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1.
SSRN; 2022.
Preprint in English | SSRN | ID: ppcovidwho-343198

ABSTRACT

The recent outbreak of one of the RNA viruses (2019-nCoV) has affected most of the population and the fatalities reported may label it as a modern-day scourge. Active research on RNA virus infections and vaccine development had more commercial impact which leads to an increase in patent filings. Patents are a goldmine of information whose mining yields crucial technological inputs for further research. In this research article, we have investigated both the patent applications and granted patents, to identify the technological trends and their impact on 2019-nCoV infection using biotechnology-related keywords such as genes, proteins, nucleic acid etc. related to the RNA virus infection. In our research, patent analysis was majorly focused on prospecting for patent data related to the diagnosis and treatment of RNA virus infections. The patent analysis specifically identified spike protein (S protein) and nucleocapsid proteins (N proteins) as the most actively researched macromolecules for vaccine and/or drug development for the diagnosis and treatment of RNA virus-based infectious diseases. The outcomes of this patent intelligence study will be useful for the researchers who are actively working in the area of vaccine or drug development for RNA virus-based infections including 2019-nCoV and other emerging viral infections in the near future.

2.
Annals of the Rheumatic Diseases ; 81:971-972, 2022.
Article in English | EMBASE | ID: covidwho-2009130

ABSTRACT

Background: Enpatoran is a selective and potent dual toll-like receptor (TLR) 7/8 inhibitor in development for the treatment of cutaneous and systemic lupus erythematosus (CLE/SLE). Enpatoran inhibits TLR7/8 activation in vitro and suppresses disease activity in lupus mouse models.1 Enpatoran was well tolerated and had linear pharmacokinetic (PK) parameters in healthy volunteers.2 As TLR7/8 mediate immune responses to single-stranded RNA viruses, including SARS-CoV-2, it was postulated that enpatoran may prevent hyperinfammation and cytokine storm in COVID-19. Objectives: In response to the COVID-19 pandemic, we conducted an exploratory Phase II trial to assess safety and determine whether enpatoran prevents clinical deterioration in patients (pts) hospitalized with COVID-19 pneumonia. PK and pharmacodynamics (PD) of enpatoran were also evaluated. Methods: ANEMONE was a randomized, double-blind, placebo (PBO)-con-trolled study conducted in Brazil, the Philippines, and the USA (NCT04448756). Pts aged 18-75 years, hospitalized with COVID-19 pneumonia (WHO 9-point scale score =4) but not mechanically ventilated, with SpO2 <94% and PaO2/FiO2 ≥150 (FiO2 maximum 0.4) were eligible. Those with a history of uncontrolled illness, active/unstable cardiovascular disease and SARS-CoV-2 vaccination were excluded. Pts received PBO or enpatoran (50 or 100 mg twice daily [BID]) for 14 days, with monitoring to Day 28 and safety follow-up to Day 60. Primary outcomes were safety and time to recovery (WHO 9-point scale ≤3). Clinical deterioration (time to clinical status >4, WHO 9-point scale) was a secondary outcome. Exploratory endpoints were enpatoran and biomarker concentrations (cytokines, C-reactive protein [CRP], D-dimer and interferon gene signature [IFN-GS] scores) assessed over time. Results: 149 pts received either PBO (n=49), or enpatoran 50 mg (n=54) or 100 mg (n=46) BID;88% completed treatment and 86% received concomitant steroids. Median age was 50 years (77% <60 years old), 66% were male, and 50% had ≥1 comorbidity (40% hypertension, 24% diabetes). Overall, 59% pts reported a treatment-emergent adverse event (TEAE) with three non-treatment-related deaths;11% reported a treatment-related TEAE. The proportion of pts in the enpatoran group reporting serious TEAEs was low (50 mg BID 9%;100 mg BID 2%) vs PBO (18%). Gastrointestinal disorders were most common (PBO 8%;50 mg BID 28%;100 mg BID 9%). The primary outcome of time to recovery with enpatoran vs PBO was not met;medians were 3.4-3.9 days. A positive signal in time to clinical deterioration from Day 1 through Day 28 was observed;hazard ratios [95% CI] for enpatoran vs PBO were 0.39 [0.13, 1.15] (50 mg BID) and 0.30 [0.08, 1.08] (100 mg BID). Mean enpatoran exposure was dose-proportional, and PK properties were within expectations. The median (quartile [Q]1-Q3) interleukin 6 (IL-6), CRP and D-dimer baseline concentration across the groups were 5.7 (4.0-13.5) pg/mL, 30.04 (11.40-98.02) and 0.62 (0.39-1.01) mg/L, respectively. Baseline IFN-GS scores were similar across groups. Conclusion: The ANEMONE trial was the frst to evaluate the safety and efficacy of a TLR7/8 inhibitor in an infectious disease for preventing cytokine storm. Enpa-toran up to 100 mg BID for 14 days was well tolerated by patients acutely ill with COVID-19 pneumonia. Time to recovery was not improved with enpatoran, perhaps due to the younger age of patients who had fewer comorbidities compared to those in similar COVID-19 trials. However, there was less likelihood for clinical deterioration with enpatoran than placebo. This trial provides important safety, tolerability, PK and PD data supporting continued development of enpatoran in SLE and CLE (NCT04647708, NCT05162586).

