scholarly journals COVID-19: CRISPR/Cas-like System of nsp3 Promotes the Mutant Recombination and Drug Resistance

2021 ◽  
Author(s):  
liu wenzhong ◽  
Li hualan
Keyword(s):  
Drug Resistance ◽  
Fungal Infections ◽  
Fungal Spores ◽  
Virus Genome ◽  
Virus Protein ◽  
Coding Region ◽  
Conserved Domains ◽  
Negative Strand ◽  
Bacteria And Fungi ◽  
Novel Coronavirus

<p>Patients with novel coronavirus pneumonia usually suffer from bacterial and fungal infections, and the drug resistance problem caused by the pandemic is becoming more and more serious. Simultaneously, the SARS-COV-2 virus has a rapid mutation phenomenon, and somegene coding regions by mutation and recombination may be related to the drug resistance of the virus. Therefore, studying the relationship between the co-infection of bacteria and fungi and the evolution of SARS-COV-2 has important guiding significance for preventing a pandemic. We found that the SARS-COV-2 virus's nsp3 protein had a CRISPR/Cas 9 (II-B)-like function by searching for conserved domains. The system could target and edit the negative-strand RNA of SARS-COV-2. We speculated that the crRNA (CRISPR RNA) produced by the CRISPR/Cas system of Pseudomonas aeruginosa carried the genetic information of the conserved domains of bacteriophages and Pseudomonas, including drug resistance. After the phage lysed the Pseudomonas, the crRNA was released and attached to the fungal spores, and then invaded the patient's cells along with the spores or hyphae. nsp3 synthesized and assembled 4Fe-4S, iron-containing molecules bound to the cas4 domain, in the mitochondria of phagocytes. The iron came from hemoglobin attacked by the SARS-COV-2 virus protein. The nsp3 protein bound the crRNA in the phagocytic cytoplasm. It targeted the negative-strand RNA of SARS-COV-2, inserting conserved domain gene fragments into the negative-strand RNA through editing and splicing. Since the Cas protein had no codon checking function, the cutting and splicing would destroy the protein-coding information in the original RNA coding region, causing mutation and recombination of the SARS-COV-2 virus genome. If crRNA carried the drug resistance gene fragments of bacteria or phage, SARS-COV-2 would have similar drug resistance. Because of the growing problem of drug resistance in COVID-19 patients, we should pay attention to preventing fungi and bacteria co-infection. Avoid the CRISPR/Cas-like system of the novel coronavirus to cause rapid mutation and recombination and increased the drug resistance problem of SARS-COV-2.</p>

scholarly journals COVID-19: CRISPR/Cas-like System of nsp3 Promotes the Mutant Recombination and Drug Resistance

2021 ◽  
Author(s):  
liu wenzhong ◽  
Li hualan
Keyword(s):  
Drug Resistance ◽  
Fungal Infections ◽  
Fungal Spores ◽  
Virus Genome ◽  
Virus Protein ◽  
Coding Region ◽  
Conserved Domains ◽  
Negative Strand ◽  
Bacteria And Fungi ◽  
Novel Coronavirus

<p>Patients with novel coronavirus pneumonia usually suffer from bacterial and fungal infections, and the drug resistance problem caused by the pandemic is becoming more and more serious. Simultaneously, the SARS-COV-2 virus has a rapid mutation phenomenon, and somegene coding regions by mutation and recombination may be related to the drug resistance of the virus. Therefore, studying the relationship between the co-infection of bacteria and fungi and the evolution of SARS-COV-2 has important guiding significance for preventing a pandemic. We found that the SARS-COV-2 virus's nsp3 protein had a CRISPR/Cas 9 (II-B)-like function by searching for conserved domains. The system could target and edit the negative-strand RNA of SARS-COV-2. We speculated that the crRNA (CRISPR RNA) produced by the CRISPR/Cas system of Pseudomonas aeruginosa carried the genetic information of the conserved domains of bacteriophages and Pseudomonas, including drug resistance. After the phage lysed the Pseudomonas, the crRNA was released and attached to the fungal spores, and then invaded the patient's cells along with the spores or hyphae. nsp3 synthesized and assembled 4Fe-4S, iron-containing molecules bound to the cas4 domain, in the mitochondria of phagocytes. The iron came from hemoglobin attacked by the SARS-COV-2 virus protein. The nsp3 protein bound the crRNA in the phagocytic cytoplasm. It targeted the negative-strand RNA of SARS-COV-2, inserting conserved domain gene fragments into the negative-strand RNA through editing and splicing. Since the Cas protein had no codon checking function, the cutting and splicing would destroy the protein-coding information in the original RNA coding region, causing mutation and recombination of the SARS-COV-2 virus genome. If crRNA carried the drug resistance gene fragments of bacteria or phage, SARS-COV-2 would have similar drug resistance. Because of the growing problem of drug resistance in COVID-19 patients, we should pay attention to preventing fungi and bacteria co-infection. Avoid the CRISPR/Cas-like system of the novel coronavirus to cause rapid mutation and recombination and increased the drug resistance problem of SARS-COV-2.</p>

scholarly journals Synonymous sites in SARS-CoV-2 genes display trends affecting translational efficiency

2020 ◽  
Author(s):  
Qingsheng Huang ◽  
Huan Gao ◽  
Lingling Zheng ◽  
Xiujuan Chen ◽  
Shuai Huang ◽  
...  
Keyword(s):  
Control Policy ◽  
Virus Genome ◽  
Multiple Infections ◽  
Translational Efficiency ◽  
Evolutionary Trend ◽  
Coding Region ◽  
Rna Dependent Rna Polymerase ◽  
Synonymous Sites ◽  
Synonymous Variant ◽  
Novel Coronavirus

ABSTRACTA novel coronavirus, SARS-CoV-2, has caused a pandemic of COVID-19. The evolutionary trend of the virus genome may have implications for infection control policy but remains obscure. We introduce an estimation of fold change of translational efficiency based on synonymous variant sites to characterize the adaptation of the virus to hosts. The increased translational efficiency of the M and N genes suggests that the population of SARS-CoV-2 benefits from mutations toward favored codons, while the ORF1ab gene has slightly decreased the translational efficiency. In the coding region of the ORF1ab gene upstream of the −1 frameshift site, the decreasing of the translational efficiency has been weakening parallel to the growth of the epidemic, indicating inhibition of synthesis of RNA-dependent RNA polymerase and promotion of replication of the genome. Such an evolutionary trend suggests that multiple infections increased virulence in the absence of social distancing.

scholarly journals Mutational hotspots and conserved domains of SARS-CoV-2 genome in African population

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Olabode E. Omotoso ◽  
Ayoade D. Babalola ◽  
Amira Matareek
Keyword(s):  
Global Economy ◽  
African Population ◽  
The Novel ◽  
Conserved Domains ◽  
Nucleocapsid Proteins ◽  
Genome Variability ◽  
Promising Strategy ◽  
Mutational Hotspots ◽  
Novel Coronavirus ◽  
Complete Protein

Abstract Background Since outbreak in December 2019, the highly infectious and pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused over a million deaths globally. With increasing burden, the novel coronavirus has posed a dire threat to public health, social interaction, and global economy. Mutations in the SARS-CoV-2 genome are moderately evolving which might have contributed to its genome variability, transmission, replication efficiency, and virulence in different regions of the world. Results The present study elucidated the mutational landscape in the SARS-CoV-2 genome among the African populace, which may have contributed to the virulence, spread, and pathogenicity observed in the region. A total of 3045 SARS-CoV-2 complete protein sequences with the reference viral sequence (EPI_ISL_402124) were mined and analyzed. SARS-CoV-2 ORF1ab, spike, ORF3, ORF8, and nucleocapsid proteins were observed as mutational hotspots in the African population and may be of keen interest in understanding the viral host relationship, while there is conservation in the ORF6, ORF7a, ORF7b, ORF10, envelope, and membrane proteins. Conclusions The accumulation of moderate mutations (though slowly), in the SARS-CoV-2 genome as seen in this present study, could be a promising strategy to develop antiviral drugs or vaccines. These antiviral interventions should target viral conserved domains and host cellular proteins and/or receptors involved in viral invasion and replication to avoid a new viral wave due to drug resistance and vaccine evasion.

scholarly journals Biochemical and genetic analysis of the role of the viral polymerase in enterovirus recombination

2016 ◽  
Vol 44 (14) ◽  
pp. 6883-6895 ◽  
Author(s):  
Andrew Woodman ◽  
Jamie J. Arnold ◽  
Craig E. Cameron ◽  
David J. Evans
Keyword(s):  
Genetic Recombination ◽  
Evolutionary Process ◽  
Virus Genome ◽  
Biochemical Assay ◽  
Strand Transfer ◽  
Turnover Rates ◽  
Coding Region ◽  
Cis Acting ◽  
Polymerase Fidelity

Abstract Genetic recombination in single-strand, positive-sense RNA viruses is a poorly understand mechanism responsible for generating extensive genetic change and novel phenotypes. By moving a critical cis-acting replication element (CRE) from the polyprotein coding region to the 3′ non-coding region we have further developed a cell-based assay (the 3′CRE-REP assay) to yield recombinants throughout the non-structural coding region of poliovirus from dually transfected cells. We have additionally developed a defined biochemical assay in which the only protein present is the poliovirus RNA dependent RNA polymerase (RdRp), which recapitulates the strand transfer events of the recombination process. We have used both assays to investigate the role of the polymerase fidelity and nucleotide turnover rates in recombination. Our results, of both poliovirus intertypic and intratypic recombination in the CRE-REP assay and using a range of polymerase variants in the biochemical assay, demonstrate that RdRp fidelity is a fundamental determinant of recombination frequency. High fidelity polymerases exhibit reduced recombination and low fidelity polymerases exhibit increased recombination in both assays. These studies provide the basis for the analysis of poliovirus recombination throughout the non-structural region of the virus genome and provide a defined biochemical assay to further dissect this important evolutionary process.

scholarly journals High concentrations of biological aerosol particles and ice nuclei during and after rain

2013 ◽  
Vol 13 (1) ◽  
pp. 1767-1793 ◽  
Author(s):  
J. A. Huffman ◽  
C. Pöhlker ◽  
A. J. Prenni ◽  
P. J. DeMott ◽  
R. H. Mason ◽  
...  
Keyword(s):  
Plant Pathogens ◽  
Dna Analysis ◽  
Fungal Spores ◽  
Ice Nuclei ◽  
Ice Nucleators ◽  
Tightly Coupled ◽  
High Concentrations ◽  
Bacterial Aggregates ◽  
Bacteria And Fungi ◽  
Biological Aerosol Particles

Abstract. Bioaerosols are relevant for public health and may play an important role in the climate system, but their atmospheric abundance, properties and sources are not well understood. Here we show that the concentration of airborne biological particles in a forest ecosystem increases dramatically during rain and that bioparticles are closely correlated with atmospheric ice nuclei (IN). The greatest increase of bioparticles and IN occurred in the size range of 2–6 μm, which is characteristic for bacterial aggregates and fungal spores. By DNA analysis we found high diversities of airborne bacteria and fungi, including human and plant pathogens (mildew, smut and rust fungi, molds, Enterobacteraceae, Pseudomonadaceae). In addition to known bacterial and fungal IN (Pseudomonas sp., Fusarium sporotrichioides), we discovered two species of IN-active fungi that were not previously known as biological ice nucleators (Isaria farinosa and Acremonium implicatum). Our findings suggest that atmospheric bioaerosols, IN and rainfall are more tightly coupled than previously assumed.

scholarly journals Pulmonary aspergillosis associated to COVID-19

2021 ◽  
Vol 69 (1) ◽  
Author(s):  
Aurelia Cebotaru ◽  
◽  
Oxana Munteanu ◽  
Eugenia Scutaru ◽  
Victor Botnaru ◽  
...  
Keyword(s):  
Diagnostic Criteria ◽  
Fungal Infections ◽  
Pulmonary Aspergillosis ◽  
Clinical Imaging ◽  
Incidence And Mortality ◽  
Novel Coronavirus ◽  
Management Challenge

Infection with novel coronavirus (SARS-CoV-2) remains one of the most important pandemics till present, becoming an equation with several unknowns, one of them being the associated fungal infections. Pulmonary mycoses have an increased incidence and mortality, the most common germ identified among cases of COVID-19 is Aspergillus spp. Due to discrepancies in defining and diagnostic criteria, but also nonspecific clinical-imaging manifestations, COVID-19-associated pulmonary aspergillosis remains a diagnostic and management challenge.

Serum biomarkers to differentiate Gram-negative, Gram-positive and fungal infection in febrile patients

2021 ◽  
Vol 70 (7) ◽  
Author(s):  
Dongguang Niu ◽  
Qian Huang ◽  
Fan Yang ◽  
Weiliang Tian ◽  
Chen Li ◽  
...  
Keyword(s):  
Bloodstream Infection ◽  
Bacterial Infections ◽  
Fungal Infections ◽  
Serum Levels ◽  
Serum Biomarker ◽  
Diagnostic Efficiency ◽  
Gram Positive ◽  
Gram Negative ◽  
Neutrophil Lymphocyte Ratio ◽  
Bacteria And Fungi

