scholarly journals A key region of molecular specificity orchestrates unique ephrin-B1 utilization by Cedar virus

2019 ◽  
Author(s):  
Rhys Pryce ◽  
Kristopher Azarm ◽  
Ilona Rissanen ◽  
Karl Harlos ◽  
Thomas A. Bowden ◽  
...  
Keyword(s):  
Viral Entry ◽  
Severe Disease ◽  
Critical Determinant ◽  
Pathogenic Potential ◽  
Receptor Repertoire ◽  
P Gene ◽  
Glycoprotein G ◽  
Molecular Specificity ◽  
Ephrin Ligands ◽  
Interferon Antagonists

AbstractThe prototypic henipaviruses (HNV), Hendra (HeV) and Nipah (NiV), are emergent zoonotic pathogens responsible for frequent and fatal outbreaks of severe disease in domestic animals and humans. The HNV attachment glycoprotein (G) is a critical determinant of host-species and cell-type tropism. Utilization of highly conserved B-type ephrin ligands as functional entry receptors engenders HNVs with a broad permissive host range, accounts for zoonotic spillover, and is closely aligned with observed disease pathologies. Recent studies have uncovered numerous divergent clades of HNVs globally. Cedar virus (CedV), the closest relative of HeV and NiV identified to date, can establish experimental infections, yet has not been observed to cause overt disease. While the apathogenic phenotype may be attributed to a lack of P-gene derived interferon antagonists, the V and W accessory proteins, additional determinants of differential HNV pathobiology could be involved. Here, through comparative functional and structural analysis of CedV-G, we characterize molecular interactions critical to viral entry. We demonstrate that CedV possesses a unique cellular entry receptor repertoire which, in addition to functional utilization of the common HNV receptor, ephrin-B2, includes the hitherto uncharacterized interaction with ephrin-B1. Crystal structures reveal a conserved recognition mode between diverse HNV-G proteins and their distinct ephrin receptors and identify a region of molecular specificity within CedV-G that is a key determinant of ephrin selectivity. This work provides a platform for understanding the functional diversity and varied receptor tropism characteristics of HNV glycoproteins that will facilitate assessment of the pathogenic potential and transmissibility of newly discovered and uncharacterized HNVs.

scholarly journals A key region of molecular specificity orchestrates unique ephrin-B1 utilization by Cedar virus

2019 ◽  
Vol 3 (1) ◽  
pp. e201900578 ◽  
Author(s):  
Rhys Pryce ◽  
Kristopher Azarm ◽  
Ilona Rissanen ◽  
Karl Harlos ◽  
Thomas A Bowden ◽  
...  
Keyword(s):  
Structural Changes ◽  
Disease Outbreaks ◽  
Broad Host Range ◽  
Human Pathogens ◽  
Fatal Disease ◽  
Receptor Repertoire ◽  
Molecular Specificity ◽  
Ephrin Ligands ◽  
The Common ◽  
Entry Receptor

The emergent zoonotic henipaviruses, Hendra, and Nipah are responsible for frequent and fatal disease outbreaks in domestic animals and humans. Specificity of henipavirus attachment glycoproteins (G) for highly species-conserved ephrin ligands underpins their broad host range and is associated with systemic and neurological disease pathologies. Here, we demonstrate that Cedar virus (CedV)—a related henipavirus that is ostensibly nonpathogenic—possesses an idiosyncratic entry receptor repertoire that includes the common henipaviral receptor, ephrin-B2, but, distinct from pathogenic henipaviruses, does not include ephrin-B3. Uniquely among known henipaviruses, CedV can use ephrin-B1 for cellular entry. Structural analyses of CedV-G reveal a key region of molecular specificity that directs ephrin-B1 utilization, while preserving a universal mode of ephrin-B2 recognition. The structural and functional insights presented uncover diversity within the known henipavirus receptor repertoire and suggest that only modest structural changes may be required to modulate receptor specificities within this group of lethal human pathogens.

scholarly journals Epigenetic dysregulation of ACE2 and interferon-regulated genes might suggest increased COVID-19 susceptibility and severity in lupus patients

