Mutant Delta Research Articles

The evaluation of SARS-CoV-2 mutations at the early stage of the pandemic in Istanbul population

BackgroundDetermination of SARS-CoV-2 variant is significant to prevent the spreads of COVID-19 disease.MethodsWe aimed to evaluate the variants of SARS-CoV-2 rate in positive patients in Kanuni Sultan Suleyman Training and Research Hospital (KSS-TRH), Istanbul, Türkiye between 1st January and 30th November 2021 by using RT-PCR method.ResultsHerein, 825,169 patients were evaluated (male:58.53% and female:41.47%) whether COVID-19 positive or not [( +):21.3% and (−):78.7%] and 175,367 patient was described as positive (53.2%-female and 46.8%-male) by RT-PCR. COVID-19 positive rate is observed highest in the 6–15- and 66–75-year age range. The frequencies were obtained as SARS-CoV-2 positive (without mutation of B.1.1.7 [B.1.1.7 (U.K), E484K, L452R, B.1.351 (S. Africa/Brazil) spike mutations] as 66.1% (n: 115,899), B.1.1.7 Variant as 23.2% (n:40,686), Delta mutation (L452R) variant as 9.8% (n:17,182), B.1.351 variant as 0.8% (n:1370) and E484K as 0.1% (n: 230). In April 2021, general SARS-CoV-2 and B.1.1.7 variant were dominantly observed. Up to July 2021, B.1.617.2 (Delta variant/ Indian variant) and E484K has been not observed. B.1.351 variant of SARS-CoV-2 has been started in February 2021 at the rarest ratio and March 2021 is the top point. September 2021 is the pick point of E484K. African/Brazil variant of SARS-CoV-2 has been started in February 2021 at the rarest ratio and March 2021 is the top point. September 2021 is the pick point of E484K. When the gender type is compared within the variants, women were found to be more prevalent in all varieties.ConclusionsThe meaning of these mutations is very important to understand the transmission capacity of the COVID-19 disease, pandemic episode, and diagnosis of the virus with mutation types. Understanding the variant type is important for monitoring herd immunity and the spread of the disease.

SARS-CoV-2 Delta and Omicron variants resist spike cleavage by human airway trypsin-like protease.

Soluble host factors in the upper respiratory tract can serve as the first line of defense against SARS-CoV-2 infection. In this study, we described the identification and function of a human airway trypsin-like protease (HAT), capable of reducing the infectivity of ancestral SARS-CoV-2. Further, in mouse models, HAT analogue expression was upregulated by SARS-CoV-2 infection. The antiviral activity of HAT functioned through the cleavage of the SARS-CoV-2 spike glycoprotein at R682. This cleavage resulted in inhibition of the attachment of ancestral spike proteins to host cells, which inhibited the cell-cell membrane fusion process. Importantly, exogenous addition of HAT notably reduced the infectivity of ancestral SARS-CoV-2 in vivo. However, HAT was ineffective against the Delta variant and most circulating Omicron variants, including the BQ.1.1 and XBB.1.5 subvariants. We demonstrate that the P681R mutation in Delta and P681H mutation in the Omicron variants, adjacent to the R682 cleavage site, contributed to HAT resistance. Our study reports what we believe to be a novel soluble defense factor against SARS-CoV-2 and resistance of its actions in the Delta and Omicron variants.

A phase II clinical trial of toripalimab in advanced solid tumors with polymerase epsilon/polymerase delta (POLE/POLD1) mutation