3.
International Journal of Biological Macromolecules ; 219:1208-1215, 2022.
Article in English | EMBASE | ID: covidwho-2007740

ABSTRACT

The recent outbreak of one of the RNA viruses (2019-nCoV) has affected most of the population and the fatalities reported may label it as a modern-day scourge. Active research on RNA virus infections and vaccine development had more commercial impact which leads to an increase in patent filings. Patents are a goldmine of information whose mining yields crucial technological inputs for further research. In this research article, we have investigated both the patent applications and granted patents, to identify the technological trends and their impact on 2019-nCoV infection using biotechnology-related keywords such as genes, proteins, nucleic acid etc. related to the RNA virus infection. In our research, patent analysis was majorly focused on prospecting for patent data related to the RNA virus infections. Our patent analysis specifically identified spike protein (S protein) and nucleocapsid proteins (N proteins) as the most actively researched macromolecules for vaccine and/or drug development for diagnosis and treatment of RNA virus based infectious diseases. The outcomes of this patent intelligence study will be useful for the researchers who are actively working in the area of vaccine or drug development for RNA virus-based infections including 2019-nCoV and other emerging and re-emerging viral infections in the near future.

4.
Journal of Public Health in Africa ; 13:74, 2022.
Article in English | EMBASE | ID: covidwho-2006823

ABSTRACT

Introduction/ Background: The COVID-19 pandemic has impacted public health laboratories with shortages and an increase in the cost of RNA extraction kits. The aim of this project was to develop and validate an RNA extraction kit for use in the diagnosis of SARS-CoV-2 infection to improve COVID-19 testing and surveillance in Nigeria. Methods: The developed kit is based on the spin-column method and named the NIMR Biotech Total RNA Extraction Kit. The kit is intended for RNA extraction from different specimens, including blood, animal tissues, cell lines, bacteria, viruses, and swabs. Analytical validation of the kit for COVID-19 diagnosis was done at six different COVID-19 testing sites on 20 different nasopharyngeal and oropharyngeal specimens, with the results compared using NIMR Biotech. Kit and another commercial RNA extraction kit (spin-column and magnetic-bead based). Results: Validation results showed an average correlation of 93% when compared to other spin-column based kits. When compared with the Qiagen RNA extraction kit, the performance indices of the kit were sensitivity of 94%, specificity of 100%, positive predictive value of 100%, negative predictive values of 94.7%, and accuracy of 95%. The NIMR Biotech total RNA kit showed a good correlation with the DaanGene and the Geneaid extraction kits. In both instances, there was only one disparity between the NIMR Biotech kit and these two kits. Impact: The developed RNA extraction kit from this study provides a suitable and cheaper alternative to high-end, commercially available RNA extraction kits. The adoption of this kit in all COVID-19 testing laboratories in Nigeria, and Africa, will help scale-up COVID-19 testing in Africa. Conclusion: NIMR Biotech's Total RNA extraction kit is sufficiently robust for the extraction of viral and human RNA from oropharyngeal and nasopharyngeal samples. The kit correlates better with the spin-columnbased RNA extraction method when compared to the magnetic-bead-based method and will be useful for monitoring SARS-CoV-2 infection and other RNA viruses.

