Cyclophilin A inhibits RSV replication by binding to RSV-N through its PPIase activity

Human Respiratory syncytial virus (hRSV) is the most common pathogen which causes acute lower respiratory infection (ALRI) in infants. Recently, virus-host interaction is a hot spot of virus related research, and it needs to be further elaborated on its host interactions during RSV infection. Here, we found that RSV infection significantly increased the expression of cypA in clinical patients, mice or epithelial cells. Therefore, we evaluated the function of cypA in RSV replication and demonstrated that virus proliferation was accelerated in cypA knockdown host cells, but restrained in cypA overexpressed host cells. Furthermore, we proved that cypA limited RSV replication depending on its PPIase activity. Moreover, we performed liquid Chromatograph Mass Spectrometer and the results showed that cypA could interact with several viral proteins, such as RSV-N, RSV-P and RSV-M2-1. Finally, the interaction between cypA and RSV-N was certificated by co-immunoprecipitation and immunofluorescence. Those results provided strong evidence that cypA may play an inhibitory role in RSV replication through interacting with RSV-N via its PPIase activity. IMPORTANCE RSV-N, packed the viral genome to form the ribonuceloprotein complex (RNP), which is recognized by RSV RNA dependent RNA polymerase (RdRp) complex to initiate the viral replication and transcription, plays an indispensable role in viral biosynthesis process. CypA, binding to RSV-N, may impair this function by weakening the interaction between RSV-N and RSV-P, thus leading to decrease viral production. Our research provides a novel insight into cypA antiviral function by binding to viral capsid protein to inhibit viral replication, which may be helpful for new antiviral drug exploration.

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Host Transcription Profiles upon Primary Respiratory Syncytial Virus Infection

Journal of Virology ◽

10.1128/jvi.02220-06 ◽

2007 ◽

Vol 81 (11) ◽

pp. 5958-5967 ◽

Cited By ~ 42

Author(s):

Riny Janssen ◽

Jeroen Pennings ◽

Hennie Hodemaekers ◽

Annemarie Buisman ◽

Marijke van Oosten ◽

...

Keyword(s):

Immune Response ◽

Respiratory Syncytial Virus ◽

Lymph Nodes ◽

Viral Replication ◽

Transcriptional Level ◽

Type I ◽

Lung Pathology ◽

Transcription Profiles ◽

Rsv Infection ◽

Syncytial Virus

ABSTRACT Respiratory syncytial virus (RSV) is a common cause of severe lower respiratory tract infection in children. Severe RSV disease is related to an inappropriate immune response to RSV resulting in enhanced lung pathology which is influenced by host genetic factors. To gain insight into the early pathways of the pathogenesis of and immune response to RSV infection, we determined the transcription profiles of lungs and lymph nodes on days 1 and 3 after infection of mice. Primary RSV infection resulted in a rapid but transient innate, proinflammatory response, as exemplified by the induction of a large number of type I interferon-regulated genes and chemokine genes, genes involved in inflammation, and genes involved in antigen processing. Interestingly, this response is much stronger on day 1 than on day 3 after infection, indicating that the strong transcriptional response in the lung precedes the peak of viral replication. Surprisingly, the set of down-regulated genes was small and none of these genes displayed strong down-regulation. Responses in the lung-draining lymph nodes were much less prominent than lung responses and are suggestive of NK cell activation. Our data indicate that at time points prior to the peak of viral replication and influx of inflammatory cells, the local lung response, measured at the transcriptional level, has already dampened down. The processes and pathways induced shortly after RSV infection can now be used for the selection of candidate genes for human genetic studies of children with severe RSV infection.

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β2-integrin LFA1 mediates airway damage following neutrophil transepithelial migration during respiratory syncytial virus infection

European Respiratory Journal ◽

10.1183/13993003.02216-2019 ◽

2020 ◽

Vol 56 (2) ◽

pp. 1902216 ◽

Cited By ~ 2

Author(s):

Jenny Amanda Herbert ◽

Yu Deng ◽

Pia Hardelid ◽

Elisabeth Robinson ◽

Luo Ren ◽

...

