scholarly journals Mutational analysis of SARS-CoV-2. ORF8 and the evolution of the Delta and Omicron variants.

2021 ◽  
Author(s):  
Gopika Trieu ◽  
Vuong N Trieu
Keyword(s):  
Immune Responses ◽  
Mutational Analysis ◽  
Structural Proteins ◽  
S Protein ◽  
High Entropy ◽  
Therapeutic Drugs ◽  
Acquired Immune Responses ◽  
Evolutionary Paths ◽  
Second Wave

SARS-CoV-2 the virus responsible for the current pandemic. This virus is continually evolving, adapting to both innate and acquired immune responses and therapeutic drugs. Therefore, it is important to understand how the virus evolving to design the appropriate therapeutic and vaccine in preparation for future variants. Here, we used the online SARS-CoV-2 databases, Nextstrain and Ourworld, to map the evolution and epidemiology of the virus. We identified 30 high entropy residues which underwent a progressive evolution to arrive at the current dominant variant - Delta variant. The virus underwent mutational waves with the first wave made up of structural proteins important in its infectivity and the second wave made up of the ORFs important for its contagion. The most important driver of the second wave is ORF8 mutations at residue 119 and 120. Further mutations of these two residues are creating new clades that are offshoots from the Delta backbone. More importantly the further expansion of the S protein in the Omicron variant is now followed with the acquisition of ORF8 mutations 119 and 120. These findings demonstrate how SARS-CoV-2 mutates and points to two evolutionary paths; 1) Mutational expansion on the Delta backbone among the ORFs and 2) Mutational expansion of the S protein on other backbone follow with mutational wave among the ORFs. Both are happening at the same time right now with the Omicron variant early in the first wave to follow with a more aggressive second wave of mutations.

scholarly journals Safety and immunogenicity of an mRNA-lipid nanoparticle vaccine candidate against SARS-CoV-2

2021 ◽  
Author(s):  
Peter G. Kremsner ◽  
Philipp Mann ◽  
Arne Kroidl ◽  
Isabel Leroux-Roels ◽  
Christoph Schindler ◽  
...  
Keyword(s):  
Immune Responses ◽  
Vaccine Candidate ◽  
Phase 1 ◽  
Lipid Nanoparticles ◽  
Enzyme Linked Immunosorbent Assay ◽  
Receptor Binding Domain ◽  
Igg Antibodies ◽  
Phase 1 Study ◽  
S Protein ◽  
Dosage Escalation

Summary Background We used the RNActive® technology platform (CureVac N.V., Tübingen, Germany) to prepare CVnCoV, a COVID-19 vaccine containing sequence-optimized mRNA coding for a stabilized form of SARS-CoV‑2 spike (S) protein encapsulated in lipid nanoparticles (LNP). Methods This is an interim analysis of a dosage escalation phase 1 study in healthy 18–60-year-old volunteers in Hannover, Munich and Tübingen, Germany, and Ghent, Belgium. After giving 2 intramuscular doses of CVnCoV or placebo 28 days apart we assessed solicited local and systemic adverse events (AE) for 7 days and unsolicited AEs for 28 days after each vaccination. Immunogenicity was measured as enzyme-linked immunosorbent assay (ELISA) IgG antibodies to SARS-CoV‑2 S‑protein and receptor binding domain (RBD), and SARS-CoV‑2 neutralizing titers (MN50). Results In 245 volunteers who received 2 CVnCoV vaccinations (2 μg, n = 47, 4 μg, n = 48, 6 μg, n = 46, 8 μg, n = 44, 12 μg, n = 28) or placebo (n = 32) there were no vaccine-related serious AEs. Dosage-dependent increases in frequency and severity of solicited systemic AEs, and to a lesser extent local AEs, were mainly mild or moderate and transient in duration. Dosage-dependent increases in IgG antibodies to S‑protein and RBD and MN50 were evident in all groups 2 weeks after the second dose when 100% (23/23) seroconverted to S‑protein or RBD, and 83% (19/23) seroconverted for MN50 in the 12 μg group. Responses to 12 μg were comparable to those observed in convalescent sera from known COVID-19 patients. Conclusion In this study 2 CVnCoV doses were safe, with acceptable reactogenicity and 12 μg dosages elicited levels of immune responses that overlapped those observed in convalescent sera.

The complexity of coagulopathy pathogenesis in COVID-19.