2020 ◽  
Author(s):  
Amr H. Sawalha ◽  
Ming Zhao ◽  
Patrick Coit ◽  
Qianjin Lu
Keyword(s):  
Oxidative Stress ◽  
Immune Response ◽  
Viral Entry ◽  
Viral Infections ◽  
Severe Disease ◽  
Disease Course ◽  
Vicious Cycle ◽  
Respiratory Complications ◽  
Disease Remission ◽  
Functional Receptor

SummaryInfection caused by SARS-CoV-2 can result in severe respiratory complications and death. Patients with a compromised immune system are expected to be more susceptible to a severe disease course. In this report we suggest that patients with systemic lupus erythematous might be especially prone to severe COVID-19 independent of their immunosuppressed state from lupus treatment. Specially, we provide evidence in lupus to suggest hypomethylation and overexpression of ACE2, which is located on the X chromosome and encodes a functional receptor for the SARS-CoV-2 spike glycoprotein. Oxidative stress induced by viral infections exacerbates the DNA methylation defect in lupus, possibly resulting in further ACE2 hypomethylation and enhanced viremia. In addition, demethylation of interferon-regulated genes, NFκB, and key cytokine genes in lupus patients might exacerbate the immune response to SARS-CoV-2 and increase the likelihood of cytokine storm. These arguments suggest that inherent epigenetic dysregulation in lupus might facilitate viral entry, viremia, and an excessive immune response to SARS-CoV-2. Further, maintaining disease remission in lupus patients is critical to prevent a vicious cycle of demethylation and increased oxidative stress, which will exacerbate susceptibility to SARS-CoV-2 infection during the current pandemic. Epigenetic control of the ACE2 gene might be a target for prevention and therapy in COVID-19.

scholarly journals Differences in Viral RNA Synthesis but Not Budding or Entry Contribute to the In Vitro Attenuation of Reston Virus Compared to Ebola Virus

2020 ◽  
Vol 8 (8) ◽  
pp. 1215
Author(s):  
Bianca S. Bodmer ◽  
Josephin Greßler ◽  
Marie L. Schmidt ◽  
Julia Holzerland ◽  
Janine Brandt ◽  
...  
Keyword(s):  
Life Cycle ◽  
Rna Synthesis ◽  
Ebola Virus ◽  
Severe Disease ◽  
Case Fatality ◽  
Viral Rna ◽  
Pathogenic Potential ◽  
Rnp Complex ◽  
Reston Virus

Most filoviruses cause severe disease in humans. For example, Ebola virus (EBOV) is responsible for the two most extensive outbreaks of filovirus disease to date, with case fatality rates of 66% and 40%, respectively. In contrast, Reston virus (RESTV) is apparently apathogenic in humans, and while transmission of RESTV from domestic pigs to people results in seroconversion, no signs of disease have been reported in such cases. The determinants leading to these differences in pathogenicity are not well understood, but such information is needed in order to better evaluate the risks posed by the repeated spillover of RESTV into the human population and to perform risk assessments for newly emerging filoviruses with unknown pathogenic potential. Interestingly, RESTV and EBOV already show marked differences in their growth in vitro, with RESTV growing slower and reaching lower end titers. In order to understand the basis for this in vitro attenuation of RESTV, we used various life cycle modeling systems mimicking different aspects of the virus life cycle. Our results showed that viral RNA synthesis was markedly slower when using the ribonucleoprotein (RNP) components from RESTV, rather than those for EBOV. In contrast, the kinetics of budding and entry were indistinguishable between these two viruses. These data contribute to our understanding of the molecular basis for filovirus pathogenicity by showing that it is primarily differences in the robustness of RNA synthesis by the viral RNP complex that are responsible for the impaired growth of RESTV in tissue culture.

scholarly journals Monitoring Viral Entry in Real-Time Using a Luciferase Recombinant Vesicular Stomatitis Virus Producing SARS-CoV-2, EBOV, LASV, CHIKV, and VSV Glycoproteins