Keyword(s):

Viral Load ◽

Respiratory Syncytial Virus ◽

Epithelial Cell ◽

Epithelial Cells ◽

Cell Damage ◽

Antiviral Treatment ◽

Beat Frequency ◽

Antiviral Drug ◽

Rsv Infection ◽

Syncytial Virus

Respiratory syncytial virus (RSV) bronchiolitis is the most common cause of infant hospital admissions, but there is limited understanding of the mechanisms of disease, and no specific antiviral treatment. Using a novel in vitro primary transepithelial neutrophil migration model and innovative imaging methods, we show that RSV infection of nasal airway epithelium increased neutrophil transepithelial migration and adhesion to infected epithelial cells, which is associated with epithelial cell damage and reduced ciliary beat frequency, but also with a reduction in infectious viral load.Following migration, RSV infection results in greater neutrophil activation, degranulation and release of neutrophil elastase into the airway surface media compared to neutrophils that migrated across mock-infected nasal epithelial cells. Blocking of the interaction between the ligand on neutrophils (the β2-integrin LFA-1) for intracellular adhesion molecule (ICAM)-1 on epithelial cells reduced neutrophil adherence to RSV-infected cells and epithelial cell damage to pre-infection levels, but did not reduce the numbers of neutrophils that migrated or prevent the reduction in infectious viral load.These findings have provided important insights into the contribution of neutrophils to airway damage and viral clearance, which are relevant to the pathophysiology of RSV bronchiolitis. This model is a convenient, quantitative preclinical model that will further elucidate mechanisms that drive disease severity and has utility in antiviral drug discovery.

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M Protein-Deficient Respiratory Syncytial Virus (RSV) Vaccine Protects Infant Baboons Against RSV Challenge

Open Forum Infectious Diseases ◽

10.1093/ofid/ofx163.755 ◽

2017 ◽

Vol 4 (suppl_1) ◽

pp. S321-S321

Author(s):

Robert C Welliver ◽

Antonius Oomens ◽

Roman Wolf ◽

James Papin ◽

Vadim Ivanov ◽

...

Keyword(s):

Viral Replication ◽

Neutralizing Antibody ◽

Airway Disease ◽

Antibody Responses ◽

M Protein ◽

Arterial Oxygen ◽

Human Infants ◽

Rsv Infection ◽

Syncytial Virus ◽

Lymphocyte Responses

Abstract Background RSV bronchiolitis is the most common cause of hospitalization of infants in the US, and may lead to the development of long-term airway disease. Inactivated vaccines may lead to enhanced disease, while replicating vaccines have caused unacceptable degrees of illness, and may revert back to wild type. We developed an RSV vaccine lacking the gene for the M protein (Mnull RSV). The M protein is responsible for reassembly of the virus after it infects cells and expresses its proteins. Infant baboons vaccinated intranasally (IN) with Mnull RSV develop serum neutralizing antibody (NA) responses, but the virus does not replicate. Methods 2-week-old baboons (n = 12) were primed IN with 107 vaccine units of Mnull RSV or a control preparation, and a similar booster dose was given 4 weeks later. Mnull RSV vaccination did not cause tachypnea, airway inflammation or other signs of illness when compared with sham-vaccinated controls. Two weeks after boosting, all infants were challenged intratracheally with human RSV A2. We continuously monitored respiratory rates and levels of overall activity. On various days following challenge, we obtained BAL fluids for leukocyte counts and degree of virus replication, and evaluated alveolar-arterial oxygen gradients (A-a O2). Results Vaccinated animals (vs. unvaccinated controls) had lower respiratory rates (P = 0.0014), improved A-a O2 (P = 0.0063) and reduced viral replication (P = 0.0014). Activity scores were higher in vaccine recipients than in unvaccinated animals. Vaccine recipients also were primed for earlier serum and secretory neutralizing antibody responses, and greater airway lymphocyte responses. Airway lymphocyte numbers (but not antibody responses) were associated with lower respiratory rates and reduced viral replication (P < 0.01). Conclusion Vaccination intranasally with Mnull RSV protected infant baboons against an RSV challenge without causing respiratory disease or enhanced illness, and is a promising candidate for use in human infants. Lymphocyte responses to vaccination may play an equal or greater role in protection against RSV infection than antibody responses. Disclosures All authors: No reported disclosures.

