scholarly journals Coronavirus genomes carry the signatures of their habitats

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0244025
Author(s):  
Yulong Wei ◽  
Jordan R. Silke ◽  
Parisa Aris ◽  
Xuhua Xia
Keyword(s):  
Vaccine Development ◽  
Bos Taurus ◽  
Homo Sapiens ◽  
Temporal Analysis ◽  
Canis Lupus Familiaris ◽  
Antiviral Protein ◽  
Cpg Dinucleotides ◽  
Viral Genomes ◽  
Host Immune Responses ◽  
Spread Of Infection

Coronaviruses such as SARS-CoV-2 regularly infect host tissues that express antiviral proteins (AVPs) in abundance. Understanding how they evolve to adapt or evade host immune responses is important in the effort to control the spread of infection. Two AVPs that may shape viral genomes are the zinc finger antiviral protein (ZAP) and the apolipoprotein B mRNA editing enzyme-catalytic polypeptide-like 3 (APOBEC3). The former binds to CpG dinucleotides to facilitate the degradation of viral transcripts while the latter frequently deaminates C into U residues which could generate notable viral sequence variations. We tested the hypothesis that both APOBEC3 and ZAP impose selective pressures that shape the genome of an infecting coronavirus. Our investigation considered a comprehensive number of publicly available genomes for seven coronaviruses (SARS-CoV-2, SARS-CoV, and MERS infecting Homo sapiens, Bovine CoV infecting Bos taurus, MHV infecting Mus musculus, HEV infecting Sus scrofa, and CRCoV infecting Canis lupus familiaris). We show that coronaviruses that regularly infect tissues with abundant AVPs have CpG-deficient and U-rich genomes; whereas those that do not infect tissues with abundant AVPs do not share these sequence hallmarks. Among the coronaviruses surveyed herein, CpG is most deficient in SARS-CoV-2 and a temporal analysis showed a marked increase in C to U mutations over four months of SARS-CoV-2 genome evolution. Furthermore, the preferred motifs in which these C to U mutations occur are the same as those subjected to APOBEC3 editing in HIV-1. These results suggest that both ZAP and APOBEC3 shape the SARS-CoV-2 genome: ZAP imposes a strong CpG avoidance, and APOBEC3 constantly edits C to U. Evolutionary pressures exerted by host immune systems onto viral genomes may motivate novel strategies for SARS-CoV-2 vaccine development.

scholarly journals Coronavirus genomes carry the signatures of their habitats

2020 ◽  
Author(s):  
Yulong Wei ◽  
Jordan R. Silke ◽  
Parisa Aris ◽  
Xuhua Xia
Keyword(s):  
Vaccine Development ◽  
Cell Entry ◽  
Antiviral Protein ◽  
Mrna Editing ◽  
Cpg Dinucleotides ◽  
Viral Genomes ◽  
Host Immune Responses ◽  
Selective Pressures ◽  
Editing Enzyme ◽  
Host Tissues

ABSTRACTCoronaviruses such as SARS-CoV-2 regularly infect host tissues that express antiviral proteins (AVPs) in abundance. Understanding how they evolve to adapt or evade host immune responses is important in the effort to control the spread of COVID-19. Two AVPs that may shape viral genomes are the zinc finger antiviral protein (ZAP) and the apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3 protein (APOBEC3). The former binds to CpG dinucleotides to facilitate the degradation of viral transcripts while the latter deaminates C into U residues leading to dysfunctional transcripts. We tested the hypothesis that both APOBEC3 and ZAP may act as primary selective pressures that shape the genome of an infecting coronavirus by considering a comprehensive number of publicly available genomes for seven coronaviruses (SARS-CoV-2, SARS-CoV, MERS, Bovine CoV, Murine MHV, Porcine HEV, and Canine CoV). We show that coronaviruses that regularly infect tissues with abundant AVPs have CpG-deficient and U-rich genomes; whereas viruses that do not infect tissues with abundant AVPs do not share these sequence hallmarks. In SARS-CoV-2, CpG is most deficient in the S protein region to evaded ZAP-mediated antiviral defense during cell entry. Furthermore, over four months of SARS-CoV-2 evolutionary history, we observed a marked increase in C to U substitutions in the 5’ UTR and ORF1ab regions. This suggests that the two regions could be under constant C to U deamination by APOBEC3. The evolutionary pressures exerted by host immune systems onto viral genomes may motivate novel strategies for SARS-CoV-2 vaccine development.