Viruses ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1457
Author(s):  
Maria Fernanda Lay Mendoza ◽  
Marissa Danielle Acciani ◽  
Courtney Nina Levit ◽  
Christopher Santa Maria ◽  
Melinda Ann Brindley
Keyword(s):  
Real Time ◽  
Vesicular Stomatitis Virus ◽  
Viral Entry ◽  
Cell Surface Receptor ◽  
Enveloped Virus ◽  
Glycoprotein G ◽  
Viral Glycoproteins ◽  
Surface Receptor ◽  
Vesicular Stomatitis ◽  
Time Required

Viral entry is the first stage in the virus replication cycle and, for enveloped viruses, is mediated by virally encoded glycoproteins. Viral glycoproteins have different receptor affinities and triggering mechanisms. We employed vesicular stomatitis virus (VSV), a BSL-2 enveloped virus that can incorporate non-native glycoproteins, to examine the entry efficiencies of diverse viral glycoproteins. To compare the glycoprotein-mediated entry efficiencies of VSV glycoprotein (G), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S), Ebola (EBOV) glycoprotein (GP), Lassa (LASV) GP, and Chikungunya (CHIKV) envelope (E) protein, we produced recombinant VSV (rVSV) viruses that produce the five glycoproteins. The rVSV virions encoded a nano luciferase (NLucP) reporter gene fused to a destabilization domain (PEST), which we used in combination with the live-cell substrate EndurazineTM to monitor viral entry kinetics in real time. Our data indicate that rVSV particles with glycoproteins that require more post-internalization priming typically demonstrate delayed entry in comparison to VSV G. In addition to determining the time required for each virus to complete entry, we also used our system to evaluate viral cell surface receptor preferences, monitor fusion, and elucidate endocytosis mechanisms. This system can be rapidly employed to examine diverse viral glycoproteins and their entry requirements.

scholarly journals Sub-Specific Populations of Verticillium dahliae and their Roles in Vascular Wilt Pathogsystems

1996 ◽  
Author(s):  
Randall C. Rowe ◽  
Jaacov Katan ◽  
Talma Katan ◽  
Leah Tsror
Keyword(s):  
Host Plant ◽  
Plant Species ◽  
Verticillium Dahliae ◽  
Severe Disease ◽  
Vegetative Compatibility ◽  
Phenotypic Traits ◽  
Potato Seed ◽  
Vascular Wilt ◽  
Large Collection ◽  
Pathogenic Potential

Verticillium dahliae is an economically important pathogen causing vascular wilt on over 160 plant species. In North America, potato early dying is a significant disease of potato, especially in the midwest and Pacific northwest states. This disease is caused by the fungus Verticillium dahliae and in some cases involves a synergistic interaction with root-lesion nematodes, primarily Pratylenchus penetrans. In Israel, Verticillium wilt occurs in many regions and inflicts serious losses in potato, cotton, and other crops. Objectives of this project were to establish a large collection of isolates of Verticillium dahliae from potato (USA) and several host plants (Israel) and to characterize and compare the isolates with regard to morphology, vegetative compatibility group (VCG), and pathogenic capabilities on several hosts. Isolations were made from 224 commercial lots of certified potato seed tubers from across N. America and 87 potato fields located in the Columbia Basin of Oregon and Washington. A large collection of isolates from central U.S. states already existed. In Israel, 47 field sites were sampled and isolates of Verticillium dahliae were recovered from 13 host plant species and from soil. Potato isolates from N. America were tested for vegetative compatibility and all found to be in VCG 4 with about 2/3 in VCG 4A and the rest in VCG 4B. VCG 4A isolates were significantly more aggressive on potato than VCG 4B isolates and were more likely to interact synergistically with P. penetrans. The Israeli isolates fell into three vegetative compatibility groups. Nearly all (> 90%) VCG2B and VCG 4B isolates were recovered from the northern and southern parts of Israel, respectively, with some overlap in central areas. Several pathotypes were defined in cotton, using cotton and eggplant together as differentials. All VCG 2B isolates from cotton caused severe disease in cotton, while VCG 2A and VCG 4B isolates from several crops were much less aggressive to cotton. When Israeli isolates of VCGs 2A, 2B and 4B were inoculated to potato and tomato, VCG 4B isolates caused much more severe disease on potato and VCG 2A isolates caused much more severe disease in tomato. Differential patterns of pathogenicity and aggressiveness of these VCGs on potato and tomato were consistent regardless of the host plant of origin. Isolates of the same VCG resembled one another more than isolates from different VCGs based on colony and microsclerotial morphology, temperature responses and, partially, in pathogenicity. Vegetative compatibility grouping of V. dahliae in Israel appears closely associated with specific pathogenicity and other phenotypic traits. The absence of VCG 4A in Israel is significant. VCG patterns among Verficillium populations are useful to predict relatedness and pathogenic potential in both countries.  

