scholarly journals Mutating the CX3C Motif in the G Protein Should Make a Live Respiratory Syncytial Virus Vaccine Safer and More Effective

2017 ◽  
Vol 91 (10) ◽  
Author(s):  
S. Boyoglu-Barnum ◽  
S. O. Todd ◽  
J. Meng ◽  
T. R. Barnum ◽  
T. Chirkova ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
G Protein ◽  
Chemokine Receptor ◽  
Airway Resistance ◽  
Disease Pathogenesis ◽  
Mucus Production ◽  
Safety And Efficacy ◽  
Syncytial Virus ◽  
Tract Infections ◽  
Receptor Cx3cr1

ABSTRACT Respiratory syncytial virus (RSV) belongs to the family Paramyxoviridae and is the single most important cause of serious lower respiratory tract infections in young children, yet no highly effective treatment or vaccine is available. Through a CX3C chemokine motif (182CWAIC186) in the G protein, RSV binds to the corresponding chemokine receptor, CX3CR1. Since RSV binding to CX3CR1 contributes to disease pathogenesis, we investigated whether a mutation in the CX3C motif by insertion of an alanine, A186, within the CX3C motif, mutating it to CX4C (182CWAIAC187), which is known to block binding to CX3CR1, might decrease disease. We studied the effect of the CX4C mutation in two strains of RSV (A2 and r19F) in a mouse challenge model. We included RSV r19F because it induces mucus production and airway resistance, two manifestations of RSV infection in humans, in mice. Compared to wild-type (wt) virus, mice infected with CX4C had a 0.7 to 1.2 log10-fold lower virus titer in the lung at 5 days postinfection (p.i.) and had markedly reduced weight loss, pulmonary inflammatory cell infiltration, mucus production, and airway resistance after challenge. This decrease in disease was not dependent on decrease in virus replication but did correspond to a decrease in pulmonary Th2 and inflammatory cytokines. Mice infected with CX4C viruses also had higher antibody titers and a Th1-biased T cell memory response at 75 days p.i. These results suggest that the CX4C mutation in the G protein could improve the safety and efficacy of a live attenuated RSV vaccine. IMPORTANCE RSV binds to the corresponding chemokine receptor, CX3CR1, through a CX3C chemokine motif (182CWAIC186) in the G protein. RSV binding to CX3CR1 contributes to disease pathogenesis; therefore, we investigated whether a mutation in the CX3C motif by insertion of an alanine, A186, within the CX3C motif, mutating it to CX4C (182CWAIAC187), known to block binding to CX3CR1, might decrease disease. The effect of this mutation and treatment with the F(ab′)2 form of the anti-RSV G 131-2G monoclonal antibody (MAb) show that mutating the CX3C motif to CX4C blocks much of the disease and immune modulation associated with the G protein and should improve the safety and efficacy of a live attenuated RSV vaccine.

scholarly journals Respiratory Syncytial Virus Infects Regulatory B Cells in Human Neonates via Chemokine Receptor CX3CR1 and Promotes Lung Disease Severity

Immunity ◽  
2017 ◽  
Vol 46 (2) ◽  
pp. 301-314 ◽  
Author(s):  
Dania Zhivaki ◽  
Sébastien Lemoine ◽  
Annick Lim ◽  
Ahsen Morva ◽  
Pierre-Olivier Vidalain ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
B Cells ◽  
Lung Disease ◽  
Disease Severity ◽  
Chemokine Receptor ◽  
Regulatory B Cells ◽  
Lung Disease Severity ◽  
Syncytial Virus ◽  
Human Neonates ◽  
Receptor Cx3cr1

scholarly journals Respiratory Syncytial Virus G Protein Sequence Variability among Isolates from St. Petersburg, Russia, during the 2013–2014 Epidemic Season

