scholarly journals Identification and Evaluation of a Highly Effective Fusion Inhibitor for Human Metapneumovirus

2007 ◽  
Vol 52 (1) ◽  
pp. 279-287 ◽  
Author(s):  
Céline Deffrasnes ◽  
Marie-Ève Hamelin ◽  
Gregory A. Prince ◽  
Guy Boivin
Keyword(s):  
Fusion Protein ◽  
Clinical Symptoms ◽  
Pulmonary Inflammation ◽  
Human Metapneumovirus ◽  
Heptad Repeat ◽  
Elderly Subjects ◽  
Monocyte Chemoattractant Protein 1 ◽  
Syncytial Virus ◽  
Tract Infections

ABSTRACT Human metapneumovirus (hMPV) can cause acute upper and lower respiratory tract infections that are particularly severe in young children, elderly subjects, and immunocompromised patients. To date, no treatments or vaccines are available for hMPV infections. Our objective was to assess the inhibitory potential of several peptides derived from the heptad repeat A and B (HRA and HRB) domains of the hMPV fusion protein. Nine candidate peptides were expressed in Escherichia coli or obtained synthetically and tested in vitro and in an animal model. Excellent in vitro inhibition of an hMPV strain of the A1 subgroup was obtained with five peptides, with 50% inhibitory concentrations ranging from 1.4 nM to 3.3 μM. One peptide, HRA2, displayed very potent activity against all four hMPV subgroups. It was also moderately active against human respiratory syncytial virus (strain A2) but displayed no activity against human parainfluenza virus type 3. BALB/c mice that received the HRA2 peptide and a lethal hMPV intranasal challenge simultaneously were completely protected from clinical symptoms and mortality. On day 5 postinfection, HRA2-treated mice had undetectable lung viral loads which were significantly less than those of untreated mice (3 × 104 50% tissue culture infective doses/lung). Pulmonary inflammation, levels of proinflammatory cytokines/chemokines (RANTES, gamma interferon, and monocyte chemoattractant protein 1) and airway obstruction were also significantly decreased in HRA2-treated mice. The results of this study demonstrate that potent antivirals can be derived from the hMPV fusion protein HR domains. Moreover, hMPV, compared to other paramyxoviruses and to the human immunodeficiency virus, seems to be more susceptible to HRA- than HRB-derived peptides.

scholarly journals The Core of the Respiratory Syncytial Virus Fusion Protein Is a Trimeric Coiled Coil

2000 ◽  
Vol 74 (13) ◽  
pp. 5911-5920 ◽  
Author(s):  
Jacqueline M. Matthews ◽  
Thomas F. Young ◽  
Simon P. Tucker ◽  
Joel P. Mackay
Keyword(s):  
Respiratory Syncytial Virus ◽  
Fusion Protein ◽  
Limited Proteolysis ◽  
Coiled Coil ◽  
Heptad Repeat ◽  
Sedimentation Equilibrium ◽  
Resonance Spectroscopy ◽  
The Core ◽  
Syncytial Virus ◽  
Tract Infections

ABSTRACT Entry into the host cell by enveloped viruses is mediated by fusion (F) or transmembrane glycoproteins. Many of these proteins share a fold comprising a trimer of antiparallel coiled-coil heterodimers, where the heterodimers are formed by two discontinuous heptad repeat motifs within the proteolytically processed chain. The F protein of human respiratory syncytial virus (RSV; the major cause of lower respiratory tract infections in infants) contains two corresponding regions that are predicted to form coiled coils (HR1 and HR2), together with a third predicted heptad repeat (HR3) located in a nonhomologous position. In order to probe the structures of these three domains and ascertain the nature of the interactions between them, we have studied the isolated HR1, HR2, and HR3 domains of RSV F by using a range of biophysical techniques, including circular dichroism, nuclear magnetic resonance spectroscopy, and sedimentation equilibrium. HR1 forms a symmetrical, trimeric coiled coil in solution (K 3 ≈ 2.2 × 1011 M−2) which interacts with HR2 to form a 3:3 hexamer. The HR1-HR2 interaction domains have been mapped using limited proteolysis, reversed-phase high-performance liquid chromatography, and electrospray-mass spectrometry. HR2 in isolation exists as a largely unstructured monomer, although it exhibits a tendency to form aggregates with β-sheet-like characteristics. Only a small increase in α-helical content was observed upon the formation of the hexamer. This suggests that the RSV F glycoprotein contains a domain that closely resembles the core structure of the simian parainfluenza virus 5 fusion protein (K. A. Baker, R. E. Dutch, R. A. Lamb, and T. S. Jardetzky, Mol. Cell 3:309–319, 1999). Finally, HR3 forms weak α-helical homodimers that do not appear to interact with HR1, HR2, or the HR1-HR2 complex. The results of these studies support the idea that viral fusion proteins have a common core architecture.