scholarly journals Longitudinal Analysis of T and B Cell Receptor Repertoire Transcripts Reveal Dynamic Immune Response in COVID-19 Patients

2020 ◽  
Vol 11 ◽  
Author(s):  
Xuefeng Niu ◽  
Song Li ◽  
Pingchao Li ◽  
Wenjing Pan ◽  
Qian Wang ◽  
...  
Keyword(s):  
B Cell ◽  
Severe Disease ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
T Cell Homeostasis ◽  
Receptor Repertoire ◽  
Polymerase Chain ◽  
Concurrent Assessment ◽  
Cell Receptor Repertoire ◽  
Immune Repertoire Analysis

Severe COVID-19 is associated with profound lymphopenia and an elevated neutrophil to lymphocyte ratio. We applied a novel dimer avoidance multiplexed polymerase chain reaction next-generation sequencing assay to analyze T (TCR) and B cell receptor (BCR) repertoires. Surprisingly, TCR repertoires were markedly diminished during the early onset of severe disease but recovered during the convalescent stage. Monitoring TCR repertoires could serve as an indicative biomarker to predict disease progression and recovery. Panoramic concurrent assessment of BCR repertoires demonstrated isotype switching and a transient but dramatic early IgA expansion. Dominant B cell clonal expansion with decreased diversity occurred following recovery from infection. Profound changes in T cell homeostasis raise critical questions about the early events in COVID-19 infection and demonstrate that immune repertoire analysis is a promising method for evaluating emergent host immunity to SARS-CoV-2 viral infection, with great implications for assessing vaccination and other immunological therapies.

scholarly journals Genome Characterization of Bird-Related Rhabdoviruses Circulating in Africa

Viruses ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2168
Author(s):  
Dong-Sheng Luo ◽  
Zhi-Jian Zhou ◽  
Xing-Yi Ge ◽  
Hervé Bourhy ◽  
Zheng-Li Shi ◽  
...  
Keyword(s):  
Matrix Protein ◽  
Genomic Structure ◽  
Bird Species ◽  
Open Reading Frames ◽  
P Gene ◽  
Glycoprotein G ◽  
Close Relationship ◽  
1960S And 1970S ◽  
The 1960S ◽  
Nucleoprotein N

Rhabdoviridae is the most diverse family of the negative, single-stranded RNA viruses, which includes 40 ecologically different genera that infect plants, insects, reptiles, fishes, and mammals, including humans, and birds. To date, only a few bird-related rhabdoviruses among the genera Sunrhavirus, Hapavirus, and Tupavirus have been described and analyzed at the molecular level. In this study, we characterized seven additional and previously unclassified rhabdoviruses, which were isolated from various bird species collected in Africa during the 1960s and 1970s. Based on the analysis of their genome sequences obtained by next generation sequencing, we observed a classical genomic structure, with the presence of the five canonical rhabdovirus genes, i.e., nucleoprotein (N), phosphoprotein (P), matrix protein (M), glycoprotein (G), and polymerase (L). In addition, different additional open reading frames which code putative proteins of unknown function were identified, with the common presence of the C and the SH proteins, within the P gene and between the M and G genes, respectively. Genetic comparisons and phylogenetic analysis demonstrated that these seven bird-related rhabdoviruses could be considered as putative new species within the genus Sunrhavirus, where they clustered into a single group (named Clade III), a companion to two other groups that encompass mainly insect-related viruses. The results of this study shed light on the high diversity of the rhabdoviruses circulating in birds, mainly in Africa. Their close relationship with other insect-related sunrhaviruses raise questions about their potential role and impact as arboviruses that affect bird communities.