Patients carrying mutations in polymerase epsilon/polymerase delta have shown positive responses to immune checkpoint inhibitors. Yet, prospective trials exploring the efficacy in those with polymerase epsilon/polymerase delta mutations are still lacking. A phase II clinical trial was initiated to evaluate the efficacy of toripalimab, a humanized IgG4K monoclonal antibody to human PD-1, in patients with advanced solid tumors with unselected polymerase epsilon/polymerase delta mutations but without microsatellite instability-high. A total of 15 patients were enrolled, 14 of whom were assessed for treatment efficacy. There was a 21.4% overall response rate, with a disease control rate of 57.1%. The median overall survival and median progression-free survival were 17.9 (95% CI 13.5-not reach) months and 2.5 (95% CI 1.4-not reach) months, respectively. For patients with exonuclease domain mutations, the objective response rate was 66.7% (2/3), with a disease control rate of 66.7% (2/3). For those with non-exonuclease domain mutations, the rates were 9.1% (1/11) and 54.5% (6/11), respectively. Notably, patients with PBRM1 gene mutations exhibited a high response rate to toripalimab at 75.0% (3/4). This study showed that neither the exonuclease domain mutations nor non-exonuclease domain mutations could fully predict the efficacy of immunotherapy, urging the need for more investigations to clarify potential immune sensitization differences within polymerase epsilon/polymerase delta mutation variants.

NMR characterization and ligand binding site of the stem-loop 2 motif from the Delta variant of SARS-CoV-2.

The stem-loop 2 motif (s2m) in SARS-CoV-2 (SCoV-2) is located in the 3'-UTR. Although s2m has been reported to display characteristics of a mobile genomic element that might lead to an evolutionary advantage, its function has remained unknown. The secondary structure of the original SCoV-2 RNA sequence (Wuhan-Hu-1) was determined by NMR in late 2020, delineating the base-pairing pattern and revealing substantial differences in secondary structure compared to SARS-CoV-1 (SCoV-1). The existence of a single G29742-A29756 mismatch in the upper stem of s2m leads to its destabilization and impedes a complete NMR analysis. With Delta, a variant of concern has evolved with one mutation compared to the original sequence that replaces G29742 by U29742. We show here that this mutation results in a more defined structure at ambient temperature accompanied by a rise in melting temperature. Consequently, we were able to identify >90% of the relevant NMR resonances using a combination of selective RNA labeling and filtered 2D NOESY as well as 4D NMR experiments. We present a comprehensive NMR analysis of the secondary structure, (sub)nanosecond dynamics, and ribose conformation of s2m Delta based on heteronuclear 13C NOE and T 1 measurements and ribose carbon chemical shift-derived canonical coordinates. We further show that the G29742U mutation in Delta has no influence on the druggability of s2m compared to the Wuhan-Hu-1 sequence. With the assignment at hand, we identify the flexible regions of s2m as the primary site for small molecule binding.

A superior heterologous prime-boost vaccination strategy against COVID-19: A bivalent vaccine based on yeast-derived RBD proteins followed by a heterologous vaccine.

Various vaccines have been challenged by SARS-CoV-2 variants. Here, we reported a yeast-derived recombinant bivalent vaccine (Bivalent wild-type [Wt]+De) based on the wtand Delta receptor-binding domain (RBD). Yeast derived RBD proteins based on the wtand Delta mutant were used as the prime vaccine. It was found that, in the presence of aluminium hydroxide (Alum) and unmethylated CpG-oligodeoxynucleotides (CpG) adjuvants, more cross-protective immunity against SARS-CoV-2 prototype and variants were elicited by bivalent vaccine than monovalent wtRBD or Delta RBD. Furthermore, a heterologous boosting strategy consisting of two doses of bivalent vaccines followed by one dose adenovirus vectored vaccine exhibited cross-neutralization capacity and specific T cell responses against Delta and Omicron (BA.1 and BA.4/5) variants in mice, superior to a homologous vaccination strategy. This study suggested that heterologous prime-boost vaccination with yeast-derived bivalent protein vaccine could be a potential approach to address the challenge of emerging variants.

A mouse xenograft long-term replication yields a SARS-CoV-2 Delta mutant with increased lethality.