scholarly journals Human Metapneumovirus Induces Mucin 19 Which Contributes to Viral Pathogenesis

Pathogens ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 726
Author(s):  
Kaitlin McBride ◽  
Ma. del Rocio Banos-Lara ◽  
Nagarjuna R. Cheemarla ◽  
Antonieta Guerrero-Plata
Keyword(s):  
Immune Response ◽  
Respiratory Tract ◽  
Viral Infections ◽  
Clinical Symptoms ◽  
Human Metapneumovirus ◽  
Hmpv Infection ◽  
Lower Lung ◽  
Tract Infections ◽  
Mouse Model Of Infection

Human Metapneumovirus (HMPV) remains one of the most common viral infections causing acute respiratory tract infections, especially in young children, elderly, and immunocompromised populations. Clinical symptoms can range from mild respiratory symptoms to severe bronchiolitis and pneumonia. The production of mucus is a common feature during HMPV infection, but its contribution to HMPV-induced pathogenesis and immune response is largely unknown. Mucins are a major component of mucus and they could have an impact on how the host responds to infections. Using an in vitro system and a mouse model of infection, we identified that Mucin 19 is predominantly expressed in the respiratory tract upon HMPV infection. Moreover, the lack of Muc19 led to an improved disease, lower lung viral titers and a decrease in the number of CD4+ T cells. These data indicate that mucin 19 contributes to the activation of the immune response to HMPV and to HMPV-induced pathogenesis.

Adult asthmatics display exaggerated IFNγ responses to human metapneumovirus and respiratory syncytial virusThis paper is one of a selection of papers in this Special Issue, entitled International Symposium on Recent Advances in Molecular, Clinical, and Social Medicine, and has undergone the Journal's usual peer-review process.

2007 ◽  
Vol 85 (2) ◽  
pp. 252-258 ◽  
Author(s):  
Renée N. Douville ◽  
Nathalie Bastien ◽  
Yan Li ◽  
F. Estelle R. Simons ◽  
Kent T. HayGlass
Keyword(s):  
Respiratory Syncytial Virus ◽  
Mononuclear Cells ◽  
Cytokine Production ◽  
Inflammatory Responses ◽  
Peer Review Process ◽  
Human Metapneumovirus ◽  
Peripheral Blood Mononuclear ◽  
Syncytial Virus ◽  
Tract Infections

Human metapneumovirus and respiratory syncytial virus are RNA viruses associated with lower respiratory tract infections. Regular symptomatic re-infection and sequelae are common, particularly in individuals with pre-existing respiratory diseases, such as asthma. Our understanding of virus-dependent cytokine responses and potential differences between allergic asthmatics and non-asthmatics is limited. To test our hypothesis that adults with mild allergic asthma, the most common form of this disease, exhibit distinct pro-inflammatory responses, we developed a model using acute in vitro infection of fresh peripheral blood mononuclear cells. For both viruses, the production of innate-immunity-associated IL-6 and IL-10 was indistinguishable in the 2 populations. Type 1 cytokine production dominated adaptive immune responses in both asthmatic and non-asthmatic individuals. Surprisingly, asthmatics exhibited stronger pro-inflammatory IFNγ production in response to human metapneumovirus than non-asthmatic adults (p = 0.01), with a similar, but statistically nonsignificant trend in the respiratory-syncytial-virus-stimulated response. Neutralizing IL-10 did not enhance the intensity of IFNγ responses, demonstrating that this pro-inflammatory bias is not counter-regulated by IL-10. Finally, anti-TLR4 blocked lipopolysaccharide, but not respiratory-syncytial-virus-driven cytokine production. Collectively, the data demonstrate that asthma is characterized by markedly stronger pro-inflammatory IFNγ responses to pneumoviruses than their non-asthmatic counterparts. This distinctive pattern of viral immunity may contribute to a worsening of asthma symptoms during respiratory virus infections.

