scholarly journals Respiratory syncytial virus M2-1 protein associates non-specifically with viral messenger RNA and with specific cellular messenger RNA transcripts

2021 ◽  
Vol 17 (5) ◽  
pp. e1009589
Author(s):  
Molly R. Braun ◽  
Sarah L. Noton ◽  
Emmeline L. Blanchard ◽  
Afzaal Shareef ◽  
Philip J. Santangelo ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Messenger Rna ◽  
Rna Virus ◽  
Elongation Factor ◽  
The Elderly ◽  
Rna Sequences ◽  
Virus Rna ◽  
Cellular Mrnas ◽  
Infected Cells ◽  
Syncytial Virus

Respiratory syncytial virus (RSV) is a major cause of respiratory disease in infants and the elderly. RSV is a non-segmented negative strand RNA virus. The viral M2-1 protein plays a key role in viral transcription, serving as an elongation factor to enable synthesis of full-length mRNAs. M2-1 contains an unusual CCCH zinc-finger motif that is conserved in the related human metapneumovirus M2-1 protein and filovirus VP30 proteins. Previous biochemical studies have suggested that RSV M2-1 might bind to specific virus RNA sequences, such as the transcription gene end signals or poly A tails, but there was no clear consensus on what RSV sequences it binds. To determine if M2-1 binds to specific RSV RNA sequences during infection, we mapped points of M2-1:RNA interactions in RSV-infected cells at 8 and 18 hours post infection using crosslinking immunoprecipitation with RNA sequencing (CLIP-Seq). This analysis revealed that M2-1 interacts specifically with positive sense RSV RNA, but not negative sense genome RNA. It also showed that M2-1 makes contacts along the length of each viral mRNA, indicating that M2-1 functions as a component of the transcriptase complex, transiently associating with nascent mRNA being extruded from the polymerase. In addition, we found that M2-1 binds specific cellular mRNAs. In contrast to the situation with RSV mRNA, M2-1 binds discrete sites within cellular mRNAs, with a preference for A/U rich sequences. These results suggest that in addition to its previously described role in transcription elongation, M2-1 might have an additional role involving cellular RNA interactions.

scholarly journals The Morphology and Assembly of Respiratory Syncytial Virus Revealed by Cryo-Electron Tomography

Viruses ◽  
2018 ◽  
Vol 10 (8) ◽  
pp. 446 ◽  
Author(s):  
Zunlong Ke ◽  
Rebecca Dillard ◽  
Tatiana Chirkova ◽  
Fredrick Leon ◽  
Christopher Stobart ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Electron Tomography ◽  
Rna Virus ◽  
3D Structure ◽  
Three Dimensional ◽  
The Elderly ◽  
Cryo Electron Tomography ◽  
Infected Cells ◽  
Syncytial Virus ◽  
Tract Disease

Human respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract disease in young children. With repeat infections throughout life, it can also cause substantial disease in the elderly and in adults with compromised cardiac, pulmonary and immune systems. RSV is a pleomorphic enveloped RNA virus in the Pneumoviridae family. Recently, the three-dimensional (3D) structure of purified RSV particles has been elucidated, revealing three distinct morphological categories: spherical, asymmetric, and filamentous. However, the native 3D structure of RSV particles associated with or released from infected cells has yet to be investigated. In this study, we have established an optimized system for studying RSV structure by imaging RSV-infected cells on transmission electron microscopy (TEM) grids by cryo-electron tomography (cryo-ET). Our results demonstrate that RSV is filamentous across several virus strains and cell lines by cryo-ET, cryo-immuno EM, and thin section TEM techniques. The viral filament length varies from 0.5 to 12 μm and the average filament diameter is approximately 130 nm. Taking advantage of the whole cell tomography technique, we have resolved various stages of RSV assembly. Collectively, our results can facilitate the understanding of viral morphogenesis in RSV and other pleomorphic enveloped viruses.

scholarly journals 4'-Fluorouridine is a broad-spectrum orally efficacious antiviral blocking respiratory syncytial virus and SARS-CoV-2 replication

2021 ◽  
Author(s):  
Julien Sourimant ◽  
Carolin Lieber ◽  
Megha Aggarwal ◽  
Robert Cox ◽  
Josef Wolf ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Broad Spectrum ◽  
Rna Virus ◽  
Oral Treatment ◽  
The Elderly ◽  
Virus Infections ◽  
Once Daily ◽  
Syncytial Virus ◽  
Well Differentiated

The COVID-19 pandemic has underscored the critical need for broad-spectrum therapeutics against respiratory viruses. Respiratory syncytial virus (RSV) is a major threat to pediatric patients and the elderly. We describe 4'-fluorouridine (4'-FlU, EIDD-2749), a ribonucleoside analog that inhibits RSV, related RNA viruses, and SARS-CoV-2 with high selectivity index in cells and well-differentiated human airway epithelia. Polymerase inhibition in in vitro RdRP assays established for RSV and SARS-CoV-2 revealed transcriptional pauses at positions i or i+3/4 post-incorporation. Once-daily oral treatment was highly efficacious at 5 mg/kg in RSV-infected mice or 20 mg/kg in ferrets infected with SARS-CoV-2 WA1/2020 or variant-of-concern (VoC) isolate CA/2020, initiated 24 or 12 hours after infection, respectively. These properties define 4'-FlU as a broad-spectrum candidate for the treatment of RSV, SARS-CoV-2 and related RNA virus infections.