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Pulmonary Susceptibility of Neonates to Respiratory Syncytial Virus Infection: A Problem of Innate Immunity?

Journal of Immunology Research ◽

10.1155/2017/8734504 ◽

2017 ◽

Vol 2017 ◽

pp. 1-13 ◽

Cited By ~ 16

Author(s):

Carole Drajac ◽

Daphné Laubreton ◽

Sabine Riffault ◽

Delphyne Descamps

Keyword(s):

Respiratory Syncytial Virus ◽

Early Period ◽

Epidemiological Studies ◽

Cell Immune Response ◽

Acute Lower Respiratory Infection ◽

Viral Agent ◽

Rsv Infection ◽

Immunological Factors ◽

Syncytial Virus ◽

Severity Of The Disease

Human respiratory syncytial virus (RSV) is a common and highly contagious viral agent responsible for acute lower respiratory infection in infants. This pathology characterized by mucus hypersecretion and a disturbed T cell immune response is one of the major causes of infant hospitalization for severe bronchiolitis. Although different risk factors are associated with acute RSV bronchiolitis, the immunological factors contributing to the susceptibility of RSV infection in infants are not clearly elucidated. Epidemiological studies have established that the age at initial infection plays a central role in the severity of the disease. Thus, neonatal susceptibility is intrinsically linked to the immunological characteristics of the young pulmonary mucosa. Early life is a critical period for the lung development with the first expositions to external environmental stimuli and microbiota colonization. Furthermore, neonates display a lung immune system that profoundly differs to those from adults, with the predominance of type 2 immune cells. In this review, we discuss the latest information about the lung immune environment in the early period of life at a steady state and upon RSV infection and how we can modulate neonatal susceptibility to RSV infection.

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Role of G2-S16 Polyanionic Carbosilane Dendrimer in the Prevention of Respiratory Syncytial Virus Infection In Vitro and In Vivo in Mice

Polymers ◽

10.3390/polym13132141 ◽

2021 ◽

Vol 13 (13) ◽

pp. 2141

Author(s):

Ignacio Rodriguez-Izquierdo ◽

Rafael Ceña-Diez ◽

Maria Jesús Serramia ◽

Rosa Rodriguez-Fernández ◽

Isidoro Martínez ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Cell Surface ◽

Host Cells ◽

Carbosilane Dendrimer ◽

Rsv Infection ◽

Host Cell Surface ◽

Syncytial Virus

The respiratory syncytial virus (RSV) causes respiratory infection and bronchiolitis, requiring hospitalization mainly in infants. The interaction between RSV, envelope glycoproteins G and F, and cell surface heparan sulfate proteoglycans (HSPG) is required for binding and entry into the host cells. A G2-S16 polyanionic carbosilane dendrimer was identified as a possible RSV inhibitor. We speculated that the G2-S16 dendrimer adheres to the host cell-surface HSPG, acts through binding to HS receptors, and prevents further RSV infection. The G2-S16 dendrimer was non-toxic when applied intranasally to Balb/c mice, and interestingly enough, this G2-S16 dendrimer inhibits 85% RSV. Therefore, our G2-S16 dendrimer could be a candidate for developing a new possible therapy against RSV infection.

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Alveolar Macrophages Can Control Respiratory Syncytial Virus Infection in the Absence of Type I Interferons

Journal of Innate Immunity ◽

10.1159/000446824 ◽

2016 ◽

Vol 8 (5) ◽

pp. 452-463 ◽

Cited By ~ 26

Author(s):

Spyridon Makris ◽

Monika Bajorek ◽

Fiona J. Culley ◽

Michelle Goritzka ◽

Cecilia Johansson

Keyword(s):