5.
Annals of Medicine and Surgery ; 81, 2022.
Article in English | EMBASE | ID: covidwho-2003851
6.
J Feline Med Surg ; 24(9):905-933, 2022.
Article in English | PubMed | ID: covidwho-2002009

ABSTRACT

CLINICAL IMPORTANCE: Feline infectious peritonitis (FIP) is one of the most important infectious diseases and causes of death in cats;young cats less than 2 years of age are especially vulnerable. FIP is caused by a feline coronavirus (FCoV). It has been estimated that around 0.3% to 1.4% of feline deaths at veterinary institutions are caused by FIP. SCOPE: This document has been developed by a Task Force of experts in feline clinical medicine as the 2022 AAFP/EveryCat Feline Infectious Peritonitis Diagnosis Guidelines to provide veterinarians with essential information to aid their ability to recognize cats presenting with FIP. TESTING AND INTERPRETATION: Nearly every small animal veterinary practitioner will see cases. FIP can be challenging to diagnose owing to the lack of pathognomonic clinical signs or laboratory changes, especially when no effusion is present. A good understanding of each diagnostic test's sensitivity, specificity, predictive value, likelihood ratio and diagnostic accuracy is important when building a case for FIP. Before proceeding with any diagnostic test or commercial laboratory profile, the clinician should be able to answer the questions of 'why this test?' and 'what do the results mean?' Ultimately, the approach to diagnosing FIP must be tailored to the specific presentation of the individual cat. RELEVANCE: Given that the disease is fatal when untreated, the ability to obtain a correct diagnosis is critical. The clinician must consider the individual patient's history, signalment and comprehensive physical examination findings when selecting diagnostic tests and sample types in order to build the index of suspicion 'brick by brick'. Research has demonstrated efficacy of new antivirals in FIP treatment, but these products are not legally available in many countries at this time. The Task Force encourages veterinarians to review the literature and stay informed on clinical trials and new drug approvals.

7.
mBio ; : e0202122, 2022 Aug 18.
Article in English | MEDLINE | ID: covidwho-1992943

ABSTRACT

RNA viruses include respiratory viruses, such as coronaviruses and influenza viruses, as well as vector-borne viruses, like dengue and West Nile virus. RNA viruses like these encounter various environments when they copy themselves and spread from cell to cell or host to host. Ex vivo differences, such as geographical location and humidity, affect their stability and transmission, while in vivo differences, such as pH and host gene expression, impact viral receptor binding, viral replication, and the host immune response against the viral infection. A critical factor affecting RNA viruses both ex vivo and in vivo, and defining the outcome of viral infections and the direction of viral evolution, is temperature. In this minireview, we discuss the impact of temperature on viral replication, stability, transmission, and adaptation, as well as the host innate immune response. Improving our understanding of how RNA viruses function, survive, and spread at different temperatures will improve our models of viral replication and transmission risk analyses.

8.
Viruses ; 14(7)2022 06 29.
Article in English | MEDLINE | ID: covidwho-1987978

ABSTRACT

Viruses have evolved numerous mechanisms to exploit the molecular machinery of their host cells, including the broad spectrum of host RNA-binding proteins (RBPs). However, the RBP interactomes of most viruses are largely unknown. To shed light on the interaction landscape of RNA viruses with human host cell RBPs, we have analysed 197 single-stranded RNA (ssRNA) viral genome sequences and found that the majority of ssRNA virus genomes are significantly enriched or depleted in motifs for specific human RBPs, suggesting selection pressure on these interactions. To facilitate tailored investigations and the analysis of genomes sequenced in future, we have released our methodology as a fast and user-friendly computational toolbox named SMEAGOL. Our resources will contribute to future studies of specific ssRNA virus-host cell interactions and support the identification of antiviral drug targets.


Subject(s)
RNA Viruses , Viruses , Base Sequence , Genome, Viral , Humans , RNA , RNA Viruses/metabolism , RNA, Viral/metabolism , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , Viruses/genetics
9.
Safety and Risk of Pharmacotherapy ; 10(1):19-33, 2022.
Article in Russian | EMBASE | ID: covidwho-1988954

ABSTRACT

The search for an effective and safe COVID-19 therapy involves, among other things, assessment of efficacy of medicines already used for the treatment of other diseases, and having potential antiviral activity against SARSCoV-2. The relevance of the presented study stems from ambiguous data on the off-label use of the antiparasitic medicine ivermectin for the treatment of COVID-19 patients. The aim of the study was to analyse ivermectin efficacy and safety for COVID-19 treatment, as reflected in the scientific literature. Ivermectin, an antiparasitic medicine from the group of macrocyclic lactones produced by Streptomyces avermitilis, stimulates release of the inhibitory neurotransmitter gamma-aminobutyric acid, which leads to impaired transmission of nerve impulses, paralysis and death of parasites. The results of preclinical studies show ivermectin's inhibitory activity against a number of RNA and DNA viruses, including SARS-CoV-2. The results of ivermectin clinical studies are ambiguous: a number of studies demonstrated a positive effect on the condition of COVID-19 patients, however, there is currently no convincing evidence of the validity and efficacy of ivermectin use for the prevention and treatment of COVID-19 patients. The safety profile of ivermectin is relatively favourable. Large randomised controlled trials are needed to fully assess the feasibility of using ivermectin in COVID-19.

10.
Embase; 2022.
Preprint in English | EMBASE | ID: ppcovidwho-342257

ABSTRACT

To identify novel cellular modulators of HIV-1 infection in IFN-stimulated myeloid cells, we have carried out a screen that combines functional and evolutionary analyses in THP-1-PMA cells that led us to the Tripartite Motif Protein 69 (Trim69), a poorly studied member of the Trim family of innate immunity regulators. Trim69 inhibits HIV-1, primate lentiviruses and the negative and positive-strand RNA viruses VSV and SARS-CoV2, overall indicating it is a broad-spectrum antiviral factor. Trim69 binds directly to microtubules and its antiviral activity is intimately linked to its ability to promote the accumulation of stable MTs, a specialized subset of microtubules. By analyzing the behavior of primary blood cells, we provide evidence that a program of MT stabilization is commonly observed in response to IFN-I in cells of the myeloid lineage and Trim69 is the key factor behind this program. Overall, our study identifies Trim69 as the first antiviral innate defense factor that regulates the properties of microtubules to limit viral spread, highlighting the possibility that the cytoskeleton may be a novel unappreciated fighting ground in the host-pathogen interactions that underlie viral infections.

11.
Biochemical and Cellular Archives ; 22(1 Part-1):887-894, 2022.
Article in English | EMBASE | ID: covidwho-1980180

ABSTRACT

As a result of the scale of the Covid 19 pandemic that launched from China in December 2019 and to limit its spread, several treatments were used to control this virus, including, hydroxychloroquine, favipiravir, lopinavir, remidesivir, tocilizumab, and anakinra. Favipiravir is an antiviral drug that works by inhibiting RNA-dependent RNA polymerase, favipiravir inhibited viral genome replication, which was most noticeable in the middle of the viral proliferation period. Favipiravir was found to have antiviral activity, Purine nucleosides or purine bases inhibit favipiravir, meaning that it competes with purine nucleosides rather than pyrimidine nucleosides, In a time-of-drugaddition test, to treat a variety of RNA viruses (influenza, West Nile, yellow fever, flaviviruses, arenaviruses, bunyaviruses and alphaviruses). Here, we show for the first time the histologycal effect of favipiravir on the liver and kidneys using albino rats, using light microscopy, where the optical microscopic revealed that normal doses in liver showed hepatic cords arranged, normal central vein and mild sinusoildal infiltration of mono nuclear leukocytes mainly lymphocytes, the hepatocytes showed mild granular cytoplasm while double doses showed little hemorrhagic foci and disarrangement of hepatic cords. The magnified sections revealed few of hepatocytes showed mild cloudy swelling associated with little figures of cellular necrosis. As for kidneys, the optical microscopic observations showed multiple foci of hemorrhage, the magnified section revealed congestion of glomerular capillary tuft and few of renal tubules showed mild granular or vacular degeneration. On the other hand, sections of renal medulla revealed normal appearance for normal doses while renal cortex and medulla were showed marked interstitial nephritis, which characterized by interstitial thickening due to infiltration of mono nuclear leukocytes and the renal tubules showed sever vacular degeneration and necrosis for double doses. These results can guide the safe use of favipiravir and reduce the risks to tissue the liver and kidney by using double doses.

12.
Rossiyskiy Vestnik Perinatologii i Pediatrii ; 67(2):28-33, 2022.
Article in Russian | EMBASE | ID: covidwho-1979825

ABSTRACT

At the end of 2019, an outbreak of a new coronavirus, SARS-CoV-2, occurred in China. This virus is highly contagious, transmitted by different routes, such as airborne and contact, but most likely among children it is also transmitted by the fecal-oral route. The disease caused by a new strain of coronavirus is COVID-19. An acute infectious disease has become a pandemic and persists to this day. Currently available data suggests that symptoms of COVID-19 in the adult population may be mild, moderate, or severe. But among children, the course of the disease is very different from that in adults with a milder course. The severe course of COVID-19 among children has been associated with the development of multisystem inflammatory syndrome or Kawasaki disease. In addition to the epidemiological history, laboratory and instrumental analysis, the gold standard for the etiological diagnosis of COVID-19 is the identification of the genetic material — the ribonucleic acid of the virus using reverse transcription polymerase chain reaction. Due to the risk of radiation, a chest CT scan in the pediatric population is only recommended when there is a suspicion of COVID-19. For the prophylaxis and prevention of future epidemics, studying the transmission of SARS-CoV-2 among children is especially important, since the majority of asymptomatic cases of the disease occur in this population. So, the purpose of our study is to review the main clinical manifestations and diagnostic methods of COVID-19 in children.

13.
Biomedical Optics Express ; 13(8):4429-4444, 2022.
Article in English | EMBASE | ID: covidwho-1978816

ABSTRACT

RNA viruses are ubiquitous in nature, many of which can cause severe infectious syndromes to humanity, e.g., the SARS-CoV-2 virus. Ultraviolet (UV) radiation has been widely studied for inactivating various species of microorganisms, including viruses. The most applicable UV light for viruses ranges from 200nm to 280nm in wavelength, i.e., UVC. More recently, the synergy of UVA light with UVC has been studied in disinfecting bacteria in polluted water. However, little attention has been paid to studying viral inactivation by coupled UVC and UVA LEDs. The necessity of such research is to find an effective and economical solution for the LEDs of these two bands. Along this track, we attempt to tackle two major challenges. The first is to find a suitable viral surrogate that can safely be used in ordinary labs. In this aspect, lentivirus is commonly used as a genetic vector and has been selected to surrogate RNA viruses. Another is to determine the effective dosage of the coupled UVC and UVA light. To this end, the surrogate lentivirus was irradiated by 280nm (UVC) LEDs, 365nm (UVA) LEDs, and their combination at various doses. Survival rates were detected to compare the efficacy of various options. Moreover, the viral RNA damage was detected by RT-qPCR to disclose the mechanism of viral death. The results have shown that for the same duration of irradiation, the effect of the full-power 280nm LEDs is equivalent to that of the half-power 280nm LEDs combined with a suitable radiant power of the 365nm LEDs. The observations have been further confirmed by the effect of damaging the viral RNA by either the 280nm or 365nm light. In conclusion, the experimental results provide clear evidence of alleviating the requirement of UVC LEDs in viral inactivation by substituting them partially with UVA LEDs.

14.
CLINICAL AND EXPERIMENTAL HEALTH SCIENCES ; 12(2):472-478, 2022.
Article in English | Web of Science | ID: covidwho-1970033

ABSTRACT

Objective: In this study, it was aimed to determine the mutation frequency in spike (S) genes of SARS CoV2 from six different regions of the world, their distribution on the gene and reflections of these mutations to the S protein. Methods: SARS CoV2 S gene sequences originating from Asia, Africa, Europe, South America, Oceania and North America were obtained from NCBI virus database. The sequences were analyzed with Geneious and BioEdit multiple sequence alignment programs. Results:865 distinct mutations on the S genes were detected in the virus samples. Among these, 59 variants with numbers of 10 and above in the virus population were detected. The D614G(A1841G) substitution was found to be the most common with an average of 88.6%. Furthermore, it was determined that 5477N(G1430A) substitution in the viruses of Oceania differed from other regions with a rate of 86.7%. The average mutation frequency of the S genes from different regions was calculated as 3,93x10(5). Conclusion: The significant differences among the mutation frequencies in SARS CoV2 S genes isolated from different regions was identified. At least five distinct amino acid substitutions with high ratios in the population were detected in the RBD domain, which is involved in the binding of the viruses to the ACE2 receptor. These substitutions are T1355G (L452R), G1430A (5477N), C1433A (T478K), G1450A (E484K) and A1501T (N501Y). Among these, the S477N is the most predominant in the population. However, the importance of these mutations needs to be demonstrated both in silico and experimental studies.