scholarly journals Human Metapneumovirus: Etiological Agent of Severe Acute Respiratory Infections in Hospitalized and Deceased Patients with a Negative Diagnosis of Influenza

Pathogens ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 85
Author(s):  
Gisela Barrera-Badillo ◽  
Beatriz Olivares-Flores ◽  
Adriana Ruiz-López ◽  
Miguel Ángel Fierro-Valdez ◽  
Rosaura Idania Gutiérrez-Vargas ◽  
...  
Keyword(s):  
Young Children ◽  
Age Groups ◽  
Simultaneous Detection ◽  
Respiratory Viruses ◽  
Human Metapneumovirus ◽  
Late Winter ◽  
Older Individuals ◽  
Severe Acute Respiratory Infection ◽  
Syncytial Virus ◽  
Tract Infections

Human metapneumovirus (HMPV) is one of the four major viral pathogens associated with acute respiratory tract infections (ARI) and creates a substantial burden of disease, particularly in young children (<5 years) and older individuals (≥65 years). The objective of this study was to determine the epidemiological behavior of HMPV in Mexico. This retrospective study was conducted over a nine-year period and used 7283 influenza-negative respiratory samples from hospitalized and deceased patients who presented Severe Acute Respiratory Infection (SARI). The samples were processed with the help of qualitative multiplex RT-PCR for simultaneous detection of 14 respiratory viruses (xTAG® RVP FAST v2). 40.8% of the samples were positive for respiratory viruses, mainly rhinovirus/enterovirus (47.6%), respiratory syncytial virus (15.9%), HMPV (11.1%) and parainfluenza virus (8.9%). Other respiratory viruses and co-infections accounted for 16.5%. HMPV infects all age groups, but the most affected group was infants between 29 days and 9 years of age (65.6%) and adults who are 40 years and older (25.7%). HMPV circulates every year from November to April, and the highest circulation was observed in late winter. The results of this study aim to raise awareness among clinicians about the high epidemiological impact of HMPV in young children and older individuals in order to reduce the economic burden in terms of health care costs.

scholarly journals Antiviral Activity of Favipiravir (T-705) against a Broad Range of ParamyxovirusesIn Vitroand against Human Metapneumovirus in Hamsters

2016 ◽  
Vol 60 (8) ◽  
pp. 4620-4629 ◽  
Author(s):  
D. Jochmans ◽  
S. van Nieuwkoop ◽  
S. L. Smits ◽  
J. Neyts ◽  
R. A. M. Fouchier ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Measles Virus ◽  
Rna Virus ◽  
Antiviral Drug ◽  
Specific Effect ◽  
Human Metapneumovirus ◽  
Drug Candidate ◽  
Emerging Viruses ◽  
Syncytial Virus

ABSTRACTThe clinical impact of infections with respiratory viruses belonging to the familyParamyxoviridaeargues for the development of antiviral therapies with broad-spectrum activity. Favipiravir (T-705) has demonstrated potent antiviral activity against multiple RNA virus families and is presently in clinical evaluation for the treatment of influenza. Here we demonstratein vitroactivity of T-705 against the paramyxoviruses human metapneumovirus (HMPV), respiratory syncytial virus, human parainfluenza virus, measles virus, Newcastle disease virus, and avian metapneumovirus. In addition, we demonstrate activity against HMPV in hamsters. T-705 treatment inhibited replication of all paramyxoviruses testedin vitro, with 90% effective concentration (EC90) values of 8 to 40 μM. Treatment of HMPV-challenged hamsters with T-705 at 200 mg/kg of body weight/day resulted in 100% protection from infection of the lungs. In all treated and challenged animals, viral RNA remained detectable in the respiratory tract. The observation that T-705 treatment had a significant effect on infectious viral titers, with a limited effect on viral genome titers, is in agreement with its proposed mode of action of viral mutagenesis. However, next-generation sequencing of viral genomes isolated from treated and challenged hamsters did not reveal (hyper)mutation. Polymerase activity assays revealed a specific effect of T-705 on the activity of the HMPV polymerase. With the reported antiviral activity of T-705 against a broad range of RNA virus families, this small molecule is a promising broad-range antiviral drug candidate for limiting the viral burden of paramyxoviruses and for evaluation for treatment of infections with (re)emerging viruses, such as the henipaviruses.