We recently established a long-term SARS-CoV-2 infection model using lung-cancer xenograft mice and identified mutations that arose in the SARS-CoV-2 genome during long-term propagation. Here, we applied our model to the SARS-CoV-2 Delta variant, which has increased transmissibility and immune escape compared with ancestral SARS-CoV-2. We observed limited mutations in SARS-CoV-2 Delta during long-term propagation, including two predominant mutations: R682W in the spike protein and L330W in the nucleocapsid protein. We analyzed two representative isolates, Delta-10 and Delta-12, with both predominant mutations and some additional mutations. Delta-10 and Delta-12 showed lower replication capacity compared with SARS-CoV-2 Delta in cultured cells; however, Delta-12 was more lethal in K18-hACE2 mice compared with SARS-CoV-2 Delta and Delta-10. Mice infected with Delta-12 had higher viral titers, more severe histopathology in the lungs, higher chemokine expression, increased astrocyte and microglia activation, and extensive neutrophil infiltration in the brain. Brain tissue hemorrhage and mild vacuolation were also observed, suggesting that the high lethality of Delta-12 was associated with lung and brain pathology. Our long-term infection model can provide mutant viruses derived from SARS-CoV-2 Delta and knowledge about the possible contributions of emergent mutations to the properties of new variants.

Interaction of toll-like receptors and ACE-2 with different variants of SARS-CoV-2: A computational analysis.

Computational studies were performed to investigate the unknown status of endosomal and cell surface receptors in SARS-CoV-2 infection. The interactions between Toll-like receptors (TLRs)- 4/7/8/9 or ACE2 receptor and different SARS-CoV-2 variants were investigated. The RNA motifs for TLR7, TLR8 and a CpG motif for TLR9 were analyzed in different variants. Molecular docking and molecular dynamics (MD) simulations were performed to investigate receptor-ligand interactions. The number of motifs recognized by TLR7/8/9 in the Alpha, Delta and Iranian variants was lower than in the wild type (WT). Docking analysis revealed that the Alpha, Delta and some Iranian spike variants had a higher affinity for ACE2 and TLR4 than the WT, which may account for their higher transmission rate. The MD simulation also showed differences in stability and structure size between the variants and the WT, indicating potential variations in viral load. It appears that Alpha and some Iranian isolates are the variants of concern due to their higher transmissibility and rapid spread. The Delta mutant is also a variant of concern, not only because of its closer interaction with ACE2, but also with TLR4. Our results emphasize the importance of ACE2 and TLR4, rather than endosomal TLRs, in mediating the effects of different viral mutations and suggest their potential therapeutic applications.

Bitter taste receptors establish a stable binding affinity with the SARS-CoV-2-spike 1 protein akin to ACE2

COVID-19 is caused by the highly contagious SARS-CoV-2 virus, which originated in Wuhan, China, resulting in the highest worldwide mortality rate. Gustatory dysfunction is common among individuals infected with the Wild-type Wuhan strain. However, there are no reported cases of gustatory dysfunction among patients infected with the mutant delta variant. The reason behind this remains elusive to date. This in-silico-based study aims to unravel this clinical factor by evaluating the overall binding affinity of predominant bitter taste receptors associated with gustatory function (T2R-4, 10, 14, 19, 31, 38, 43, and 46) with the Receptor Binding Domain (RBD) of spike 1 (S1) protein of Wuhan (Wild)/delta-SARS-CoV-2 (mut1-T478K; mut2-E484K) variants. Based on docking and MM/PBSA free binding energy scores, the Wild RBD showed a stronger interaction with T2R-46 compared to the ACE2 protein. However, both delta variant mutants (mut1 and mut2) could not establish a stronger binding affinity with bitter taste receptor proteins, except for T2R-43 against mut1. In conclusion, the delta variants could not establish a better binding affinity with bitter taste receptors, contradicting the Wild variant that determines the severity of gustatory dysfunction among patients exposed to the delta and Wild SARS-CoV-2 variants. The study’s inference also proposes T2R-46 as an alternate binding receptor target for RBD-S1 of Wild SARS-CoV-2, augmenting its virulence in all functional organs with compromised α-gustducin interaction and bitter sensitization. This in-silico-based study needs further wet-lab-based validation for a better understanding of the role of T2R-46-based viral entry in the human host. Communicated by Ramaswamy H. Sarma

POLD1 DEDD Motif Mutation Confers Hypermutation in Endometrial Cancer and Durable Response to Pembrolizumab.