scholarly journals DEVELOPMENT AND PROPERTIES OF NEUTRALIZING MONOCLONAL ANTIBODIES FOR FUSION PROTEIN OF RESPIRATORY SYNCYTIAL VIRUS

2019 ◽  
Vol 64 (2) ◽  
pp. 90-96
Author(s):  
A. A. Kushch ◽  
R. R. Klimova ◽  
N. E. Fedorova ◽  
O. V. Masalova ◽  
A. A. Niconova ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Respiratory Syncytial Virus ◽  
Culture Method ◽  
The Elderly ◽  
F Protein ◽  
Wide Range ◽  
Infected Cells ◽  
Syncytial Virus ◽  
Tract Infections

Introduction. Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections in infants and the elderly. The absence of a wide range of therapeutic drugs and vaccines indicates to the high relevance of the development of new effective drugs for the prevention and treatment of RSV infections. Purpose: to obtain highly active and specific monoclonal antibodies (MAbs) capable of detecting RSV in infected cells and neutralizing the infectious activity of the virus in vitro. Material and methods. RSV reference strains of group A 2 subgroups (A2 and Long) were propagated in HEp-2 and MA-104 cell lines, respectively. Mice were immunized with purified RSV A2 virus. MAbs were obtained using hybridoma technology. Results. A panel of 6 MAbs reacting with RSV strains А2 and Long has been obtained. Four MAbs were IgG (IgG2a or IgG2b subtype), two MAbs were IgM. All MAbs reacted with RSV F-protein in immunochemical tests. The MAbs actively reacted with RSV in ELISA, in immufluorescence and peroxidase staining of infected cells, and in immunodot test. Five out of 6 MAbs neutralized of RSV in cell culture. Different properties of MAbs suggest that they target different antigenic sites of F-protein. Discussion. Comparative analysis suggests that the obtained MAbs can be used for the development of diagnostic preparations, for RSV detection in clinical materials and confirmation of infection etiology by rapid culture method. Conclusion. High activity and specificity of MAbs indicate that they can serve as a basis for development vaccines and preventive medicines.

scholarly journals Considerations for a Respiratory Syncytial Virus Vaccine Targeting an Elderly Population

Vaccines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 624
Author(s):  
Laura M. Stephens ◽  
Steven M. Varga
Keyword(s):  
Respiratory Syncytial Virus ◽  
Disease Burden ◽  
Elderly Population ◽  
Vaccine Development ◽  
The Elderly ◽  
The United States ◽  
Susceptible Population ◽  
Age Related ◽  
Syncytial Virus ◽  
Tract Infections

Respiratory syncytial virus (RSV) is most commonly associated with acute lower respiratory tract infections in infants and children. However, RSV also causes a high disease burden in the elderly that is often under recognized. Adults >65 years of age account for an estimated 80,000 RSV-associated hospitalizations and 14,000 deaths in the United States annually. RSV infection in aged individuals can result in more severe disease symptoms including pneumonia and bronchiolitis. Given the large disease burden caused by RSV in the aged, this population remains an important target for vaccine development. Aging results in lowered immune responsiveness characterized by impairments in both innate and adaptive immunity. This immune senescence poses a challenge when developing a vaccine targeting elderly individuals. An RSV vaccine tailored towards an elderly population will need to maximize the immune response elicited in order to overcome age-related defects in the immune system. In this article, we review the hurdles that must be overcome to successfully develop an RSV vaccine for use in the elderly, and discuss the vaccine candidates currently being tested in this highly susceptible population.

scholarly journals Evaluation of Small Molecule Combinations against Respiratory Syncytial Virus In Vitro

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2607
Author(s):  
Yuzhen Gao ◽  
Jingjing Cao ◽  
Pan Xing ◽  
Ralf Altmeyer ◽  
Youming Zhang
Keyword(s):  
Respiratory Syncytial Virus ◽  
Confidence Interval ◽  
The Elderly ◽  
Term Treatment ◽  
Fusion Inhibitors ◽  
Long Term Treatment ◽  
Statistical Program ◽  
Syncytial Virus

Respiratory syncytial virus (RSV) is a major pathogen that causes severe lower respiratory tract infection in infants, the elderly and the immunocompromised worldwide. At present no approved specific drugs or vaccines are available to treat this pathogen. Recently, several promising candidates targeting RSV entry and multiplication steps are under investigation. However, it is possible to lead to drug resistance under the long-term treatment. Therapeutic combinations constitute an alternative to prevent resistance and reduce antiviral doses. Therefore, we tested in vitro two-drug combinations of fusion inhibitors (GS5806, Ziresovir and BMS433771) and RNA-dependent RNA polymerase complex (RdRp) inhibitors (ALS8176, RSV604, and Cyclopamine). The statistical program MacSynergy II was employed to determine synergism, additivity or antagonism between drugs. From the result, we found that combinations of ALS8176 and Ziresovir or GS5806 exhibit additive effects against RSV in vitro, with interaction volume of 50 µM2% and 31 µM2% at 95% confidence interval, respectively. On the other hand, all combinations between fusion inhibitors showed antagonistic effects against RSV in vitro, with volume of antagonism ranging from −50 µM2 % to −176 µM2 % at 95% confidence interval. Over all, our results suggest the potentially therapeutic combinations in combating RSV in vitro could be considered for further animal and clinical evaluations.