Respiratory Syncytial Virus ◽

Viral Replication ◽

Alveolar Macrophages ◽

Ex Vivo ◽

Type I Interferons ◽

Type I ◽

Proinflammatory Mediators ◽

Rsv Infection ◽

Syncytial Virus ◽

Tract Infections

Respiratory syncytial virus (RSV) is a common cause of lower respiratory tract infections. Immunity to RSV is initiated upon detection of the virus by pattern recognition receptors, such as RIG-I-like receptors. RIG-I-like receptors signal via MAVS to induce the synthesis of proinflammatory mediators, including type I interferons (IFNs), which trigger and shape antiviral responses and protect cells from infection. Alveolar macrophages (AMs) are amongst the first cells to encounter invading viruses and the ones producing type I IFNs. However, it is unclear whether IFNs act to prevent AMs from serving as vehicles for viral replication. In this study, primary AMs from MAVS (Mavs-/-)- or type I IFN receptor (Ifnar1-/-)-deficient mice were exposed to RSV ex vivo. Wild-type (wt) AMs but not Mavs-/- and Ifnar1-/- AMs produced inflammatory mediators in response to RSV. Furthermore, Mavs-/- and Ifnar1-/- AMs accumulated more RSV proteins than wt AMs, but the infection was abortive. Thus, RIG-I-like receptor-MAVS and IFNAR signalling are important for the induction of proinflammatory mediators from AMs upon RSV infection, but this signalling is not central for controlling viral replication. The ability to restrict viral replication makes AMs ideal sensors of RSV infection and important initiators of immune responses in the lung.

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The Immunogenicity and Safety of Rsv Vaccines in Development: A Systematic Review

10.20944/preprints202005.0477.v1 ◽

2020 ◽

Author(s):

Jing Shan

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Respiratory Syncytial Virus ◽

Pregnant Women ◽

Vaccine Candidate ◽

Controlled Vocabulary ◽

Acute Lower Respiratory Infection ◽

Vaccine Candidates ◽

Rsv Infection ◽

Syncytial Virus

Background: Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory infection globally. There are vaccines in pipeline to prevent it but a systematic review on immunogenicity and safety of vaccine is lacking. Methods: This systematic review of RSV vaccine clinical trials was undertaken using 4 databases. Searches were conducted using both controlled vocabulary terms such as ‘Respiratory Syncytial Virus, Human’, ‘Respiratory Syncytial Virus Infections’, ‘Respiratory Syncytial Virus Vaccines’, ‘Immunization’, ‘Immunization Programs’ and ‘Vaccines’ and corresponding text word terms. The searches for published papers were limited to clinical trials published from January 2000 to August 6th, 2018. RSV infection case was defined as RSV associated medically attended acute respiratory illness (MAARI) or RSV infection by serologically-confirmed test (Western Blot) during the RSV surveillance period. We calculated the relative risk of each vaccine trial with RSV infection case. Results: Of 4395 publications, 24 were included and data were extracted covering 4 major types of RSV vaccine candidates, these being live-attenuated/chimeric (n=9), recombinant-vector (n=10), subunit (n=1) and nanoparticle vaccines (n=4). For RSV infection cases, 7 trials were involved and none of them showed a vaccine-related increased MAARI during RSV surveillance season. Conclusion: LID ∆M2-2, MEDI M2-2, and RSVcps2 (live-attenuated) were considered the most promising vaccine candidates in infant and children. In the elderly, a nanoparticle F vaccine candidate was considered as a potential effective vaccine. Although no promising vaccine was identified from pregnant-women test, RSV F-024 subunit vaccine candidate and an RSV F nanoparticle vaccine showed encouraging results in healthy non-pregnant women.

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Association Between Respiratory Syncytial Virus-Associated Acute Lower Respiratory Infection in Early Life and Recurrent Wheeze and Asthma in Later Childhood

The Journal of Infectious Diseases ◽

10.1093/infdis/jiz311 ◽

2019 ◽

Vol 222 (Supplement_7) ◽

pp. S628-S633 ◽

Cited By ~ 7

Author(s):