scholarly journals Coronavirus Disease (COVID-19): Comprehensive Review of Clinical Presentation

2021 ◽  
Vol 8 ◽  
Author(s):  
Om Prakash Mehta ◽  
Parshal Bhandari ◽  
Akshay Raut ◽  
Salah Eddine Oussama Kacimi ◽  
Nguyen Tien Huy
Keyword(s):  
Viral Entry ◽  
Clinical Presentation ◽  
Early Stage ◽  
Severe Disease ◽  
Clinical Manifestations ◽  
Endocrine System ◽  
Extensive Literature ◽  
First Case ◽  
Clinical Presentations ◽  
Organ Systems

COVID-19 is a rapidly growing pandemic with its first case identified during December 2019 in Wuhan, Hubei Province, China. Due to the rampant rise in the number of cases in China and globally, WHO declared COVID-19 as a pandemic on 11th March 2020. The disease is transmitted via respiratory droplets of infected patients during coughing or sneezing and affects primarily the lung parenchyma. The spectrum of clinical manifestations can be seen in COVID-19 patients ranging from asymptomatic infections to severe disease resulting in mortality. Although respiratory involvement is most common in COVID-19 patients, the virus can affect other organ systems as well. The systemic inflammation induced by the disease along with multisystem expression of Angiotensin Converting Enzyme 2 (ACE2), a receptor which allows viral entry into cells, explains the manifestation of extra-pulmonary symptoms affecting the gastrointestinal, cardiovascular, hematological, renal, musculoskeletal, and endocrine system. Here, we have reviewed the extensive literature available on COVID-19 about various clinical presentations based on the organ system involved as well as clinical presentation in specific population including children, pregnant women, and immunocompromised patients. We have also briefly discussed about the Multisystemic Inflammatory Syndrome occurring in children and adults with COVID-19. Understanding the various clinical presentations can help clinicians diagnose COVID-19 in an early stage and ensure appropriate measures to be undertaken in order to prevent further spread of the disease.

scholarly journals Molecular Mechanisms Lead to Sex-Specific COVID-19 Prognosis and Targeted Therapies

2020 ◽  
Vol 7 ◽  
Author(s):  
Thushara Galbadage ◽  
Brent M. Peterson ◽  
Jeffrey S. Wang ◽  
Avishka Jayasekara ◽  
Danny A. Ramirez ◽  
...  
Keyword(s):  
Risk Factor ◽  
Viral Entry ◽  
Targeted Therapies ◽  
Molecular Mechanisms ◽  
Severe Disease ◽  
Renin Angiotensin System ◽  
Epidemiological Studies ◽  
Endocrine Regulation ◽  
Regulatory Systems ◽  
Males And Females

Clinical and epidemiological studies have identified male sex as an important risk factor for COVID-19 clinical outcomes and mortality. This raises the question as to how this risk factor can be addressed in the prognosis, clinical management, and the treatment of patients with Coronavirus disease 2019 (COVID-19). Currently, there are no guidelines or protocols to help alter the course of sex-specific COVID-19 prognosis, especially in severe disease presentations. This is partly due to the lack of research studies characterizing the differences in male vs. female host response to the severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) infection and a lack of a well-rounded understanding of the molecular mechanisms involved. Here, we discuss three distinct but interconnected molecular-level differences in males and females that likely play an essential role in the COVID-19 prognosis. We review interactions of SARS-CoV-2 with host cell angiotensin-converting enzyme 2 (ACE2) in the viral entry between males vs. females and discuss the differential regulation of the renin-angiotensin system (RAS) between the two sexes. Next, we present immune response disparities and how immune function and endocrine regulation may render males increasingly vulnerable to severe COVID-19. We describe the interconnected roles of these three regulatory systems in males and females in response to SARS-CoV-2 infection. Finally, we highlight the clinical implications of these mechanisms to patients with COVID-19 and propose putative targeted therapies that can help reduce COVID-19 severity in those critically ill.

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