Respiratory Syncytial Virus (RSV) Diseases

2022 ◽  
Author(s):  
Heinz-Josef Schmitt ◽  
Khrystyna Hrynkevych
Keyword(s):  
Respiratory Syncytial Virus ◽  
Rna Virus ◽  
Passive Immunization ◽  
Active Immunization ◽  
F Protein ◽  
Hospitalization Rates ◽  
Syncytial Virus ◽  
Repeated Infections ◽  
Long Acting ◽  
Underlying Diseases

The respiratory syncytial virus (RSV) is an RNA virus that causes annual ARI outbreaks during winter with mild URTI in the general population, but with severe LRTI particularly among young children (bronchiolitis), patients with underlying diseases and people >65 years of age. RSV does not induce a long-lasting protective immunity and repeated infections throughout life are the norm. Basically, all children have been infected by 2 years of age and of those hospitalized, >50% are <3 months and 75% are <6 months of age. The overall CFR is 1/500. For adults ≥65 years, RSV hospitalization rates are 90–250/105. There is no specific therapy, general preventive measures include general hygiene and isolation/separation of patients. A monoclonal anti-F-protein antibody is available for passive immunization of selected high-risk children. It requires monthly injections, comes at a high cost and has limited efficacy (50% against RSV hospitalization). Active immunization failed in the past, probably as the post-fusion conformation of the F-protein was used. Long-acting monoclonal antibodies (for infants) as well as stabilized pre-fusion F-protein vaccines (for immunization of pregnant women, children, older adults) produced on various platforms are in late stages of clinical development.

scholarly journals Potential Neurocognitive Symptoms Due to Respiratory Syncytial Virus Infection

Pathogens ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 47
Author(s):  
Catalina A. Andrade ◽  
Alexis M. Kalergis ◽  
Karen Bohmwald
Keyword(s):  
Respiratory Syncytial Virus ◽  
Viral Infections ◽  
Respiratory Infections ◽  
The Elderly ◽  
Cell Types ◽  
Potential Effect ◽  
Viral Agent ◽  
Pulmonary Manifestations ◽  
Syncytial Virus ◽  
Tract Infections

Respiratory infections are among the major public health burdens, especially during winter. Along these lines, the human respiratory syncytial virus (hRSV) is the principal viral agent causing acute lower respiratory tract infections leading to hospitalization. The pulmonary manifestations due to hRSV infection are bronchiolitis and pneumonia, where the population most affected are infants and the elderly. However, recent evidence suggests that hRSV infection can impact the mother and fetus during pregnancy. Studies have indicated that hRSV can infect different cell types from the placenta and even cross the placenta barrier and infect the fetus. In addition, it is known that infections during the gestational period can lead to severe consequences for the development of the fetus due not only to a direct viral infection but also because of maternal immune activation (MIA). Furthermore, it has been described that the development of the central nervous system (CNS) of the fetus can be affected by the inflammatory environment of the uterus caused by viral infections. Increasing evidence supports the notion that hRSV could invade the CNS and infect nervous cells, such as microglia, neurons, and astrocytes, promoting neuroinflammation. Moreover, it has been described that the hRSV infection can provoke neurological manifestations, including cognitive impairment and behavioral alterations. Here, we will review the potential effect of hRSV in brain development and the potential long-term neurological sequelae.

scholarly journals Chemokine regulation of inflammation during respiratory syncytial virus infection

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 1837 ◽  
Author(s):  
Rinat Nuriev ◽  
Cecilia Johansson
Keyword(s):  
Respiratory Syncytial Virus ◽  
The Elderly ◽  
Infection Process ◽  
Viral Control ◽  
Small Proteins ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
Tract Infections ◽  
Developed World ◽  
Immune Detection

Respiratory syncytial virus (RSV) can cause severe lower respiratory tract infections especially in infants, immunocompromised individuals and the elderly and is the most common cause of infant hospitalisation in the developed world. The immune responses against RSV are crucial for viral control and clearance but, if dysregulated, can also result in immunopathology and impaired gas exchange. Lung immunity to RSV and other respiratory viruses begins with the recruitment of immune cells from the bloodstream into the lungs. This inflammatory process is controlled largely by chemokines, which are small proteins that are produced in response to innate immune detection of the virus or the infection process. These chemokines serve as chemoattractants for granulocytes, monocytes, lymphocytes and other leukocytes. In this review, we highlight recent advances in the field of RSV infection and disease, focusing on how chemokines regulate virus-induced inflammation.

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