15.
Appl Environ Microbiol ; 88(14): e0076422, 2022 07 26.
Article in English | MEDLINE | ID: covidwho-1962070

ABSTRACT

Most studies on surface persistence of SARS-CoV-2 have been conducted at temperatures between 20°C and 30°C. There is limited data on the survival of SARS-CoV-2 at low temperatures. In this study, the stability of SARS-CoV-2 Alpha and Delta variants on stainless steel was investigated at two temperatures (4°C and 24°C). The results show that both variants decayed more rapidly at 24°C compared with 4°C. At 24°C, Alpha and Delta variants showed reductions of 0.33 log10 and 1.02 log10, respectively, within the first 2.5 h. However, at 4°C, Alpha variant showed a reduction of 0.16 log10 within the first 2.5 h while no reduction was observed with Delta variant. After remaining in situ for 24 h at 24°C, log10 reductions of 2.66 (Alpha) and 3.11 (Delta) were observed. No viable Alpha and Delta variant was recovered after 48 h and 72 h, respectively. After 24 h in a refrigerated environment (4°C) log10 reductions of 1.16 (Alpha) and 0.95 (Delta) were observed. Under these experimental conditions, both viruses survived on stainless steel for at least 1 week. No viable Alpha and Delta variant was recovered after 10 days. These findings support the potential for increased fomite transmission of SARS-CoV-2 during winter months in colder regions worldwide and in some industrial sectors. IMPORTANCE Human transmission is believed to occur primarily through direct transfer of infectious droplets or aerosols. However, fomite transmission through contact with contaminated surfaces may also play an important role. This study provides novel evidence comparing the stability of Alpha and Delta variants on stainless steel surfaces at 4°C and 24°C. At 4°C both variants were found to be still detectable for up to 7 days. At 24°C Delta variant could be recovered over 2 days compared with Alpha variant which could not be recovered after 2 days. This has implications for fomite transmission interventions for people living and working in cold environments.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , SARS-CoV-2/genetics , Stainless Steel , Temperature
16.
1st International Conference on Technologies for Smart Green Connected Society 2021, ICTSGS 2021 ; 107:17933-17940, 2022.
Article in English | Scopus | ID: covidwho-1950336

ABSTRACT

A coronavirus is the novel coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). It's a nonsegmented enveloped positive sense RNA virus with 82 percent genetic similarity to the SARS coronavirus (SARSCoV), which sparked an outbreak in early 2003. Respiratory droplets are assumed to be the primary mechanism of transmission because the virus is found in respiratory secretions. Conjunctival transmission and aerosol transmission have also been proposed, however they are also problematic. Fever, tiredness, and dry mouth are the three most prevalent COVID19 clinical symptoms. In several patients, however, conjunctivitis was the initial symptom. The disease's respiratory complications have been the focus of diagnostic and therapeutic efforts, However, a number of ocular concerns have surfaced. Infected patients' tears have been confirmed to contain SARSCov2 RNA, and studies indicate that the virus is spreading. For viral transmission, the ocular surface could serve as both an entry point and a reservoir. COVID19 has been linked to mild conjunctivitis, which can be the disease's first and only symptom. Ocular symptoms can be treated with observation without therapy, antibacterial eye drops, antiviral eye drops, and antiallergic eye drops, according to clinical trials..As a result, the only recommended treatment for COVID19related ocular manifestations is close observation cough. The motivation behind this examination was to investigate the event of visual appearances in patients who had been determined to have Covid illness 2019 (Coronavirus) because of serious intense respiratory condition. 2(SARS-CoV-2). © The Electrochemical Society

17.
Cell Mol Life Sci ; 79(8): 425, 2022 Jul 16.
Article in English | MEDLINE | ID: covidwho-1935748

ABSTRACT

Positive single-strand RNA (+ RNA) viruses can remodel host cell membranes to induce a replication organelle (RO) isolating the replication of their genome from innate immunity mechanisms. Some of these viruses, including severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), induce double-membrane vesicles (DMVs) for this purpose. Viral non-structural proteins are essential for DMV biogenesis, but they cannot form without an original membrane from a host cell organelle and a significant supply of lipids. The endoplasmic reticulum (ER) and the initial mechanisms of autophagic processes have been shown to be essential for the biogenesis of SARS-CoV-2 DMVs. However, by analogy with other DMV-inducing viruses, it seems likely that the Golgi apparatus, mitochondria and lipid droplets are also involved. As for hepatitis C virus (HCV), pores crossing both membranes of SARS-CoV-2-induced DMVs have been identified. These pores presumably allow the supply of metabolites essential for viral replication within the DMV, together with the export of the newly synthesized viral RNA to form the genome of future virions. It remains unknown whether, as for HCV, DMVs with open pores can coexist with the fully sealed DMVs required for the storage of large amounts of viral RNA. Interestingly, recent studies have revealed many similarities in the mechanisms of DMV biogenesis and morphology between these two phylogenetically distant viruses. An understanding of the mechanisms of DMV formation and their role in the infectious cycle of SARS-CoV-2 may be essential for the development of new antiviral approaches against this pathogen or other coronaviruses that may emerge in the future.