scholarly journals Molecular Diagnosis of Human Metapneumovirus in Hospitalized Children with Acute Respiratory Tract Infections using RT-LAMP: A Population-Based Prospective Study

2021 ◽  
Vol 11 (2) ◽  
pp. 146-150
Author(s):  
Ahmed Osman Gasim Attar ◽  
Khalid Enan ◽  
Sara Abdelghani ◽  
Lienda Bashier Eltayeb
Keyword(s):  
Respiratory Tract ◽  
Respiratory Tract Infections ◽  
Clinical Symptoms ◽  
Diagnostic Technique ◽  
Lamp Assay ◽  
Human Metapneumovirus ◽  
Hospitalized Children ◽  
Age Group ◽  
Acute Respiratory Tract Infections ◽  
Tract Infections

Background: Human metapneumovirus (hMPV) is a major novel cause of acute respiratory infections ranging from wheezing to bronchiolitis and pneumonia in children worldwide. The aim of this study was to detect hMPV in hospitalized children with acute respiratory tract infections (ARTIs) by using reverse transcription-loop mediated isothermal amplification (RT-LAMP) assay. Methods and Results: A total of 68 children with ARTIs who were clinically suspected of acquiring hMPV were included in the study in the period between January 2019 and February 2020. Posterior-pharyngeal (throat) swabs were obtained from each patient. hMPV RNA was revealed in 18(26.5%) cases. The age range was from <1 year to 10 years (mean age of 5.25±2.62). Sixteen (23.5%) of the participants were in the age group of <1 year, where the majority of hMPV-positive subjects (n=11) were found (16.2% of the total number of infected children) (P=0.0025). The majority of hMPV-negative subjects (n=15) were found in the age group of 5-10 years (22% of the total number of infected children) (P=0.0025). Cough, fever, and shortness of breath were common symptoms in hMPV-positive children: 15(83.3%), 13(72.2%), and 12(66.7%), respectively. There was a statistically significant correlation between common clinical symptoms and the age group of hMPV-positive children: symptoms were common in the age group of <1 year. Conclusion: Our study represents the first report in Khartoum, Sudan, on the detection of hMPV using RT-LAMP. RT-LAMP is a valuable, quick diagnostic technique for hMPV detection.

scholarly journals RSV attenuates epithelial cell restitution by inhibiting actin cytoskeleton-dependent cell migration

2021 ◽  
Author(s):  
Debra T Linfield ◽  
Nannan Gao ◽  
Andjela Raduka ◽  
Terri J Harford ◽  
Giovanni Piedimonte ◽  
...  
Keyword(s):  
Cell Migration ◽  
Epithelial Cell ◽  
Wound Repair ◽  
Focal Adhesions ◽  
Fiber Formation ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
Tract Infections

The airway epithelium's ability to repair itself after injury, known as epithelial restitution, is an essential mechanism enabling the respiratory tract's normal functions. Respiratory Syncytial Virus (RSV) is the leading cause of lower respiratory tract infections worldwide. We sought to determine whether RSV delays the airway epithelium wound repair process both in vitro and in vivo. We found that RSV infection attenuated epithelial cell migration, a step in wound repair, promoted stress fiber formation, and mediated assembly of large focal adhesions (FA). Inhibition of Rho kinase (ROCK), a master regulator of actin function, reversed these effects. There was increased RhoA and phospho-myosin light chain (pMLC2) following RSV infection. In vivo, mice were intraperitoneally inoculated with naphthalene to induce lung injury, followed by RSV infection. RSV infection delayed re-epithelialization. There were increased concentrations of pMLC2 in day 7 naphthalene plus RSV animals which normalized by day 14. This study suggests a key mechanism by which RSV infection delays wound healing.

scholarly journals Long Noncoding RNA NRAV Promotes Respiratory Syncytial Virus Replication by Targeting the MicroRNA miR-509-3p/Rab5c Axis To Regulate Vesicle Transportation

2020 ◽  
Vol 94 (10) ◽  
Author(s):  
Jian Li ◽  
Miao Li ◽  
Xiuli Wang ◽  
Mengfei Sun ◽  
Cuiqing Ma ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Respiratory Virus ◽  
Antiviral Response ◽  
Negative Regulator ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
Tract Infections