Mutations in the DNA polymerase delta 1 (POLD1) exonuclease domain cause DNA proofreading defects, hypermutation, hereditary colorectal and endometrial cancer, and are predictive of immunotherapy response. Exonuclease activity is carried out by two magnesium cations, bound to four highly conserved, negatively charged amino acids (AA) consisting of aspartic acid at amino acid position 316 (p.D316), glutamic acid at position 318 (p.E318), p.D402, and p.D515 (termed DEDD motif). Germline polymorphisms resulting in charge-discordant AA substitutions in the DEDD motif are classified as variants of uncertain significance (VUSs) by laboratories and thus would be considered clinically inactionable. We hypothesize this mutation class is clinically pathogenic. A review of clinical presentation was performed in our index patient with a POLD1(p.D402N) heterozygous proband with endometrial cancer. Implications of this mutation class were evaluated by a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review, in silico analysis with orthogonal biochemical confirmation, and whole-exome and RNA sequencing analysis of the patient's tumor and engineered cell lines. Our systematic review favored a Mendelian disease mutation class associated with endometrial and colorectal cancers. In silico analysis predicted defective protein function, confirmed by biochemical assay demonstrating loss of nuclease activity. A POLD1-specific mutational signature was found in both the patient's tumor and POLD1(p.D402N) overexpressing cell. Furthermore, paired whole-exome/transcriptome analysis of endometrial tumor demonstrated hypermutation and T cell-inflamed gene expression profile (GEP), which are joint predictive biomarkers for pembrolizumab. Our patient showed a deep, durable response to immune checkpoint inhibitor (ICI). Charge-discordant AA substitution in the DEDD motif of POLD1 is detrimental to DNA proofreading and should be reclassified as likely pathogenic and possibly predictive of ICI sensitivity.

Fruits from tomato carotenoid mutants have altered susceptibility to grey mold

The necrotrophic fungus Botritys cinerea takes advantage of the oxidative burst to facilitate tissue infection, leading to substantial losses during tomato postharvest. Tomato fruit is a source of carotenoids, pigments with a wide variety of isomeric configurations that determine their antioxidant capacity. Here, fruit susceptibility to B. cinerea was assessed in Micro-Tom Near Isogenic lines harboring mutations that alter the profile of carotenoids. Wound-inoculated fruit of the mutants Delta carotene (Del) and tangerine (t), which show large variety of carotenoids rather than the major accumulation of trans-lycopene, were less susceptible to the pathogen. Differences in susceptibility between the mutants were only observed in ripe fruit, after the formation of carotenoids, and they were associated with attenuation of damage caused by reactive oxygen species. The greater variety of carotenoid isomers, which in turn contributed to the greater lipophilic antioxidant capacity of fruit, was associated with the less susceptible mutants, Del and t. Together, our data reveals a potential activity of carotenoids in fruit defense, in addition to the well-known and widespread ecological role as attractors of seed dispersers.

Macromolecules: Synthesis, antimicrobial, POM analysis and computational approaches of some glucoside derivatives bearing acyl moieties

Macromolecules i.e., carbohydrate derivatives are crucial to biochemical and medical research. Herein, we designed and synthesized eight methyl α-D-glucopyranoside (MGP) derivatives (2–8) in good yields following the regioselective direct acylation method. The structural configurations of the synthesized MGP derivatives were analyzed and verified using multiple physicochemical and spectroscopic techniques. Antimicrobial experiments revealed that almost all derivatives demonstrated noticeable antifungal and antibacterial efficacy. The synthesized derivatives showed minimum inhibitory concentration (MIC) values ranging from 0.75 µg/mL to 1.50 µg/mL and minimum bactericidal concentrations (MBCs) ranging from 8.00 µg/mL to 16.00 µg/mL. Compound 6 inhibited Ehrlich ascites carcinoma (EAC) cell proliferation by 10.36% with an IC50 of 2602.23 μg/mL in the MTT colorimetric assay. The obtained results were further rationalized by docking analysis of the synthesized derivatives against 4URO and 4XE3 receptors to explore the binding affinities and nonbonding interactions of MGP derivatives with target proteins. Compound 6 demonstrated the potential to bind with the target with the highest binding energy. In a stimulating environment, a molecular dynamics study showed that MGP derivatives have a stable conformation and binding pattern. The MGP derivatives were examined using POM (Petra/Osiris/Molinspiration) bioinformatics, and as a result, these derivatives showed good toxicity, bioavailability, and pharmacokinetics. Various antifungal/antiviral pharmacophore (Oδ−, O′δ−) sites were identified by using POM investigations, and compound 6 was further tested against other pathogenic fungi and viruses, such as Micron and Delta mutants of SARS-CoV-2.