Subject(s)
COVID-19 , Hepatitis C , Endoplasmic Reticulum/metabolism , Hepacivirus/genetics , Humans , RNA, Viral/genetics , RNA, Viral/metabolism , SARS-CoV-2 , Viral Nonstructural Proteins/genetics , Virus Replication
18.
Pathogens ; 11(7)2022 Jul 15.
Article in English | MEDLINE | ID: covidwho-1938932

ABSTRACT

Pathogenic viruses with an RNA genome represent a challenge for global human health since they have the tremendous potential to develop into devastating pandemics/epidemics. The management of the recent COVID-19 pandemic was possible to a certain extent only because of the strong foundations laid by the research on previous viral outbreaks, especially Ebola Virus Disease (EVD). A clear understanding of the mechanisms of the host immune response generated upon viral infections is a prime requisite for the development of new therapeutic strategies. Hence, we present here a comparative study of alterations in immune response upon SARS-CoV-2 and Ebola virus infections that illustrate many common features. Vaccination and pregnancy are two important aspects that need to be studied from an immunological perspective. So, we summarize the outcomes and immune responses in vaccinated and pregnant individuals in the context of COVID-19 and EVD. Considering the significance of immunomodulatory approaches in combating both these diseases, we have also presented the state of the art of such therapeutics and prophylactics. Currently, several vaccines against these viruses have been approved or are under clinical trials in various parts of the world. Therefore, we also recapitulate the latest developments in these which would inspire researchers to look for possibilities of developing vaccines against many other RNA viruses. We hope that the similar aspects in COVID-19 and EVD open up new avenues for the development of pan-viral therapies.

19.
Virologie ; 26(2):150-151, 2022.
Article in English | EMBASE | ID: covidwho-1913207

ABSTRACT

Nidovirales is an extraordinary order of complex positive-stranded RNA viruses including some of the largest RNA genomes (12-41 kb) among which notable human health burdens: SARS-CoV-1, SARS-CoV-2, MERS-CoV, etc. Recent advance in genome sequencing is slowly filling the gaps between and beyond the classified nidoviral families. Still, the research is lagging behind to understand the evolution of RNA genomes. For example, how are these large genome RNA viruses able to bypass the length and stability constraints of an RNA molecule? Is there any link between increasing length and gaining a functional domain or a special structural feature? To answer these questions, we started with database mining to extract novel nidoviral genomes and annotated different domains in polyproteins of classified and unclassified nidoviruses using HHpred and HHblits tools (Zimmermann L, et al. 2018). We observed a significant variation across the order regarding presence/absence, fold/structure type, co-factor (or enhancer) presence/absence, presence of one motif or the other and genome location of enzymes: Exonuclease (ExoN), N-7 Methyltransferase (MTase), 2'-O-MTase and RNA dependent RNA polymerase (RdRp). A trend seen with this bioinformatic analysis directly implies that stable RNA genome increase as well as maintenance is driven by the synergy of modifying enzymes: MTases, RNA proofreading by ExoNs and fast & processive RdRps (Ferron F, et al. 2021). Next, after their identification, we are trying to characterize these large RNA genome genetic markers: MTase(s) & ExoN, to have a comprehensive understanding of nidoviruses evolution. We have identified, expressed and purified a new nidoviral MTase from a Tobaniviridae family member, White Bream Virus (WBV). This enzyme is unique in terms of its location in ORF1a and not in ORF1b (Ferron F, et al. 2019). Functional and mutational studies show this new MTase to contain N-7 guanine specific, S-adenosyl-methionine (SAM) dependent capping activity (cap-0). Aligning with our predictions, structural characterization confirms that it has a Rossmann fold (RF) SAMdependent RNA-cap N7-guanine MTase. This study answers the missing link of capping activity in these members, which is somewhat only established for coronaviruses in this large genome order. Evaluating such enzymes is a step forward in the direction of fundamental understanding of how these RNA viruses are successfully expanding and maintaining their large genomes as well as coping up to fight against the host innate immunity.