ABSTRACT Respiratory syncytial virus (RSV) is an enveloped RNA virus which is responsible for approximately 80% of lower respiratory tract infections in children. Current lines of evidence have supported the functional involvement of long noncoding RNA (lncRNA) in many viral infectious diseases. However, the overall biological effect and clinical role of lncRNAs in RSV infection remain unclear. In this study, lncRNAs related to respiratory virus infection were obtained from the lncRNA database, and we collected 144 clinical sputum specimens to identify lncRNAs related to RSV infection. Quantitative PCR (qPCR) detection indicated that the expression of lncRNA negative regulator of antiviral response (NRAV) in RSV-positive patients was significantly lower than that in uninfected patients, but lncRNA psoriasis-associated non-protein coding RNA induced by stress (PRINS), nuclear paraspeckle assembly transcript 1 (NEAT1), and Nettoie Salmonella pas Theiler’s (NeST) showed no difference in vivo and in vitro. Meanwhile, overexpression of NRAV promoted RSV proliferation in A549 and BEAS-2B cells, and vice versa, indicating that the downregulation of NRAV was part of the host antiviral defense. RNA fluorescent in situ hybridization (FISH) confirmed that NRAV was mainly located in the cytoplasm. Through RNA sequencing, we found that Rab5c, which is a vesicle transporting protein, showed the same change trend as NRAV. Subsequent investigation revealed that NRAV was able to favor RSV production indirectly by sponging microRNA miR-509-3p so as to release Rab5c and facilitate vesicle transportation. The study provides a new insight into virus-host interaction through noncoding RNA, which may contribute to exploring potential antivirus targets for respiratory virus. IMPORTANCE The mechanism of interaction between RSV and host noncoding RNAs is not fully understood. In this study, we found that the expression of long noncoding RNA (lncRNA) negative regulator of antiviral response (NRAV) was reduced in RSV-infected patients, and overexpression of NRAV facilitated RSV production in vitro, suggesting that the reduction of NRAV in RSV infection was part of the host antiviral response. We also found that NRAV competed with vesicle protein Rab5c for microRNA miR509-3p in cytoplasm to promote RSV vesicle transport and accelerate RSV proliferation, thereby improving our understanding of the pathogenic mechanism of RSV infection.

Respiratory Syncytial Virus (RSV) Infections in Immunocompromized Children.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5300-5300
Author(s):  
Alan Kwok Shing Chiang ◽  
Godfrey Chi Fung Chan ◽  
Shau Yin Ha ◽  
Kwok Hung Chan
Keyword(s):  
Respiratory Syncytial Virus ◽  
Clinical Symptoms ◽  
Bone Marrow Failure ◽  
Severe Pneumonia ◽  
Viral Clearance ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
The Individual ◽  
Tract Infections ◽  
Oncology Unit

Abstract Eleven children who were immunocompromized due to chemotherapy were infected with respiratory syncytial virus (RSV) during an outbreak of RSV infection in the Pediatric Oncology Unit of Queen Mary Hospital, The University of Hong Kong. The clinical symptoms, effect on treatment regimen, outcome of infection and viral clearance had been followed prospectively in all 11 children. Viral clearance was documented by immunofluorescence and PCR studies of nasopharyngeal aspirates or nasal/throat swabs. Eight of the 11 children had upper respiratory symptoms with the remaining 3 patients progressing to lower respiratory tract infections (LRTI). All except one had protracted viral symptoms but eventually recovered without the need for specific anti-viral treatment or intensive support. However, the chemotherapy regimen or scheduled BMT had been significantly interrupted. One patient developed progressively severe pneumonia which was further complicated by adenovirus reactivation causing bone marrow failure and severe sepsis resulting in death of this patient. The viral clearance of RSV was delayed in all patients with median of 20 days (range 9–81 days). One patient had recurrence of RSV detected by PCR 35 days after intial documentation of clearance, after a BMT procedure. The delayed viral clearance correlated with protracted viral symptoms. In conclusion, RSV clearance is delayed in immunocompromized hosts causing protracted viral symptoms, progression to LRTI and interruption to chemotherapy treatment. The delay in viral clearance appears proportional to the degree of immunosuppression of the individual.

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