2020 ◽  
Author(s):  
Е.П. Харченко
Keyword(s):  
Antiviral Effect ◽  
Surface Proteins ◽  
Structural Proteins ◽  
Atypical Pneumonia ◽  
Positive Polarity ◽  
S Protein ◽  
Immune Systems ◽  
Hemostasis System ◽  
Relationship Of

Введение. Коронавирус SARS-CoV-2 является новым вирусом, обладающим способностью осуществлять трансмиссию воздушно-капельным путем, вызывая тяжелое течение атипичной пневмонии, нередко сочетающейся с коагулопатиями. Роль структурных белков коронавируса в их патогенезе неизвестна. Цель исследования: с помощью биоинформационного анализа выявить в структурных белках коронавируса SARS-CoV-2 последовательности, гомологичные белкам системы гемостаза, и рассмотреть возможные сценарии их участия в патогенезе коагулопатий при COVID-19, а также объяснить существование вирусостатического эффекта гепарина. Материалы и методы. Для компьютерного анализа были использованы доступные в Интернете базы данных первичных структур белков коронавирусов и их рецепторов, а также поверхностных белков других вирусов, белков системы гемостаза и иммунной системы. Сравнивали аминокислотный состав белков и распределение оснόвных аминокислот (аргинина и лизина) в их первичных последовательностях. С целью выявления пептидного (иммуноэпитопного) родства структурных белков коронавирусов с белками системы гемостаза человека был выполнен поиск гомологичных последовательностей в их белках. Результаты. В структурных белках коронавируса SARS-CoV-2 выявлено множество последовательностей, гомологичных белкам системы гемостаза и иммунной системы. В отличие от коронавирусов SARS-CoV и MERS-CoV, S1-субъединица S-белка коронавируса SARS-CoV-2 имеет положительную полярность. Заключение. Множество последовательностей в структурных белках коронавируса SARS-CoV-2, гомологичных белкам системы гемостаза, потенциально способны вы- зывать различные сценарии патогенеза коагулопатий. Положительная полярность S1-субъединицы S-белка коронавируса SARS-CoV-2 позволяет объяснить неспецифическое взаимодействие ее с гепарином и его вирусостатический (неантикоагулянтный) эффект. Background. The coronavirus SARS-CoV-2 is a new virus capable of human-human transmission and inducing a severe atypical pneumonia often associated with coagulopathy. A role of SARS-CoV-2 structural proteins in coagulopathy pathogenesis is unknown. Objectives: to use a bioinformation analysis to identify SARS-CoV-2 sequences in the structural proteins that are homologous to hemostasis system proteins, regard their possible participation in coagulopathy pathogenesis and explain the antiviral effect of heparin. Materials / Methods. For computer analysis, Internet databases were used of the primary structures of coronavirus proteins and their receptors, as well as surface proteins of other viruses, proteins of hemostasis and immune systems. The amino acid composition of proteins and the distribution of basic amino acids (arginine and lysine) in their primary sequences were compared. For detection of peptide (immunoepitopic) relationship of coronaviruses structural proteins with human hemostasis proteins, a search for homologous sequences in their proteins was performed. Results. Many sequences have been identified in structural proteins of SARS-CoV-2 coronavirus that are homologous to the proteins of hemostasis and immune systems. In contrast with SARS-CoV and MERS-CoV coronaviruses, the S1-subunit of SARS-CoV-2 coronavirus S-protein has a positive polarity. Conclusions. Many sequences in SARS-CoV-2 structural proteins that homologous to hemostasis system proteins are potentially responsible for coagulopathy pathogenesis. The positive polarity of the S1-subunit of SARS-CoV-2 S-protein explains its nonspecific interaction with heparin and its virostatic (non-anticoagulant) effect.

scholarly journals Rho-mDia1 pathway is required for adhesion, migration, and T-cell stimulation in dendritic cells

Blood ◽  
2010 ◽  
Vol 116 (26) ◽  
pp. 5875-5884 ◽  
Author(s):  
Hideaki Tanizaki ◽  
Gyohei Egawa ◽  
Kayo Inaba ◽  
Tetsuya Honda ◽  
Saeko Nakajima ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
T Cell ◽  
Immune Responses ◽  
Lymph Nodes ◽  
Actin Polymerization ◽  
Cell Stimulation ◽  
T Cell Stimulation ◽  
Acquired Immune Responses