Mutational spectrum of HBD gene in the Chinese population: Description of 36 mutations including 11 novel variants.

Mutations in the hemoglobin subunit delta (HBD) gene (MIM#142000) are associated with decreased levels of the Hemoglobin A2 (Hb A2 ) fraction. We aimed to examine the prevalence of HBD gene mutations and summarize their characteristics in the Chinese population. Individuals who exhibited Hb A2 levels below 1.8%, with or without Hb A2 variant peaks, were chosen for further investigation. Hemoglobin analysis was conducted using capillary electrophoresis. Common α and β-thalassemia in China were detected using gap-PCR and reverse dot blot hybridization. The presence of HBD gene mutations was confirmed by DNA sequencing. A total of 188 patients were identified as carriers of the HBD gene mutation, with a prevalence of approximately 0.46%. We discovered 36 types of mutations, 30 of which resulted in δ-globin variants, while the remaining 6 resulted in δ-thalassemia. The most common mutation was HBD:c.-127 T > C, accounting for 87.2% of δ-thalassemia cases. In addition, we identified 11 novel HBD gene mutations and found 10 cases compounded with other common thalassemias. We observed a high prevalence of HBD gene mutations in southern China. Our findings provide a genetic basis for screening for δ-thalassemia and enrich the spectrum of HBD gene mutations.

Key Substitutions in the Spike Protein of SARS-CoV-2 Delta and Omicron Variants

The delta and omicron variants of SARS-CoV-2 (PANGO B.1.617.2. and B.1.1.529) outcompeted the earlier variations shortly after they were discovered due to their quick global dissemination. While the majority of these changes are extremely unlikely to alter the spike protein's composition or function, some might increase the virus's susceptibility to infection or make it less susceptible to vaccination, in which case they are referred to as "variants of concern" (VOC). According to previous research, the severity and transmissibility of mutant spike proteins might change if certain critical changes were present. Based on the verified mutations of spike protein, this article will discuss the specific amino acid mutations effects on the change in its transmissibility and severity. The main mechanisms affected by the mutation are the cleavage of S1 subunit1/S2 subunit2 and conformation alteration of the receptor binding domain (RBD). In conclusion, mutations in delta drastically increased its transmissibility, and mutations in omicron increased its transmissibility by becoming more stable in the environment with compromised cell fusion ability, leading to lower severity. These results emphasize the intricate relationships between alterations happened in the spike protein which influence virus stability, neutralization, and cell entering.

Evolution of the SARS-CoV-2 Mutational Spectrum.

SARS-CoV-2 evolves rapidly in part because of its high mutation rate. Here, we examine whether this mutational process itself has changed during viral evolution. To do this, we quantify the relative rates of different types of single-nucleotide mutations at 4-fold degenerate sites in the viral genome across millions of human SARS-CoV-2 sequences. We find clear shifts in the relative rates of several types of mutations during SARS-CoV-2 evolution. The most striking trend is a roughly 2-fold decrease in the relative rate of G→T mutations in Omicron versus early clades, as was recently noted by Ruis et al. (2022. Mutational spectra distinguish SARS-CoV-2 replication niches. bioRxiv, doi:10.1101/2022.09.27.509649). There is also a decrease in the relative rate of C→T mutations in Delta, and other subtle changes in the mutation spectrum along the phylogeny. We speculate that these changes in the mutation spectrum could arise from viral mutations that affect genome replication, packaging, and antagonization of host innate-immune factors, although environmental factors could also play a role. Interestingly, the mutation spectrum of Omicron is more similar than that of earlier SARS-CoV-2 clades to the spectrum that shaped the long-term evolution of sarbecoviruses. Overall, our work shows that the mutation process is itself a dynamic variable during SARS-CoV-2 evolution and suggests that human SARS-CoV-2 may be trending toward a mutation spectrum more similar to that of other animal sarbecoviruses.