scholarly journals CpG Dinucleotides Inhibit HIV-1 Replication through Zinc Finger Antiviral Protein (ZAP)-Dependent and -Independent Mechanisms

2019 ◽  
Vol 94 (6) ◽  
Author(s):  
Mattia Ficarelli ◽  
Irati Antzin-Anduetza ◽  
Rupert Hugh-White ◽  
Andrew E. Firth ◽  
Helin Sertkaya ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Zinc Finger ◽  
Splice Site ◽  
Viral Genome ◽  
Rna Virus ◽  
Antiviral Protein ◽  
Cpg Dinucleotides ◽  
Viral Genomes ◽  
Hiv 1 ◽  
Cpg Suppression

ABSTRACT CpG dinucleotides are suppressed in the genomes of many vertebrate RNA viruses, including HIV-1. The cellular antiviral protein ZAP (zinc finger antiviral protein) binds CpGs and inhibits HIV-1 replication when CpGs are introduced into the viral genome. However, it is not known if ZAP-mediated restriction is the only mechanism driving CpG suppression. To determine how CpG dinucleotides affect HIV-1 replication, we increased their abundance in multiple regions of the viral genome and analyzed the effect on RNA expression, protein abundance, and infectious-virus production. We found that the antiviral effect of CpGs was not correlated with their abundance. Interestingly, CpGs inserted into some regions of the genome sensitize the virus to ZAP antiviral activity more efficiently than insertions into other regions, and this sensitivity can be modulated by interferon treatment or ZAP overexpression. Furthermore, the sensitivity of the virus to endogenous ZAP was correlated with its sensitivity to the ZAP cofactor KHNYN. Finally, we show that CpGs in some contexts can also inhibit HIV-1 replication by ZAP-independent mechanisms, and one of these is the activation of a cryptic splice site at the expense of a canonical splice site. Overall, we show that the location and sequence context of the CpG in the viral genome determines its antiviral activity. IMPORTANCE Some RNA virus genomes are suppressed in the nucleotide combination of a cytosine followed by a guanosine (CpG), indicating that they are detrimental to the virus. The antiviral protein ZAP binds viral RNA containing CpGs and prevents the virus from multiplying. However, it remains unknown how the number and position of CpGs in viral genomes affect restriction by ZAP and whether CpGs have other antiviral mechanisms. Importantly, manipulating the CpG content in viral genomes could help create new vaccines. HIV-1 shows marked CpG suppression, and by introducing CpGs into its genome, we show that ZAP efficiently targets a specific region of the viral genome, that the number of CpGs does not predict the magnitude of antiviral activity, and that CpGs can inhibit HIV-1 gene expression through a ZAP-independent mechanism. Overall, the position of CpGs in the HIV-1 genome determines the magnitude and mechanism through which they inhibit the virus.

scholarly journals Complex ecological interactions across a focus of cutaneous leishmaniasis in Eastern Colombia: novel description of Leishmania species, hosts and phlebotomine fauna

2020 ◽  
Vol 7 (7) ◽  
pp. 200266
Author(s):  
Claudia M. Sandoval-Ramírez ◽  
Carolina Hernández ◽  
Aníbal A. Teherán ◽  
Reinaldo Gutierrez-Marin ◽  
Ruth A. Martínez-Vega ◽  
...  
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Bos Taurus ◽  
Homo Sapiens ◽  
Leishmania Species ◽  
Ecological Interactions ◽  
Canis Lupus Familiaris ◽  
Coffee Plantations ◽  
Forest Remnants ◽  
Frequent Feeding ◽  
Feeding Sources