Abstract Dendritic cells (DCs) are essential for the initiation of acquired immune responses through antigen acquisition, migration, maturation, and T-cell stimulation. One of the critical mechanisms in this response is the process actin nucleation and polymerization, which is mediated by several groups of proteins, including mammalian Diaphanous-related formins (mDia). However, the role of mDia in DCs remains unknown. Herein, we examined the role of mDia1 (one of the isoforms of mDia) in DCs. Although the proliferation and maturation of bone marrow-derived DCs were comparable between control C57BL/6 and mDia1-deficient (mDia1−/−) mice, adhesion and spreading to cellular matrix were impaired in mDia1−/− bone marrow–derived DCs. In addition, fluorescein isothiocyanate-induced cutaneous DC migration to draining lymph nodes in vivo and invasive migration and directional migration to CCL21 in vitro were suppressed in mDia1−/− DCs. Moreover, sustained T-cell interaction and T-cell stimulation in lymph nodes were impaired by mDia1 deficiency. Consistent with this, the DC-dependent delayed hypersensitivity response was attenuated by mDia1-deficient DCs. These results suggest that actin polymerization, which is mediated by mDia1, is essential for several aspects of DC-initiated acquired immune responses.

scholarly journals Essential functions of Runx/Cbfβ in gut conventional dendritic cells for priming Rorγt+ T cells

2019 ◽  
Vol 3 (1) ◽  
pp. e201900441 ◽  
Author(s):  
Mari Tenno ◽  
Alicia Yoke Wei Wong ◽  
Mika Ikegaya ◽  
Eiji Miyauchi ◽  
Wooseok Seo ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Cell Polarization ◽  
Th Cells ◽  
Th Cell ◽  
Intrinsic Mechanism ◽  
Specific Effector ◽  
Acquired Immune Responses ◽  
Type 3

Acquired immune responses are initiated by activation of CD4+ helper T (Th) cells via recognition of antigens presented by conventional dendritic cells (cDCs). DCs instruct Th-cell polarization program into specific effector Th subset, which will dictate the type of immune responses. Hence, it is important to unravel how differentiation and/or activation of DC are linked with Th-cell–intrinsic mechanism that directs differentiation toward a specific effector Th subset. Here, we show that loss of Runx/Cbfβ transcription factors complexes during DC development leads to loss of CD103+CD11b+ cDC2s and alters characteristics of CD103−CD11b+ cDCs in the intestine, which was accompanied with impaired differentiation of Rorγt+ Th17 cells and type 3 Rorγt+ regulatory T cells. We also show that a Runx-binding enhancer in the Rorc gene is essential for T cells to integrate cDC-derived signals to induce Rorγt expression. These findings reveal that Runx/Cbfβ complexes play crucial and complementary roles in cDCs and Th cells to shape converging type 3 immune responses.

scholarly journals Emergence of a new SARS-CoV-2 variant from GR clade with a novel S glycoprotein mutation V1230L in West Bengal, India

2021 ◽  
Author(s):  
Rakesh Sarkar ◽  
Ritubrita Saha ◽  
Pratik Mallick ◽  
Ranjana Sharma ◽  
Amandeep Kaur ◽  
...  
Keyword(s):  
South African ◽  
West Bengal ◽  
Transmembrane Domain ◽  
Mutational Analysis ◽  
Viral Envelope ◽  
Protein Coding ◽  
S Protein ◽  
Genomic Epidemiology ◽  
Clade B ◽  
New Variant

India is currently facing the devastating second wave of COVID-19 pandemic resulting in approximately 4000 deaths per day. To control this pandemic continuous mutational surveillance and genomic epidemiology of circulating strains is very important. In this study, we performed mutational analysis of the protein coding genes of SARS-CoV-2 strains (n=2000) collected during January 2021 to March 2021. Our data revealed the emergence of a new variant in West Bengal, India, which is characterized by the presence of 11 co-existing mutations including D614G, P681H and V1230L in S-glycoprotein. This new variant was identified in 70 out of 412 sequences submitted from West Bengal. Interestingly, among these 70 sequences, 16 sequences also harbored E484K in the S glycoprotein. Phylogenetic analysis revealed strains of this new variant emerged from GR clade (B.1.1) and formed a new cluster. We propose to name this variant as GRL or lineage B.1.1/S:V1230L due to the presence of V1230L in S glycoprotein along with GR clade specific mutations. Co-occurrence of P681H, previously observed in UK variant, and E484K, previously observed in South African variant and California variant, demonstrates the convergent evolution of SARS-CoV-2 mutation. V1230L, present within the transmembrane domain of S2 subunit of S glycoprotein, has not yet been reported from any country. Substitution of valine with more hydrophobic amino acid leucine at position 1230 of the transmembrane domain, having role in S protein binding to the viral envelope, could strengthen the interaction of S protein with the viral envelope and also increase the deposition of S protein to the viral envelope, and thus positively regulate virus infection. P618H and E484K mutation have already been demonstrated in favor of increased infectivity and immune invasion respectively. Therefore, the new variant having G614G, P618H, P1230L and E484K is expected to have better infectivity, transmissibility and immune invasion characteristics, which may pose additional threat along with B.1.617 in the ongoing COVID-19 pandemic in India.

scholarly journals SARS CoV-2 Variants and Spike Mutations Involved in Second Wave of COVID-19 Pandemic in India

2021 ◽  
Author(s):  
Muttineni Radhakrishna ◽  
Binitha R ◽  
Kalyani Putty ◽  
Kavitha Marpakala ◽  
Panyam Jaslin ◽  
...  
Keyword(s):  
Biological Significance ◽  
Transmembrane Region ◽  
Genome Sequences ◽  
Neutralising Antibodies ◽  
S Protein ◽  
Terminal Domain ◽  
Alpha Variant ◽  
National Trends ◽  
Second Wave ◽  
Peptide Region

Against the backdrop of the second wave of COVID-19 pandemic in India that started in March 2021, we have monitored the spike (S) protein mutations in all the reported (GISAID portal) whole genome sequences of SARS CoV-2 circulating in India from 1 January 2021 to 31 August 2021. In the 43,102 SARS-CoV-2 genomic sequences analysed, we have identified 24, 260 mutations in the S protein, based on which 265 pango lineages could be categorised. The dominant lineage in most of the 28 states of India and its 8 union territories was B.1.617.2 (the delta variant). However, the states Madhya Pradesh, Jammu & Kashmir, and Punjab had B.1.1.7 (alpha variant) as the major lineage, while the Himachal Pradesh state reported B.1.36 as the dominating lineage. A detailed analysis of various domains of S protein was carried out for detecting mutations having a prevalence of >1%; 70, 18, 7, 3, 9, 4, and 1 (N=112) such mutations were observed in the N -terminal domain, receptor binding domain, C -terminal domain, fusion peptide region, heptapeptide repeat (HR)-1 domains, signal peptide domain, and transmembrane region, respectively. However, no mutations were recorded in the HR-2, and cytoplasmic domains of the S protein. Interestingly, 13.39% (N=15) of these mutations were reported to increase the infectivity and pathogenicity of the virus; 2%(N=3) were known to be vaccine breakthrough mutations; and 0.89%(N=1) were known to escape neutralising antibodies. Biological significance of 82% (N=92) of the reported mutations is yet unknown. As SARS-CoV-2 variants are emerging rapidly, it is critical to continuously monitor local viral mutations to understand national trends of virus circulation. This can tremendously help in designing better preventive regimens in the country, and avoid vaccine breakthrough infections.

scholarly journals Immunostimulatory Effects of Recombinant Erysipelothrix rhusiopathiae Expressing Porcine Interleukin-18 in Mice and Pigs

2012 ◽  
Vol 19 (9) ◽  
pp. 1393-1398 ◽  
Author(s):  
Yohsuke Ogawa ◽  
Yu Minagawa ◽  
Fang Shi ◽  
Masahiro Eguchi ◽  
Yoshihiro Muneta ◽  
...  
Keyword(s):  
Immune Responses ◽  
Peritoneal Macrophages ◽  
Erysipelothrix Rhusiopathiae ◽  
Interleukin 18 ◽  
Murine Splenocytes ◽  
Content Type ◽  
Immunostimulatory Effect ◽  
Ifn Γ ◽  
Acquired Immune Responses

ABSTRACTInterleukin-18 (IL-18), which was originally called gamma interferon (IFN-γ)-inducing factor, has been shown to play an important role in innate and acquired immune responses. In this study, attenuatedErysipelothrix rhusiopathiaestrains were engineered to produce porcine IL-18 (poIL-18) and evaluated for their potential immunostimulatory effect in animals. Recombinant poIL-18 was successfully expressed in the recombinantE. rhusiopathiaestrains YS-1/IL-18 and KO/IL-18. The culture supernatant of YS-1/IL-18 was confirmed to induce IFN-γ production in murine splenocytesin vitro, and this production was inhibited by incubation with anti-poIL-18 monoclonal antibodies. Furthermore, more IFN-γ production was induced upon stimulation of splenocytes with concanavalin A for splenocytes from mice that were intraperitoneally inoculated with YS-1/IL-18 than for splenocytes from control mice inoculated with the parent strain YS-1. Peritoneal macrophages from mice preinoculated with YS-1/IL-18 exhibited enhanced phagocytosis ofSalmonella entericasubsp.entericaserovar Typhimurium compared with peritoneal macrophages from control mice preinoculated with YS-1. We also confirmed the immunostimulatory effect on humoral immune responses against antigens ofE. rhusiopathiaeandMycoplasma hyopneumoniaein gnotobiotic pigs that were orally preinoculated with KO/IL-18. Thus, these results provide evidence thatE. rhusiopathiaeis a promising vector for the expression of host cytokines and suggest the potential utility ofE. rhusiopathiaevector-encoded cytokines in the activation of host innate and acquired immune responses.

scholarly journals Recent Progress on the Versatility of Virus-Like Particles

Vaccines ◽  
2020 ◽  
Vol 8 (1) ◽  
pp. 139 ◽  
Author(s):  
Ciying Qian ◽  
Xinlin Liu ◽  
Qin Xu ◽  
Zhiping Wang ◽  
Jie Chen ◽  
...  
Keyword(s):  
Immune Responses ◽  
Small Molecules ◽  
Genetic Material ◽  
Structural Proteins ◽  
Cell Penetration ◽  
Virus Like Particles ◽  
Humoral Immune ◽  
Specific Targeting ◽  
Humoral Immune Responses ◽  
Antigenic Epitopes

Virus-like particles (VLPs) are multimeric nanostructures composed of one or more structural proteins of a virus in the absence of genetic material. Having similar morphology to natural viruses but lacking any pathogenicity or infectivity, VLPs have gradually become a safe substitute for inactivated or attenuated vaccines. VLPs can achieve tissue-specific targeting and complete and effective cell penetration. With highly ordered epitope repeats, VLPs have excellent immunogenicity and can induce strong cellular and humoral immune responses. In addition, as a type of nanocarrier, VLPs can be used to display antigenic epitopes or deliver small molecules. VLPs have thus become powerful tools for vaccinology and biomedical research. This review highlights the versatility of VLPs in antigen presentation, drug delivery, and vaccine technology.

scholarly journals Dendritic Cells/Macrophages-Targeting Feature of Ebola Glycoprotein and its Potential as Immunological Facilitator for Antiviral Vaccine Approach

2019 ◽  
Vol 7 (10) ◽  
pp. 402
Author(s):  
Titus Abiola Olukitibi ◽  
Zhujun Ao ◽  
Mona Mahmoudi ◽  
Gary A. Kobinger ◽  
Xiaojian Yao
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Ebola Virus ◽  
Vaccine Development ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Immunological Approach ◽  
Vaccine Approach ◽  
Acquired Immune Responses ◽  
Diverse Virus

In the prevention of epidemic and pandemic viral infection, the use of the antiviral vaccine has been the most successful biotechnological and biomedical approach. In recent times, vaccine development studies have focused on recruiting and targeting immunogens to dendritic cells (DCs) and macrophages to induce innate and adaptive immune responses. Interestingly, Ebola virus (EBOV) glycoprotein (GP) has a strong binding affinity with DCs and macrophages. Shreds of evidence have also shown that the interaction between EBOV GP with DCs and macrophages leads to massive recruitment of DCs and macrophages capable of regulating innate and adaptive immune responses. Therefore, studies for the development of vaccine can utilize the affinity between EBOV GP and DCs/macrophages as a novel immunological approach to induce both innate and acquired immune responses. In this review, we will discuss the unique features of EBOV GP to target the DC, and its potential to elicit strong immune responses while targeting DCs/macrophages. This review hopes to suggest and stimulate thoughts of developing a stronger and effective DC-targeting vaccine for diverse virus infection using EBOV GP.

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