20.
Trace Elements and Electrolytes ; 39(2):82-83, 2022.
Article in English | EMBASE | ID: covidwho-1913119

ABSTRACT

The novel coronavirus SARSCoV- 2 is causing an ongoing worldwide pandemic of COVID-19. The infection with this single-stranded RNA virus appears to be completely asymptomatic in a large fraction of people and many other patients may experience mild symptoms such as fever, cough, anosmia, and myalgia. Some patients need hospitalization and some will develop an acute respiratory distress syndrome (ARDS), and a significant subset will require treatment in the intensive care unit to provide respiratory ventilator support. Unfortunately, there is no causal curative treatment, so far. In this context, the potential prophylactic and therapeutic options for the novel SARS-CoV-2 infection and corresponding COVID-19, as well as interventions with special nutrients like zinc or vitamin D are discussed, especially due to their role in the immune system [1]. Possible drugs for the treatment of COVID-19 increase the risk of QT interval prolongation, e.g., chloroquine, hydroxychloroquine, azithromycin, lopinavir, ritonavir. QT prolongation can provoke life-threatening torsade-de-pointes arrhythmias (TdP) and sudden cardiac death. Mg deficiency and other electrolyte imbalances also belong to the known risk factors for QT prolongation and TdP. Consequently, it is recommended to obtain baseline assessment of Mg and other electrolytes and to correct deficiencies before using QT-prolonging drugs. Keeping serum potassium levels and Mg levels above 4 mmol/L and 3 mg/ dL (= 1.23 mmol/L), respectively, in COVID-19 patients treated with QT-prolonging drugs proved to be effective in preventing QT prolongation, and no arrhythmias or sudden cardiac arrest were registered. This is above the upper limit of the reference range (usually ∼ 1.1 mmol/L). In a single-center study (n = 524), a specially designed monitoring process in COVID-19 patients (with COVID-19-related medication) identified a high proportion of patients with QT prolongation (n = 103, corresponding to 19.7%). As part of the medical support, reaching Mg and potassium in the reference range was recommended [2, 3]. Administration of intravenous Mg sulfate is the therapy of choice for hemodynamically stable TdP, regardless of whether the patient is hypomagnesemic or has a normal serum Mg concentration. This may be a relevant reason why the German Federal Institute of Drugs and Medical Devices (BfArM) put Mg (parenteral) on a list with drugs whose need is greatly increased with treatment of COVID-19 patients in intensive care units [4]. On the other hand, hypomagnesemia generally is a common occurrence in intensive care patients (regardless of COVID-19) with a prevalence up to 65%, associated with an increased mortality rate, higher need for ventilator support, increased incidence of sepsis, and longer hospital stays [5]. There is increasing evidence that viral infection of the endothelial cells plays a key role in multiorgan participation and severe courses of COVID-19. This finding provides a rationale for therapies to stabilize the endothelium, in particular for vulnerable patients with pre-existing endothelial dysfunction which can be found for example in cardiovascular disease, diabetes, hypertension, obesity, all of which are associated with adverse outcomes in COVID-19. Interestingly, Mg is known to be crucial for endothelial function and its deficiency causes endothelial dysfunction with impaired endothelial-dependent vasodilation. In a meta-analysis of randomized, controlled trials (RCTs), oral Mg supplementation was shown to improve flow-mediated dilation as a marker of endothelial function. It is therefore plausible to assume that Mg deficiency further worsens the consequences of an infection with SARS-CoV-2 via induction of endothelial dysfunction. In this context, the frequent occurrence of thrombotic embolism in COVID-19 is worth mentioning. Animal and human data suggest that Mg functions as an antithrombotic agent. Hence, increased platelet reactivity and thrombosis are possible cardiovascular manifestations of Mg deficiency [6, 7]. Furthermore, increased inflammation in Mg deficiency has to be kept in mind. Experimental studies show an increased incidence of markers for inflammation in case of Mg deficiency, e.g., leukocyte and macrophage activation, pro-inflammatory molecules such as interleukin-1, interleukin-6, tumor necrosis factor, vascular cell adhesion molecule-1, plasminogen activator inhibitor-1, and excessive production of free radicals. Generally, Mg deficiency is considered as a significant contributor to chronic lowgrade inflammation and, therefore, risk factor for a variety of pathological conditions such as cardiovascular disease, hypertension, and diabetes. In meta-analyses of RCTs, Mg supplementation was shown to reduce C-reactive protein levels. Whether Mg deficiency or Mg supplementation may impact the inflammatory event in COVID-19 has to be investigated in clinical studies [7, 8]. To our knowledge, there are no systematic studies so far examining Mg status in COVID-19 patients. In a pooled analysis, Lippi et al. [6] confirmed that COVID-19 severity was associated with lower serum concentrations of sodium, potassium, and calcium. Therefore, measuring electrolytes at initial presentation and monitoring during hospitalization is recommended in order to be able to take appropriate corrective measures in good time. Unfortunately, serum Mg was not determined in the studies analyzed. In the above-mentioned study of Jain et al. [3], 30.1% of the COVID-19 patients with QT prolongation showed hypomagnesemia. Conclusion: In view of the relationships described, it is plausible to assume that Mg deficiency may decrease the resistance against infection with SARS-CoV-2 and, most notably, may worsen the course of COVID-19. Hence, Mg deficiency could be a risk factor for severe COVID-19, comparable to cardiovascular disease, diabetes, chronic respiratory disease, older age, obesity, amongst others. Interestingly, Mg deficiency is often associated with these risk factors or seen as comorbidity. However, more research questions need to be addressed before definitive conclusions can be drawn [8, 9].

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