This study aimed to analyse the patterns of diversity, blood sources and Leishmania species of phlebotomines in a focus of cutaneous leishmaniasis in Arboledas, Eastern Colombia. In total, 1729 phlebotomines were captured in two localities (62.3% Siravita and 37.7% Cinera) and five environments of Norte de Santander. We identified 18 species of phlebotomines: Pintomyia ovallesi (29.8%), Psychodopygus davisi (20.3%), Pi. spinicrassa (18.5%) and Lutzomyia gomezi (15.8%) showed the highest abundance. Species diversities were compared between Cinera (15.00) and Siravita (20.00) and among five microenvironments: forest remnants (19.49), coffee plantations (12.5), grassland (12.99), cane plantations (11.66) and citrus plantations (12.22). Leishmania DNA was detected in 5.8% (80/1380) of females, corresponding mainly to Pi . ovallesi (22/80; 27.2%), Lu . gomezi (17/80; 21.3%) and Pi . spinicrassa (11/80; 13.8%). Leishmania species were 63.1% L. braziliensis , 18.5% L . panamensis , 13.2% L . infantum and 6.1% L . amazonensis . The most frequent feeding sources were Homo sapiens (50%), Bos taurus (13.8%) and Canis lupus familiaris (10.3%). This focus of cutaneous leishmaniasis has a high diversity of Leishmania -carrying phlebotomines that feed on domestic animals. The transmission of leishmaniasis to human hosts was mainly associated with Lu . gomezi , Pi . ovallesi and L . braziliensis .

scholarly journals Mechanisms of Attenuation by Genetic Recoding of Viruses

mBio ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Daniel Gonçalves-Carneiro ◽  
Paul D. Bieniasz
Keyword(s):  
Zinc Finger ◽  
Molecular Mechanisms ◽  
Vaccine Development ◽  
Rnase L ◽  
Antiviral Protein ◽  
Viral Genomes ◽  
Synonymous Mutations ◽  
New Biology ◽  
Attenuated Viruses ◽  
Synthetic Virology

ABSTRACT The development of safe and effective vaccines against viruses is central to disease control. With advancements in DNA synthesis technology, the production of synthetic viral genomes has fueled many research efforts that aim to generate attenuated viruses by introducing synonymous mutations. Elucidation of the mechanisms underlying virus attenuation through synonymous mutagenesis is revealing interesting new biology that can be exploited for vaccine development. Here, we review recent advancements in this field of synthetic virology and focus on the molecular mechanisms of attenuation by genetic recoding of viruses. We highlight the action of the zinc finger antiviral protein (ZAP) and RNase L, two proteins involved in the inhibition of viruses enriched for CpG and UpA dinucleotides, that are often the products of virus recoding algorithms. Additionally, we discuss current challenges in the field as well as studies that may illuminate how other host functions, such as translation, are potentially involved in the attenuation of recoded viruses.

scholarly journals Latest Advances of Virology Research Using CRISPR/Cas9-Based Gene-Editing Technology and Its Application to Vaccine Development

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 779
Author(s):  
Man Teng ◽  
Yongxiu Yao ◽  
Venugopal Nair ◽  
Jun Luo
Keyword(s):  
Biological Sciences ◽  
Gene Therapy ◽  
Genetic Engineering ◽  
Gene Function ◽  
Viral Genome ◽  
Gene Editing ◽  
Vaccine Development ◽  
Future Prospects ◽  
Dna Viruses ◽  
Viral Genomes

In recent years, the CRISPR/Cas9-based gene-editing techniques have been well developed and applied widely in several aspects of research in the biological sciences, in many species, including humans, animals, plants, and even in viruses. Modification of the viral genome is crucial for revealing gene function, virus pathogenesis, gene therapy, genetic engineering, and vaccine development. Herein, we have provided a brief review of the different technologies for the modification of the viral genomes. Particularly, we have focused on the recently developed CRISPR/Cas9-based gene-editing system, detailing its origin, functional principles, and touching on its latest achievements in virology research and applications in vaccine development, especially in large DNA viruses of humans and animals. Future prospects of CRISPR/Cas9-based gene-editing technology in virology research, including the potential shortcomings, are also discussed.

scholarly journals IMGT® Biocuration and Comparative Analysis of Bos taurus and Ovis aries TRA/TRD Loci

Genes ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 30
Author(s):  
Perrine Pégorier ◽  
Morgane Bertignac ◽  
Viviane Nguefack Ngoune ◽  
Géraldine Folch ◽  
Joumana Jabado-Michaloud ◽  
...  
Keyword(s):  
Immune Response ◽  
Comparative Analysis ◽  
T Cell ◽  
T Cell Receptors ◽  
Bos Taurus ◽  
Homo Sapiens ◽  
Adaptive Immune Response ◽  
Ovis Aries ◽  
Cell Receptors ◽  
Adaptive Immune

