriptomic and proteomic) of ACE2 (to which SARS-CoV-2 binds through the S-spike) was found to be enriched in the lower gastrointestinal tract (GIT) (highest in small intestine, followed by colon and rectum), and was undetectable in the upper GIT components: mouth cavity (tongue, oral mucosa, and salivary glands), esophagus, and stomach. High expression of ACE2 was noted in the glandular cells as well as in the enterocytes in the lining epithelium (including brush border epithelium). Among other digestive system organs, Gall bladder (GB) showed high expression of ACE2 in glandular cells, while any protein expression was undetectable in liver and pancreas. TMPRSS2 was found enhanced in GIT and exocrine glands of pancreas, and co-localized with ACE2 in enterocytes. ConclusionsBased on the findings of this study and supportive evidence from the literature we propose that a SARS-CoV-2 binding with ACE2 mediates dysregulation of the sodium dependent nutrient transporters and hence may be a plausible basis for the digestive symptoms in COVID-19 patients. ACE2 mediated dysregulation of sodium dependent glucose transporter (SGLT1 or SLC5A1) in the intestinal epithelium also links it to the pathogenesis of diabetes mellitus which can be a possible reason for the associated mortality in COVID-19 patients with diabetes. High expression of ACE2 in mucosal cells of the intestine and GB make these organs potential sites for the virus entry and replication. Continued replication of the virus at these ACE2 enriched sites may be a basis for the disease recurrence reported in some, thought to be cured, patients. Graphical Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY