scholarly journals Tinjauan Molekuler dan Epidemiologi Mutasi pada Virus SARS-CoV-2

bionature ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Hartono Hartono ◽  
Yenni Yusuf
Keyword(s):  
Immune System ◽  
Literature Review ◽  
Viral Entry ◽  
Host Cells ◽  
Spike Protein ◽  
Wild Type ◽  
Viral Binding ◽  
Viral Mutation ◽  
Alpha Beta ◽  
The Impact

Abstract. The SARS-CoV-2 virus which is the cause of the COVID-19 pandemic since the end of 2019 has undergone many mutations that gave rise to several variants of concern (VOC) with higher transmission, virulence, and ability to evade the immune system than the initial variant (wild-type). Until now, there are four variants included in the VOC of the virus, namely alpha, beta, gamma and delta variants. The increased transmission and virulence of these VOCs were associated with mutational changes in the spike protein, which is the structure of the virus that plays a role in binding to host cells. In this article, we conduct a literature review on VOCs from the SARS-CoV-2 virus related to mutations that occur and their impact on the viral binding process. To gain an understanding of the impact of mutations in these variants, we also reviewed the structure of the spike protein and the process of viral entry into host cells. Keywords: viral mutation, variants of concern (VOC), COVID-19, SARS-CoV-2.

scholarly journals Investigation of Interaction Between the Spike Protein of SARS-CoV-2 and ACE2-Expressing Cells Using an In Vitro Cell Capturing System

2021 ◽  
Author(s):  
Yuning Shang ◽  
Feixiang Chen ◽  
Shasha Li ◽  
Lijuan Song ◽  
Yunzhen Gao ◽  
...  
Keyword(s):  
Viral Entry ◽  
Living Cells ◽  
Host Cells ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Wild Type ◽  
Protein Variant ◽  
In Vitro System ◽  
Angiotensin Converting Enzyme 2

Abstract Background: The Interaction between severe acute respiratory syndrome coronavirus 2 ( SARS-CoV-2 ) spike protein with Angiotensin converting enzyme 2 (ACE2) on the host cells is a crucial step for the viral entry and infection. Therefore, investigating the molecular mechanism underlying the interaction is of great importance for the prevention of the infection of SARS-CoV-2. In this study, we aimed to establish a virus-free in vitro system to study the interaction between the spike protein and host cells of SARS-CoV-2.Results: Our results show that ACE2-overexpressing HEK293T cells are captured by immobilized spike protein, and the cell capturing process can be inhibited by the receptor binding domain of the spike protein or antibodies against S protein. Furthermore, spike protein variant with D614G mutant show a higher cell capturing ability than wild type spike protein. In addition, the captured cells can be eluted as living cells for further investigation.Conclusions: This study provides a new in vitro system for investigating the interaction between SARS-CoV-2 and host cells and purifying ACE2-expressing cells.

scholarly journals The Effects of Aβ1-42 Binding to the SARS-CoV-2 Spike Protein S1 Subunit and Angiotensin-Converting Enzyme 2

2021 ◽  
Vol 22 (15) ◽  
pp. 8226
Author(s):  
John Tsu-An Hsu ◽  
Chih-Feng Tien ◽  
Guann-Yi Yu ◽  
Santai Shen ◽  
Yi-Hsuan Lee ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Viral Entry ◽  
Negative Impact ◽  
Spike Protein ◽  
Infection Model ◽  
Converting Enzyme ◽  
Viral Receptor ◽  
Angiotensin Converting Enzyme 2 ◽  
People With Dementia ◽  
The Impact

Increasing evidence suggests that elderly people with dementia are vulnerable to the development of severe coronavirus disease 2019 (COVID-19). In Alzheimer’s disease (AD), the major form of dementia, β-amyloid (Aβ) levels in the blood are increased; however, the impact of elevated Aβ levels on the progression of COVID-19 remains largely unknown. Here, our findings demonstrate that Aβ1-42, but not Aβ1-40, bound to various viral proteins with a preferentially high affinity for the spike protein S1 subunit (S1) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the viral receptor, angiotensin-converting enzyme 2 (ACE2). These bindings were mainly through the C-terminal residues of Aβ1-42. Furthermore, Aβ1-42 strengthened the binding of the S1 of SARS-CoV-2 to ACE2 and increased the viral entry and production of IL-6 in a SARS-CoV-2 pseudovirus infection model. Intriguingly, data from a surrogate mouse model with intravenous inoculation of Aβ1-42 show that the clearance of Aβ1-42 in the blood was dampened in the presence of the extracellular domain of the spike protein trimers of SARS-CoV-2, whose effects can be prevented by a novel anti-Aβ antibody. In conclusion, these findings suggest that the binding of Aβ1-42 to the S1 of SARS-CoV-2 and ACE2 may have a negative impact on the course and severity of SARS-CoV-2 infection. Further investigations are warranted to elucidate the underlying mechanisms and examine whether reducing the level of Aβ1-42 in the blood is beneficial to the fight against COVID-19 and AD.

scholarly journals The Roles of Prebiotics on Impaired Immune System in Preterm Infants: A Narrative Literature Review

2021 ◽  
Vol 5 (1SP) ◽  
pp. 21
Author(s):  
Zakiudin Munasir
Keyword(s):  
Immune System ◽  
Breast Milk ◽  
Literature Review ◽  
Gut Microbiota ◽  
Preterm Infants ◽  
Human Breast Milk ◽  
Immune System Development ◽  
Narrative Literature ◽  
Narrative Literature Review ◽  
The Impact

ABSTRACT Background: After birth, preterm infants face numerous challenges, including short and long-term morbidities, to survive and grow well with impaired immune and gastrointestinal systems. According to data from 184 countries, preterm birth rate ranges from 5-18%, accounting for 35% of all new born deaths. Purpose: This literature review aimed to summarize the evidence for the impact of prematurity on immune system development and the benefit of prebiotics on gut microbiota and immune responses. Discussion: Various studies in this narrative literature review showed that preterm infants have both qualitative and quantitative immune response deficits compared to term infants. Preterm newborns also have impaired intestinal immunity, underdeveloped intestinal mucosa barrier, and gut dysbiosis, which predisposes them to life-threatening infections. Early balanced gut microbiota in infants believed to be essential for adequate intestinal physiological functions and immune system maturation. The use of prebiotics, including human milk oligosaccharides (HMOs) in human breast milk, has been found to decrease the risk of various infections and cognitive impairment. A previous study found that prebiotic oligosaccharides supplementation was well-tolerated, significantly increased Bifidobacteria growth, and reduced the presence of gut pathogens. Conclusions: There was robust evidence that breast milk and prebiotics supplementation may support the gut microbiome and immune system in preterm infants. However, different types of synthetic prebiotics offer different benefits, and the protective effect seems to depend on the supplementation duration and dosage.

scholarly journals Inhibition of SARS-CoV-2 viral entry upon blocking N- and O-glycan elaboration

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Qi Yang ◽  
Thomas A Hughes ◽  
Anju Kelkar ◽  
Xinheng Yu ◽  
Kai Cheng ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Viral Entry ◽  
Multiple Roles ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Mechanistic Studies ◽  
Post Translational Modification ◽  
Minor Contribution ◽  
Chemical Inhibitors ◽  
The Impact

The Spike protein of SARS-CoV-2, its receptor-binding domain (RBD), and its primary receptor ACE2 are extensively glycosylated. The impact of this post-translational modification on viral entry is yet unestablished. We expressed different glycoforms of the Spike-protein and ACE2 in CRISPR-Cas9 glycoengineered cells, and developed corresponding SARS-CoV-2 pseudovirus. We observed that N- and O-glycans had only minor contribution to Spike-ACE2 binding. However, these carbohydrates played a major role in regulating viral entry. Blocking N-glycan biosynthesis at the oligomannose stage using both genetic approaches and the small molecule kifunensine dramatically reduced viral entry into ACE2 expressing HEK293T cells. Blocking O-glycan elaboration also partially blocked viral entry. Mechanistic studies suggest multiple roles for glycans during viral entry. Among them, inhibition of N-glycan biosynthesis enhanced Spike-protein proteolysis. This could reduce RBD presentation on virus, lowering binding to host ACE2 and decreasing viral entry. Overall, chemical inhibitors of glycosylation may be evaluated for COVID-19.

scholarly journals Engineered ACE2 receptor traps potently neutralize SARS-CoV-2

2020 ◽  
Vol 117 (45) ◽  
pp. 28046-28055 ◽  
Author(s):  
Anum Glasgow ◽  
Jeff Glasgow ◽  
Daniel Limonta ◽  
Paige Solomon ◽  
Irene Lui ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Viral Entry ◽  
Neutralizing Antibodies ◽  
Surface Display ◽  
Random Mutagenesis ◽  
Yeast Surface Display ◽  
Host Cells ◽  
Spike Protein ◽  
Receptor Protein ◽  
Yeast Surface

An essential mechanism for severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection begins with the viral spike protein binding to the human receptor protein angiotensin-converting enzyme II (ACE2). Here, we describe a stepwise engineering approach to generate a set of affinity optimized, enzymatically inactivated ACE2 variants that potently block SARS-CoV-2 infection of cells. These optimized receptor traps tightly bind the receptor binding domain (RBD) of the viral spike protein and prevent entry into host cells. We first computationally designed the ACE2–RBD interface using a two-stage flexible protein backbone design process that improved affinity for the RBD by up to 12-fold. These designed receptor variants were affinity matured an additional 14-fold by random mutagenesis and selection using yeast surface display. The highest-affinity variant contained seven amino acid changes and bound to the RBD 170-fold more tightly than wild-type ACE2. With the addition of the natural ACE2 collectrin domain and fusion to a human immunoglobulin crystallizable fragment (Fc) domain for increased stabilization and avidity, the most optimal ACE2 receptor traps neutralized SARS-CoV-2–pseudotyped lentivirus and authentic SARS-CoV-2 virus with half-maximal inhibitory concentrations (IC50s) in the 10- to 100-ng/mL range. Engineered ACE2 receptor traps offer a promising route to fighting infections by SARS-CoV-2 and other ACE2-using coronaviruses, with the key advantage that viral resistance would also likely impair viral entry. Moreover, such traps can be predesigned for viruses with known entry receptors for faster therapeutic response without the need for neutralizing antibodies isolated from convalescent patients.

scholarly journals Cytoplasmic tail truncation of SARS-CoV-2 Spike protein enhances titer of pseudotyped vectors but masks the effect of the D614G mutation

2021 ◽  
Author(s):  
Hsu-Yu Chen ◽  
Chun Huang ◽  
Lu Tian ◽  
Xiaoli Huang ◽  
Chennan Zhang ◽  
...  
Keyword(s):  
Viral Entry ◽  
High Titer ◽  
Cytoplasmic Tail ◽  
Cell Types ◽  
Spike Protein ◽  
Tangential Flow Filtration ◽  
Tangential Flow ◽  
Protein Functions ◽  
Flow Filtration ◽  
The Impact

The high pathogenicity of SARS-CoV-2 requires it to be handled under biosafety level 3 conditions. Consequently, Spike protein pseudotyped vectors are a useful tool to study viral entry and its inhibition, with retroviral, lentiviral (LV) and vesicular stomatitis virus (VSV) vectors the most commonly used systems. Methods to increase the titer of such vectors commonly include concentration by ultracentrifugation and truncation of the Spike protein cytoplasmic tail. However, limited studies have examined whether such a modification also impacts the protein’s function. Here, we optimized concentration methods for SARS-CoV-2 Spike pseudotyped VSV vectors, finding that tangential flow filtration produced vectors with more consistent titers than ultracentrifugation. We also examined the impact of Spike tail truncation on transduction of various cell types and sensitivity to convalescent serum neutralization. We found that tail truncation increased Spike incorporation into both LV and VSV vectors and resulted in enhanced titers, but had no impact on sensitivity to convalescent serum inhibition. In addition, we analyzed the effect of the D614G mutation, which became a dominant SARS-CoV-2 variant early in the pandemic. Our studies revealed that, similar to the tail truncation, D614G independently increases Spike incorporation and vector titers, but that this effect is masked by also including the cytoplasmic tail truncation. Therefore, the use of full-length Spike protein, combined with tangential flow filtration, is recommended as a method to generate high titer pseudotyped vectors that retain native Spike protein functions.

scholarly journals In-vivo Protection from SARS-CoV-2 infection by ATN-161 in k18-hACE2 transgenic mice

2021 ◽  
Author(s):  
Amruta Narayanappa ◽  
Elizabeth B Engler-Chiurazzi ◽  
Isabel C Murray-Brown ◽  
Timothy E Gressett ◽  
Ifechukwude J Biose ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Viral Entry ◽  
Therapeutic Potential ◽  
Host Cells ◽  
Spike Protein ◽  
Cell Infection ◽  
Integrin Alpha5beta1 ◽  
Chemokine Ligand

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an infectious disease that has spread worldwide. Current treatments are limited in both availability and efficacy, such that improving our understanding of the factors that facilitate infection is urgently needed to more effectively treat infected individuals and to curb the pandemic. We and others have previously demonstrated the significance of interactions between the SARS-CoV-2 spike protein, integrin alpha5beta1 and human ACE2 to facilitate viral entry into host cells in vitro. We previously found that inhibition of integrin alpha5beta1 by the clinically validated small peptide ATN-161 inhibits these spike protein interactions and cell infection in vitro. In continuation with our previous findings, here we have further evaluated the therapeutic potential of ATN-161 on SARS-CoV-2 infection in k18-hACE2 transgenic (SARS-CoV-2 susceptible) mice in vivo. We discovered that treatment with single- or repeated intravenous doses of ATN-161 (1 mg/kg) within 48 hours after intranasal inoculation with SARS-CoV-2 lead to a reduction of lung viral load, viral immunofluorescence and improved lung histology in a majority of mice 72 hours post-infection. Furthermore, ATN-161 reduced SARS-CoV-2-induced increased expression of lung integrin alpha 5 and alpha v (an alpha 5-related integrin that has also been implicated in SARS-CoV-2 interactions) as well as the C-X-C motif chemokine ligand 10 (Cxcl10), further supporting the potential involvement of these integrins, and the anti-inflammatory potential of ATN-161, respectively, in SARS-CoV-2 infection. To the best of our knowledge, this is the first study demonstrating the potential therapeutic efficacy of targeting integrin alpha5beta1 in SARS-CoV-2 infection in vivo and supports the development of ATN-161 as a novel SARS-CoV-2 therapy.

scholarly journals The Impact of Broadly Relevant Novel Discoveries on Student Project Ownership in a Traditional Lab Course Turned CURE

2019 ◽  
Vol 18 (4) ◽  
pp. ar57 ◽  
Author(s):  
Katelyn M. Cooper ◽  
Joseph N. Blattman ◽  
Taija Hendrix ◽  
Sara E. Brownell
Keyword(s):  
Immune System ◽  
Mutant Strain ◽  
Student Outcomes ◽  
Scientific Community ◽  
Undergraduate Research ◽  
Wild Type ◽  
Research Experiences ◽  
Undergraduate Research Experiences ◽  
The Impact ◽  
Insight Into

Course-based undergraduate research experiences (CUREs) have been shown to lead to multiple student benefits, but much is unknown about how CUREs lead to specific student outcomes. In this study, we examined the extent to which students making “broadly relevant novel discoveries” impacted student project ownership by comparing the experiences of students in a CURE and a traditional lab course. The CURE and traditional lab were similar in most aspects; students were exposed to an identical curriculum taught by the same instructor. However, there was one major difference between the two types of courses: the type of data that the students produced. Students in the traditional lab characterized the immune system of wild-type mice, thereby confirming results already known to the scientific community, while students in the CURE characterized the immune system of a mutant strain of mice, which produced broadly relevant novel discoveries. Compared with traditional lab students, CURE students reported higher cognitive and emotional ownership over their projects. Students’ perceptions of collaboration and making broadly relevant novel discoveries were significantly and positively related to their cognitive and emotional ownership. This work provides insight into the importance of integrating opportunities for broadly relevant novel discoveries in lab courses.

scholarly journals Porphyromonas gingivalis Sphingolipid Synthesis Limits the Host Inflammatory Response

2020 ◽  
Vol 99 (5) ◽  
pp. 568-576 ◽  
Author(s):  
F.G. Rocha ◽  
Z.D. Moye ◽  
G. Ottenberg ◽  
P. Tang ◽  
D.J. Campopiano ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Porphyromonas Gingivalis ◽  
Potential Role ◽  
Host Cells ◽  
Cell Contact ◽  
Rna Seq ◽  
Wild Type ◽  
Working Hypothesis ◽  
The Impact ◽  
Host Inflammatory Response

Porphyromonas gingivalis, like other bacteria belonging to the phylum Bacteroidetes, synthesizes sphingolipids (SLs). However, their exact roles in microbial physiology and their potential role in mediating interactions with their eukaryotic host are unclear. Our working hypothesis for this study was that synthesis of SLs (host-like lipids) affords a mechanism that allows P. gingivalis to persist in homeostasis with its host. In a previous study, we deleted a gene (PG1780 in strain W83) predicted to encode a serine palmitoyl transferase (SPT)—the enzyme that catalyzes the first conserved step in the synthesis of SLs—and we determined that the mutant was unable to synthesize SLs. Here, we characterized the SPT enzyme encoded by PG1780, analyzed the impact of SPT deletion on P. gingivalis gene expression (RNA-Seq analysis), and began to define the impact of SL synthesis on its interactions with host cells. Enzymatic analysis verified that the protein encoded by PG1780 is indeed an SPT. RNA-Seq analysis determined that a lack of SL synthesis results in differential expression of extracytoplasmic function sigma factors, components of the type IX secretion system (T9SS), and CRISPR and cas genes. Our data demonstrate that when human THP1 macrophage-like cells were challenged with the wild type (W83) and the SL-null mutant (W83 ΔSPT), the SL-null strain elicited a robust inflammatory response (elevated IL-1β, IL-6, IL-10, IL-8, RANTES, and TNFα) while the response to the parent strain W83 was negligible. Interestingly, we also discovered that SLs produced by P. gingivalis can be delivered to host cells independent of cell-to-cell contact. Overall, our results support our working hypothesis that synthesis of SLs by P. gingivalis is central to its ability to manipulate the host inflammatory response, and they demonstrate the integral importance of SLs in the physiology of P. gingivalis.

COVID-19 Vaccines and Dentistry

Dental Update ◽  
2021 ◽  
Vol 48 (1) ◽  
pp. 76-81
Author(s):  
Lakshman Samaranayake ◽  
Kausar Sadia Fakhruddin
Keyword(s):  
Decision Making ◽  
Immune System ◽  
Antibody Response ◽  
Viral Proteins ◽  
Host Cells ◽  
Bad News ◽  
Host Immune System ◽  
Dental Practice ◽  
The Impact ◽  
Gift Wrapping

Transplant pioneer, Peter Medawar, once said that a virus is ‘simply a piece of bad news wrapped in protein’. One could opine then, that the new COVID-19 vaccines are ‘Bits of corona viral proteins in gift wrapping.’ For, most of the COVID-19 vaccines are based on the principle that pre-exposure of the vaccinee's host immune system to the spike proteins of SARS-CoV-2, the first part of the viral anatomy that touches the vulnerable host cells, will elicit an effective antibody response to curb potential future infections. COVID-19 vaccines come in many sizes and shapes, and clearly, a return to normal, post-COVID dental practice entails protecting all members of the dental team with an appropriate vaccine, as and when available. We provide a thumbnail sketch of the COVID-19 vaccines currently in the offing, which we hope will be helpful for decision-making for choice of vaccine. The commentary ends with a discussion of the impact of COVID-19 vaccines on dentistry, in general.

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