Identification of natural compounds as SARS-CoV-2 inhibitors via molecular docking and molecular dynamic simulation.

Base mutations increase the contagiousness and transmissibility of the Delta and Lambda strains and lead to the severity of the COVID-19 pandemic. Molecular docking and molecular dynamics (MD) simulations are frequently used for drug discovery and relocation. Small molecular compounds from Chinese herbs have an inhibitory effect on the virus. Therefore, this study used computational simulations to investigate the effects of small molecular compounds on the spike (S) protein and the binding between them and angiotensin-converting enzyme 2 (ACE2) receptors. In this study, molecular docking, MD simulation, and protein-protein analysis were used to explore the medicinal target inhibition of Chinese herbal medicinal plant chemicals on SARS-CoV-2. 12,978 phytochemicals were screened against S proteins of SARS-CoV-2 Lambda and Delta mutants. Molecular docking showed that 65.61% and 65.28% of the compounds had the relatively stable binding ability to the S protein of Lambda and Delta mutants (docking score ≤ -6). The top five compounds with binding energy with Lambda and Delta mutants were clematichinenoside AR2 (-9.7), atratoglaucoside,b (-9.5), physalin b (-9.5), atratoglaucoside, a (-9.4), Ochnaflavone (-9.3) and neo-przewaquinone a (-10), Wikstrosin (-9.7), xilingsaponin A (-9.6), ardisianoside G (-9.6), and 23-epi-26-deoxyactein (-9.6), respectively. Four compounds (Casuarictin, Heterophylliin D, Protohypericin, and Glansrin B) could interact with S protein mutation sites of Lambda and Delta mutants, respectively, and MD simulation results showed that four plant chemicals and spike protein have good energy stable complex formation ability. In addition, protein-protein docking was carried out to evaluate the changes in ACE2 binding ability caused by the formation of four plant chemicals and S protein complexes. The analysis showed that the binding of four plant chemicals to the S protein could reduce the stability of the binding to ACE2, thereby reducing the replication ability of the virus. To sum up, the study concluded that four phytochemicals (Casuarictin, Heterophylliin D, Protohypericin, and Glansrin B) had significant effects on the binding sites of the SARS-CoV-2 S protein. This study needs further in vitro and in vivo experimental validation of these major phytochemicals to assess their potential anti-SARS-CoV-2. Graphical abstract.

Beta, Delta, and Omicron, Deadliest Among SARS-CoV-2 Variants: A Computational Repurposing Approach

SARS-CoV-2 has been highly susceptible to mutations since its emergence in Wuhan, China, and its subsequent propagation due to containing an RNA as its genome. The emergence of variants with improved transmissibility still poses a grave threat to global health. The spike protein mutation is mainly responsible for higher transmissibility and risk severity. This study retrieved SARS-CoV-2 variants structural and nonstructural proteins (NSPs) sequences from several geographic locations, including Africa, Asia, Europe, Oceania, and North and South America. First, multiple sequence alignments with BioEdit and protein homology modeling were performed using the SWISS Model. Then the structure visualization and structural analysis were performed by superimposing against the Wuhan sequence by Pymol to retrieve the RMSD values. Sequence alignment revealed familiar, uncommon regional among variants and, interestingly, a few unique mutations in Beta, Delta, and Omicron. Structural analysis of such unique mutations revealed that they caused structural deviations in Beta, Delta, and Omicron spike proteins. In addition, these variants were more severe in terms of hospitalization, sickness, and higher mortality, which have a substantial relationship with the structural deviations because of those unique mutations. Such evidence provides insight into the SARS-CoV-2 spike protein vulnerability toward mutation and their structural and functional deviations, particularly in Beta, Delta, and Omicron, which might be the cause of their broader coverage. This knowledge can help us with regional vaccine strain selection, virus pathogenicity testing, diagnosis, and treatment with more specific vaccines.