The adaptive immune response provides the vertebrate immune system with the ability to recognize and remember specific pathogens to generate immunity, and mount stronger attacks each time the pathogen is encountered. T cell receptors are the antigen receptors of the adaptive immune response expressed by T cells, which specifically recognize processed antigens, presented as peptides by the highly polymorphic major histocompatibility (MH) proteins. T cell receptors (TR) are divided into two groups, αβ and γδ, which express distinct TR containing either α and β, or γ and δ chains, respectively. The TRα locus (TRA) and TRδ locus (TRD) of bovine (Bos taurus) and the sheep (Ovis aries) have recently been described and annotated by IMGT® biocurators. The aim of the present study is to present the results of the biocuration and to compare the genes of the TRA/TRD loci among these ruminant species based on the Homo sapiens repertoire. The comparative analysis shows similarities but also differences, including the fact that these two species have a TRA/TRD locus about three times larger than that of humans and therefore have many more genes which may demonstrate duplications and/or deletions during evolution.

scholarly journals Porcine Reproductive and Respiratory Syndrome Virus: Immune Escape and Application of Reverse Genetics in Attenuated Live Vaccine Development

Vaccines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 480
Author(s):  
Honglei Wang ◽  
Yangyang Xu ◽  
Wenhai Feng
Keyword(s):  
Immune Responses ◽  
Reverse Genetics ◽  
Vaccine Development ◽  
Immune Escape ◽  
Rna Virus ◽  
Economic Losses ◽  
Respiratory Syndrome Virus ◽  
Live Vaccines ◽  
Host Immune Responses ◽  
Inactivated Vaccines

Porcine reproductive and respiratory syndrome virus (PRRSV), an RNA virus widely prevalent in pigs, results in significant economic losses worldwide. PRRSV can escape from the host immune response in several processes. Vaccines, including modified live vaccines and inactivated vaccines, are the best available countermeasures against PRRSV infection. However, challenges still exist as the vaccines are not able to induce broad protection. The reason lies in several facts, mainly the variability of PRRSV and the complexity of the interaction between PRRSV and host immune responses, and overcoming these obstacles will require more exploration. Many novel strategies have been proposed to construct more effective vaccines against this evolving and smart virus. In this review, we will describe the mechanisms of how PRRSV induces weak and delayed immune responses, the current vaccines of PRRSV, and the strategies to develop modified live vaccines using reverse genetics systems.

Catalytically active holo Homo sapiens adenosine deaminase I adopts a closed conformation

2022 ◽  
Vol 78 (1) ◽  
Author(s):  
Minh Thu Ma ◽  
Maria Rain Jennings ◽  
John Blazeck ◽  
Raquel L. Lieberman
Keyword(s):  
Adenosine Deaminase ◽  
T Cell Activation ◽  
Cell Activation ◽  
Catalytic Mechanism ◽  
Biochemical Characterization ◽  
Bos Taurus ◽  
Homo Sapiens ◽  
Severe Combined Immunodeficiency ◽  
Closed Conformation ◽  
Catalytically Active

Homo sapiens adenosine deaminase 1 (HsADA1; UniProt P00813) is an immunologically relevant enzyme with roles in T-cell activation and modulation of adenosine metabolism and signaling. Patients with genetic deficiency in HsADA1 suffer from severe combined immunodeficiency, and HsADA1 is a therapeutic target in hairy cell leukemias. Historically, insights into the catalytic mechanism and the structural attributes of HsADA1 have been derived from studies of its homologs from Bos taurus (BtADA) and Mus musculus (MmADA). Here, the structure of holo HsADA1 is presented, as well as biochemical characterization that confirms its high activity and shows that it is active across a broad pH range. Structurally, holo HsADA1 adopts a closed conformation distinct from the open conformation of holo BtADA. Comparison of holo HsADA1 and MmADA reveals that MmADA also adopts a closed conformation. These findings challenge previous assumptions gleaned from BtADA regarding the conformation of HsADA1 that may be relevant to its immunological interactions, particularly its ability to bind adenosine receptors. From a broader perspective, the structural analysis of HsADA1 presents a cautionary tale for reliance on homologs to make structural inferences relevant to applications such as protein engineering or drug development.

scholarly journals Use of a small DNA virus model to investigate mechanisms of CpG dinucleotide-induced attenuation of virus replication