Introduction. Contamination of specimens and overuse of broad spectrum antibiotics contribute to false positives and false negatives, respectively. Therefore, useful and applicable biomarkers of bacteremia are still required. Hypothesis/Gap Statement. IL-6 can be used as a serum biomarker to discriminate among bacterial infections and fungal infections in febrile patients with a bloodstream infection. Aim. We aimed to evaluate the diagnostic efficiency of neutrophil/lymphocyte ratio (NLR), procalcitonin (PCT) and interleukin-6 (IL-6) in discriminating Gram-negative (G−) bacteria from Gram-positive (G+) bacteria and fungi in febrile patients. Methodology. A total of 567 patients with fever were evaluated. Serum levels of IL-6, PCT, NLR and CRP were compared among a G− group (n=188), a G+ group (n=168), a fungal group (n=38) and a culture negative group (n=173). Sensitivity, specificity, Yuden’s index and area under the Receiver operating characteristic (ROC) curve (AUC) were obtained to analyse the diagnostic abilities of these biomarkers in discriminating bloodstream infection caused by different pathogens. Results. Serum IL-6 and PCT in the G− group increased significantly when compared with both the G+ group and fungal group (P <0.05). AUC of IL-6 (0.767, 95 % CI:0.725–0.805) is higher than AUC of PCT (0.751, 95 % CI:0.708–0.796) in discriminating the G− group from G+ group. When discriminating the G− group from fungal group, the AUC of IL-6 (0.695, 95 % CI:0.651–0.747) with a cut-off value of 464.3 pg ml−1 was also higher than the AUC of PCT (0.630, 95 % CI:0.585–0.688) with a cut-off value of 0.68 ng ml−1. Additionally, AUC of NLR (0.685, 95 % CI:0.646–0.727) in discriminating the fungal group from G+ group at the cut-off value of 9.03, was higher than AUC of IL-6, PCT and CRP. Conclusion. This study suggests that IL-6 could be used as a serum biomarker to discriminate among bacterial infections and fungal infections in febrile patients with a bloodstream infection. In addition, NLR is valuable to discriminate fungal infections from Gram-positive infections in febrile patients with a bloodstream infection.

Anti-Candida activity of existing antibiotics and their derivatives when used alone or in combination with antifungals

2019 ◽  
Vol 14 (10) ◽  
pp. 899-915 ◽  
Author(s):  
Yaxin Liu ◽  
Weixin Wang ◽  
Haiying Yan ◽  
Decai Wang ◽  
Min Zhang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Fungal Infections ◽  
Therapeutic Strategies ◽  
Candida Infection ◽  
Immunocompromised Patients ◽  
Derivatives Of

Fungal infections are a growing challenge in immunocompromised patients, especially candidiasis. The prolonged use of traditional antifungals to treat Candida infection has caused the emergence of drug resistance, especially fluconazole. Therefore, new therapeutic strategies for Candida infection are warranted. Recently, attention has been paid to the anti- Candida activity of antibiotics and their derivatives. Studies revealed that a series of antibiotics/derivatives displayed potential anti- Candida activity and some of them could significantly increase the susceptibility of antifungals. Interestingly, the derivatives of aminoglycosides were even more active than fluconazole/itraconazole/posaconazole. This article reviews the anti- Candida activities and mechanisms of antibiotics/derivatives used alone or in combination with antifungals. This review will helpfully provide novel insights for overcoming Candida resistance and discovering new antifungals.

Characterization of the African swine fever virus protein p49: a new late structural polypeptide

Microbiology ◽  
2000 ◽  
Vol 81 (1) ◽  
pp. 59-65 ◽  
Author(s):  
Inmaculada Galindo ◽  
Eladio Viñuela ◽  
Angel L. Carrascosa
Keyword(s):  
Cell Attachment ◽  
African Swine Fever Virus ◽  
Rabbit Antiserum ◽  
African Swine Fever ◽  
Virus Genome ◽  
Fever Virus ◽  
Virus Protein ◽  
Significant Similarity ◽  
Reading Frame ◽  
Cell Extracts

The open reading frame B438L, located within the EcoRI B fragment of the African swine fever virus genome, is predicted to encode a protein of 438 amino acids with a molecular mass of 49·3 kDa. It presents a cell attachment RGD (Arg–Gly–Asp) motif but no other significant similarity to protein sequences in databases. Northern blot and primer extension analysis showed that B438L is transcribed only at late times during virus infection. The B438L gene product has been expressed in Escherichia coli, purified and used as an antigen for antibody production. The rabbit antiserum specific for pB438L recognized a protein of about 49 kDa in virus-infected cell extracts. This protein was synthesized late in infection by all the virus strains tested, was located in cytoplasmic virus factories and appeared as a structural component of purified virus particles.

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