Viruses ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 119
Author(s):  
Vera Krivitskaya ◽  
Kseniya Komissarova ◽  
Maria Pisareva ◽  
Maria Sverlova ◽  
Artem Fadeev ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Amino Acid ◽  
G Protein ◽  
Single Amino Acid ◽  
Clinical Samples ◽  
Antigenic Determinants ◽  
Sequence Variability ◽  
Antiviral Immune Response ◽  
Syncytial Virus ◽  
Tract Infections

Human respiratory syncytial virus (RSV) is the most common cause of upper and lower respiratory tract infections in infants and young children. It is actively evolving under environmental and herd immunity influences. This work presents, for the first time, sequence variability analysis of RSV G gene and G protein using St. Petersburg (Russia) isolates. Viruses were isolated in a cell culture from the clinical samples of 61 children hospitalized (January–April 2014) with laboratory-confirmed RSV infection. Real-time RT-PCR data showed that 56 isolates (91.8%) belonged to RSV-A and 5 isolates (8.2%) belonged to RSV-B. The G genes were sequenced for 27 RSV-A isolates and all of them belonged to genotype ON1/GA2. Of these RSV-A, 77.8% belonged to the ON1(1.1) genetic sub-cluster, and 14.8% belonged to the ON1(1.2) sub-cluster. The ON1(1.3) sub-cluster constituted a minor group (3.7%). Many single-amino acid substitutions were identified in the G proteins of St. Petersburg isolates, compared with the Canadian ON1/GA2 reference virus (ON67-1210A). Most of the amino acid replacements were found in immunodominant B- and T-cell antigenic determinants of G protein. These may affect the antigenic characteristics of RSV and influence the host antiviral immune response to currently circulating viruses.

scholarly journals Functional Features of the Respiratory Syncytial Virus G Protein

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1214
Author(s):  
Larry J. Anderson ◽  
Samadhan J. Jadhao ◽  
Clinton R. Paden ◽  
Suxiang Tong
Keyword(s):  
Respiratory Syncytial Virus ◽  
Drug Development ◽  
G Protein ◽  
Antiviral Drug ◽  
The Elderly ◽  
Surface Binding ◽  
Young Infants ◽  
Functional Features ◽  
Syncytial Virus ◽  
Tract Infections

Respiratory syncytial virus (RSV) is a major cause of serious lower respiratory tract infections in children <5 years of age worldwide and repeated infections throughout life leading to serious disease in the elderly and persons with compromised immune, cardiac, and pulmonary systems. The disease burden has made it a high priority for vaccine and antiviral drug development but without success except for immune prophylaxis for certain young infants. Two RSV proteins are associated with protection, F and G, and F is most often pursued for vaccine and antiviral drug development. Several features of the G protein suggest it could also be an important to vaccine or antiviral drug target design. We review features of G that effect biology of infection, the host immune response, and disease associated with infection. Though it is not clear how to fit these together into an integrated picture, it is clear that G mediates cell surface binding and facilitates cellular infection, modulates host responses that affect both immunity and disease, and its CX3C aa motif contributes to many of these effects. These features of G and the ability to block the effects with antibody, suggest G has substantial potential in vaccine and antiviral drug design.

Expression of chemokine receptor CX3CR1 in infants with respiratory syncytial virus bronchiolitis

2008 ◽  
Vol 19 (2) ◽  
pp. 148-156 ◽  
Author(s):  
Alma-Martina Cepika ◽  
Alenka Gagro ◽  
Ana Bace ◽  
Dorian Tjesic-Drinkovic ◽  
Jadranka Kelecic ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Chemokine Receptor ◽  
Respiratory Syncytial Virus Bronchiolitis ◽  
Syncytial Virus ◽  
Receptor Cx3cr1

Genetic characterization of G protein in respiratory syncytial virus ON-1 genotype in Tehran

2020 ◽  
Vol 15 (11) ◽  
pp. 725-734
Author(s):  
Somayeh Shatizadeh Malekshahi ◽  
Yazdan Samieipour ◽  
Ali Akbar Rahbarimanesh ◽  
Anahita Izadi ◽  
Nastaran Ghavami ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Amino Acid ◽  
G Protein ◽  
Genetic Characterization ◽  
Common Amino Acid ◽  
Epidemiological Surveys ◽  
Syncytial Virus ◽  
Tract Infections ◽  
Insight Into