Analysis of CT signs, radiomic features and clinical characteristics for delta variant COVID-19 patients with different vaccination status

ObjectiveTo explore the characteristics of peripheral blood, high resolution computed tomography (HRCT) imaging and the radiomics signature (RadScore) in patients infected with delta variant virus under different coronavirus disease (COVID-19) vaccination status.Methods123 patients with delta variant virus infection collected from November 1, 2021 to March 1, 2022 were analyzed retrospectively. According to COVID-19 vaccination Status, they were divided into three groups: Unvaccinated group, partially vaccinated group and full vaccination group. The peripheral blood, chest HRCT manifestations and RadScore of each group were analyzed and compared.ResultsThe mean lymphocyte count 1.22 ± 0.49 × 10^9/L, CT score 7.29 ± 3.48, RadScore 0.75 ± 0.63 in the unvaccinated group; The mean lymphocyte count 1.55 ± 0.70 × 10^9/L, CT score 5.27 ± 2.72, RadScore 1.03 ± 0.46 in the partially vaccinated group; The mean lymphocyte count 1.87 ± 0.70 × 10^9/L, CT score 3.59 ± 3.14, RadScore 1.23 ± 0.29 in the fully vaccinated group. There were significant differences in lymphocyte count, CT score and RadScore among the three groups (all p < 0.05); Compared with the other two groups, the lung lesions in the unvaccinated group were more involved in multiple lobes, of which 26 cases involved the whole lung.ConclusionsThrough the analysis of clinical features, pulmonary imaging features and radiomics, we confirmed the positive effect of COVID-19 vaccine on pulmonary inflammatory symptoms and lymphocyte count (immune system) during delta mutant infection.

Structural Profiles of SARS-CoV-2 Variants in India.

India was severely affected by several waves of SARS-CoV-2 infection that occurred during April-June 2021 (second wave) and December 2021-January 2022 (third wave) and thereafter, resulting in >10 million new infections and a significant number of deaths. Global Initiative on Sharing Avian Influenza Data database was used to collect the sequence information of ~10,000 SARS-CoV-2 patients from India and our sequence analysis identified three variants B.1.1.7 (alpha, α), B1.617.2 (delta, Δ), B.1.1.529 (Omicron, Oo) and one Omicron sub-variant BA.2.75 as the primary drivers for SARS-CoV-2 waves in India. Structural visualization and analysis of important mutations of alpha, delta, Omicron and its sub-variants of SARS-CoV-2 Receptor-Binding Domain (RBD) was performed and our analysis clearly shows that mutations occur throughout the RBD, including the RBD surface responsible for human angiotensin-converting enzyme 2 (hACE-2) receptor-binding. A comparison between alpha, delta and omicron variants/sub-variants reveals many omicron mutations in the hACE-2 binding site and several other mutations within 5Å of this binding region. Further, computational analysis highlights the importance of electrostatic interactions in stabilizing RBD-hACE-2-binding, especially in the omicron variant. Our analysis explores the likely role of key alpha, delta and omicron mutations on binding with hACE-2. Taken together, our study provides novel structural insights into the implications of RBD mutations in alpha, delta and omicron and its sub-variants that were responsible for India's SARS-CoV-2 surge.

LBODP030 A Rare Case Of Partial Lipodystrophy From Mpdl (mandibular Hypoplasia, Deafness, Progeroid, Lipodystrophy Syndrome) Due To Pold1 Gene Mutation