2020 ◽  
Vol 101 (11) ◽  
pp. 1202-1218
Author(s):  
Lisa Loew ◽  
Niluka Goonawardane ◽  
Jeremy Ratcliff ◽  
Dung Nguyen ◽  
Peter Simmonds
Keyword(s):  
Mutational Analysis ◽  
A549 Cells ◽  
Translation Efficiency ◽  
Antiviral Protein ◽  
Dna Virus ◽  
Dna Viruses ◽  
Cpg Dinucleotides ◽  
Functional Basis ◽  
Cpg Dinucleotide ◽  
Cpg Suppression

Suppression of the CpG dinucleotide is widespread in RNA viruses infecting vertebrates and plants, and in the genomes of retroviruses and small mammalian DNA viruses. The functional basis for CpG suppression in the latter was investigated through the construction of mutants of the parvovirus, minute virus of mice (MVM) with increased CpG or TpA dinucleotides in the VP gene. CpG-high mutants displayed extraordinary attenuation in A9 cells compared to wild-type MVM (>six logs), while TpA elevation showed no replication effect. Attenuation was independent of Toll-like receptor 9 and STING-mediated DNA recognition pathways and unrelated to effects on translation efficiency. While translation from codon-optimized VP RNA was enhanced in a cell-free assay, MVM containing this sequence was highly attenuated. Further mutational analysis indicated that this arose through its increased numbers of CpG dinucleotides (7→70) and separately from its increased G+C content (42.3→57.4 %), which independently attenuated replication. CpG-high viruses showed impaired NS mRNA expression by qPCR and reduced NS and particularly VP protein expression detected by immunofluorescence and replication in A549 cells, effects reversed in zinc antiviral protein (ZAP) knockout cells, even though nuclear relocalization of VP remained defective. The demonstrated functional basis for CpG suppression in MVM and potentially other small DNA viruses and the observed intolerance of CpGs in coding sequences, even after codon optimization, has implications for the use of small DNA virus vectors in gene therapy and immunization.

scholarly journals Use of a Sendai virus-based vector for effcient transduction of pinniped fbroblasts

2019 ◽  
Vol 22 (8) ◽  
pp. 1020-1025 ◽  
Author(s):  
V. R. Beklemisheva ◽  
A. G. Menzorov
Keyword(s):  
Transgene Expression ◽  
Viral Vectors ◽  
Lentiviral Vector ◽  
Sendai Virus ◽  
Homo Sapiens ◽  
Fluorescent Proteins ◽  
American Mink ◽  
Ips Cells ◽  
Canis Lupus Familiaris ◽  
Induced Pluripotent

Generation of induced pluripotent stem (iPS) cells expanded possibilities of pluripotency and early development studies. Generation of order Carnivora iPS cells from dog (Canis lupus familiaris), snow leopard (Panthera uncia), and American mink (Neovison vison) was previously reported. The aim of the current study was to examine conditions of pinniped fbroblast reprogramming. Pinnipeds are representatives of the suborder Caniformia sharing conservative genomes. There are several ways to deliver reprogramming transcription factors: RNA, proteins, plasmids, viral vectors etc. The most effective delivery systems for mouse and human cells are based on viral vectors. We compared a lentiviral vector which integrates into the genome and a Sendai virus­based vector, CytoTune EmGFP Sendai Fluorescence Reporter. The main advantage of Sendai virus­based vectors is that they do not integrate into the genome. We performed delivery of genetic constructions carrying fluorescent proteins to fbroblasts of seven Pinnipeds: northern fur seal (Callorhinus ursinus), Steller sea lion (Eumetopias jubatus), walrus (Odobenus rosmarus), bearded seal (Erignathus barbatus), Baikal seal (Pusa sibirica), ringed seal (Phoca hispida), and spotted seal (Phoca largha). We also transduced American mink (N. vison), human (Homo sapiens), and mouse (Mus musculus) fbroblasts as a control. We showed that the Sendai virus­based transduction system provides transgene expression one­two orders of magnitude higher than the lentiviral system at a comparable multiplicity of infection. Also, transgene expression after Sendai virus­based transduction is quite stable and changes only slightly at day four compared to day two. These data allow us to suggest that Sendai virus­based vectors are preferable for generation of Pinniped iPS cells.

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