Aim: We investigated the genetic characterization of the respiratory syncytial virus (RSV) ON-1 genotypes and their different lineages based on the G gene among children <2 years of age presenting with acute respiratory tract infections in Tehran, Iran. Materials & methods: A phylogenetic tree from the Iranian samples and ON-1 strains of various parts of the world were constructed. The amino acid composition of the RSV G protein of the ON-1 genotype was mapped. Results: Human RSV ON-1 genotypes from the Iranian samples clustered in three lineages. The most common amino acid substitutions were as follows: X218Q, I240S, L289P, Y304H and L310P. Conclusion: Continuing molecular epidemiological surveys in other regions of Iran will provide deeper insight into the nature of this replacement of the dominant RSV genotype from GA2 to ON-1 in Iran.

scholarly journals Extracellular amoebal-vesicles: potential transmission vehicles for respiratory viruses

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Rafik Dey ◽  
Melanie A. Folkins ◽  
Nicholas J. Ashbolt
Keyword(s):  
Respiratory Syncytial Virus ◽  
Respiratory Tract ◽  
Respiratory Tract Infections ◽  
Respiratory Viruses ◽  
Environmental Persistence ◽  
Viral Dissemination ◽  
Acute Respiratory Tract Infections ◽  
High Concentrations ◽  
Syncytial Virus ◽  
Tract Infections

AbstractHuman respiratory syncytial virus (RSV) is a major cause of acute respiratory tract infections in children and immunocompromised adults worldwide. Here we report that amoebae-release respirable-sized vesicles containing high concentrations of infectious RSV that persisted for the duration of the experiment. Given the ubiquity of amoebae in moist environments, our results suggest that extracellular amoebal-vesicles could contribute to the environmental persistence of respiratory viruses, including potential resistance to disinfection processes and thereby offering novel pathways for viral dissemination and transmission.

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 Bacterial and Viral Coinfections with the Human Respiratory Syncytial Virus

2021 ◽  
Vol 9 (6) ◽  
pp. 1293
Author(s):  
Gaspar A. Pacheco ◽  
Nicolás M. S. Gálvez ◽  
Jorge A. Soto ◽  
Catalina A. Andrade ◽  
Alexis M. Kalergis
Keyword(s):  
Respiratory Syncytial Virus ◽  
Influenza A ◽  
Human Respiratory Syncytial Virus ◽  
Respiratory Pathogens ◽  
Parainfluenza Viruses ◽  
Starting Point ◽  
The Social ◽  
Syncytial Virus ◽  
Tract Infections ◽  
Polymicrobial Infections

The human respiratory syncytial virus (hRSV) is one of the leading causes of acute lower respiratory tract infections in children under five years old. Notably, hRSV infections can give way to pneumonia and predispose to other respiratory complications later in life, such as asthma. Even though the social and economic burden associated with hRSV infections is tremendous, there are no approved vaccines to date to prevent the disease caused by this pathogen. Recently, coinfections and superinfections have turned into an active field of study, and interactions between many viral and bacterial pathogens have been studied. hRSV is not an exception since polymicrobial infections involving this virus are common, especially when illness has evolved into pneumonia. Here, we review the epidemiology and recent findings regarding the main polymicrobial infections involving hRSV and several prevalent bacterial and viral respiratory pathogens, such as Staphylococcus aureus, Pseudomonas aeruginosa, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Klebsiella pneumoniae, human rhinoviruses, influenza A virus, human metapneumovirus, and human parainfluenza viruses. As reports of most polymicrobial infections involving hRSV lack a molecular basis explaining the interaction between hRSV and these pathogens, we believe this review article can serve as a starting point to interesting and very much needed research in this area.

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