Abstract MDPL (Mandibular hypoplasia, Deafness, Progeroid, Lipodystrophy syndrome) caused by a mutation in the polymerase delta 1 (POLD1) gene is an extremely rare progeroid syndrome associated with partial lipodystrophy. Currently, there are about 24 cases reported worldwide(1), mostly in people of European descent. We are reporting one such rare case in a Hispanic patient. The patient is a 37 year old male from Honduras who was referred to us by genetics for diabetes management. Family members noted extremely thin limbs and he did not walk till 2 years of age. Family history was negative with 8 full siblings, all reportedly healthy. On examination, his BMI was 15.19 kg/m2. He was noted to have birdlike facies with mid-face hypoplasia, beaked nose, retrognathia, dental malocclusion, and protruding maxillary teeth. He also had bilateral proptosis. His extremities were thin, lacking subcutaneous fat and muscle bulk with distal joint contractures in elbow, hands and feet. Genitourinary showed low testicular volumes (&amp;lt;3 ml). Genetic testing revealed a recurring mutation in the active site of POLD1 gene, which is diagnostic for MDPL. His clinical presentation was classic with dysmorphism, deafness, lipodystrophy and metabolic abnormalities. Due to the rarity of the disorder, there is very limited data on management of these patients. A symptom-based management was recommended. In terms of his diabetes, it was diagnosed at age 33 when his HbA1c was 11.2 and he was started on insulin. Patients with this syndrome tend to have insulin resistance. C-peptide was 2.88 ng/ml (ref. range: 0.78 - 5.19 ng/mL) with glucose 160 mg/dL indicating adequate beta-cell reserve; GAD-65 and anti-pancreatic islet cell antibodies were negative. Insulin was weaned off and currently, his diabetes is being managed with diet and lifestyle changes. He was found to have elevated total cholesterol and triglycerides. Hepatic steatosis was seen on liver ultrasonography. He was started on fenofibrate and low-fat diet; lipid panel has normalized. His echocardiogram was normal. In addition, males are known to have hypogonadotropic hypogonadism however this patient had a low testosterone and high FSH and LH, indicative of primary hypogonadism. A scrotal ultrasound was ordered. DXA scan showed low bone mineral density with the lowest Z-score of -3.6 at the lumbar spine. He was started on testosterone replacement with Vitamin D. Testosterone therapy will help replace the testosterone deficiency in addition to slowing down bone loss. MDPL syndrome is an exceedingly rare clinical entity associated with multiple endocrinopathies. We plan to periodically monitor labs and imaging to continue managing this patient with a symptom-based approach. (1) Wang, Xiu-Wen; Lu, Ling-Yun; Xie, Ying1; Yu, Xi-Jie1 A Chinese girl with (MDPL) diagnosed via POLD1 mutation detection, Chinese Medical Journal: August 20, 2020 - Volume 133 - Issue 16 - p 2009-2011 Presentation: No date and time listed

Evidence for the heterologous benefits of prior BCG vaccination on COVISHIELD™ vaccine-induced immune responses in SARS-CoV-2 seronegative young Indian adults.

This proof-of-concept study tested if prior BCG revaccination can qualitatively and quantitively enhance antibody and T-cell responses induced by Oxford/AstraZeneca ChAdOx1nCoV-19 or COVISHIELD™, an efficacious and the most widely distributed vaccine in India. We compared COVISHIELD™ induced longitudinal immune responses in 21 BCG re-vaccinees (BCG-RV) and 13 BCG-non-revaccinees (BCG-NRV), all of whom were BCG vaccinated at birth; latent tuberculosis negative and SARS-CoV-2 seronegative prior to COVISHIELD™ vaccination. Compared to BCG-NRV, BCG-RV displayed significantly higher and persistent spike-specific neutralizing (n) Ab titers and polyfunctional CD4+ and CD8+ T-cells for eight months post COVISHIELD™ booster, including distinct CD4+IFN-γ+ and CD4+IFN-γ- effector memory (EM) subsets co-expressing IL-2, TNF-α and activation induced markers (AIM) CD154/CD137 as well as CD8+IFN-γ+ EM,TEMRA (T cell EM expressing RA) subset combinations co-expressing TNF-α and AIM CD137/CD69. Additionally, elevated nAb and T-cell responses to the Delta mutant in BCG-RV highlighted greater immune response breadth. Mechanistically, these BCG adjuvant effects were associated with elevated markers of trained immunity, including higher IL-1β and TNF-α expression in CD14+HLA-DR+monocytes and changes in chromatin accessibility highlighting BCG-induced epigenetic changes. This study provides first in-depth analysis of both antibody and memory T-cell responses induced by COVISHIELD™ in SARS-CoV-2 seronegative young adults in India with strong evidence of a BCG-induced booster effect and therefore a rational basis to validate BCG, a low-cost and globally available vaccine, as an adjuvant to enhance heterologous adaptive immune responses to current and emerging COVID-19 vaccines.