Ting Shi ◽

Yujing Ooi ◽

Ei Mon Zaw ◽

Natasa Utjesanovic ◽

Harry Campbell ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Early Life ◽

Subsequent Development ◽

Respiratory Morbidity ◽

Acute Lower Respiratory Infection ◽

High Risk Population ◽

Rsv Infection ◽

Recurrent Wheeze ◽

Syncytial Virus

Abstract Background Recurrent wheeze and asthma in childhood are commons causes of chronic respiratory morbidity globally. We aimed to explore the association between respiratory syncytial virus (RSV) infection in early life and subsequent respiratory sequelae up to age 12 years. Methods We estimated the strength of association by 3 control groups and 3 follow-up age groups, with data from studies published between January 1995 and May 2018. We also estimated associations by diagnostic criteria, age at infection, and high-risk population. Results Overall, we included 41 studies. A statistically significant association was observed between early life RSV infection and subsequent childhood recurrent wheeze, in comparison to those who were healthy or those without respiratory symptoms: OR 3.05 (95% confidence interval [CI], 2.50–3.71) for 0 to <36 months follow-up age; OR 2.60 (95% CI, 1.67–4.04) for 36–72 months; and OR 2.14 (95% CI, 1.33–3.45) for 73–144 months. For the subsequent development of asthma, a statistically significant association was observed only in relation to those aged 73–144 months at follow-up: OR 2.95 (95% CI, 1.96–4.46). Conclusions Further studies using standardized definitions and from diverse settings are needed to elucidate the role of confounders and provide more robust estimates.

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TLR-4 andCD14 Polymorphisms in Respiratory Syncytial Virus Associated Disease

Disease Markers ◽

10.1155/2006/865890 ◽

2006 ◽

Vol 22 (5-6) ◽

pp. 303-308 ◽

Cited By ~ 55

Author(s):

Beena Puthothu ◽

Johannes Forster ◽

Andrea Heinzmann ◽

Marcus Krueger

Keyword(s):

Immune Response ◽

Respiratory Syncytial Virus ◽

Amino Acid ◽

Adaptive Immune Response ◽

Host Cells ◽

Respiratory Pathogen ◽

Trend Test ◽

Associated Diseases ◽

Rsv Infection ◽

Syncytial Virus

Respiratory syncytial virus (RSV) is the most common viral respiratory pathogen during infancy world wide. It induces innate and adaptive immune response in host cells. The toll like receptor 4 (TLR4)/CD14 complex is particularly important for the initiation of an innate immune response to RSV. Thus we were interested whether an association exists between severe RSV associated diseases and polymorphisms within TLR4 and CD14.We genotyped the CD14 promotor polymorphism -C159T and the two common TLR4 amino acid variants (D259G, and T359I) in 131 infants with severe RSV associated diseases and 270 controls. Statistical analyses of single polymorphisms made use of the Armitage’s trend test, haplotypes were calculated by FAMHAP, FASTEHPLUS and Arlequin.All polymorphisms were in Hardy Weinberg Equilibrium. We found marginal association between amino acid exchange D259G in TLR4 with RSV infectionp= 0.0545). Furthermore, haplotypes analysis of the two TLR4 polymorphisms by three independent programs revealed association of haplotypes with severe RSV infection (p≤ 0.0010). In contrast, the promotor polymorphism within CD14 was not associated with susceptibility to RSV disease. We conclude from our study, that TLR4 polymorphisms, and particularly the haplotypes, may influence the genetic predisposition to severe RSV infection.

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Respiratory Syncytial Virus Nonstructural Proteins NS1 and NS2 Mediate Inhibition of Stat2 Expression and Alpha/Beta Interferon Responsiveness

Journal of Virology ◽

10.1128/jvi.79.14.9315-9319.2005 ◽

2005 ◽

Vol 79 (14) ◽

pp. 9315-9319 ◽

Cited By ~ 181

Author(s):

Mindy S. Lo ◽

Robert M. Brazas ◽

Michael J. Holtzman

Keyword(s):

Respiratory Syncytial Virus ◽

Host Range ◽

Marked Decrease ◽

Host Cells ◽

Nonstructural Proteins ◽

Beta Interferon ◽

Rsv Infection ◽

Alpha Beta ◽

Syncytial Virus ◽

Viral Host Range

ABSTRACT Respiratory syncytial virus (RSV) subverts the antiviral interferon (IFN) response, but the mechanism for this evasion was unclear. Here we show that RSV preferentially inhibits IFN-α/β signaling by expression of viral NS1 and NS2. Thus, RSV infection or expression of recombinant NS1 and NS2 in epithelial host cells causes a marked decrease in Stat2 levels and the consequent downstream IFN-α/β response. Similarly, NS1/NS2-deficient RSV no longer decreases Stat2 levels or IFN responsiveness. RSV infection decreased human but not mouse Stat2 levels, so this mechanism of IFN antagonism may contribute to viral host range, as well as immune subversion.

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