In vitro modeling of respiratory syncytial virus infection of pediatric bronchial epithelium, the primary target of infection in vivo

Villenave, Rémi; Thavagnanam, Surendran; Sarlang, Séverine; Parker, Jeremy; Douglas, Isobel; Skibiński, Grzegorz; Heaney, Liam G.; McKaigue, James P.; Coyle, Peter; Shields, Michael; Power, Ultan F.

doi:10.1073/pnas.1110203109

Cited by 174 publications

(260 citation statements)

References 41 publications

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“…Previous studies have shown that RSV infects ciliated and bronchiolar airway epithelial cells in the respiratory tract, 34-36 as well as type II pneumocytes 37 38 Consistent with these findings, viral antigen expression was present on these cell types in the hRSV-infected lambs, with a significant correlation between hRSV expression in alveoli and bronchioles (Figure 8a).…”

Section: Discussionsupporting

confidence: 76%

Delivery of ALX-0171 by inhalation greatly reduces respiratory syncytial virus disease in newborn lambs

Mora

Detalle

Gallup

et al. 2018

mAbs

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Respiratory syncytial virus (RSV) is a common cause of acute lower respiratory disease in infants and young children worldwide. Currently, treatment is supportive and no vaccines are available. The use of newborn lambs to model hRSV infection in human infants may provide a valuable tool to assess safety and efficacy of new antiviral drugs and vaccines. ALX-0171 is a trivalent Nanobody targeting the hRSV fusion (F) protein and its therapeutic potential was evaluated in newborn lambs infected with a human strain of RSV followed by daily ALX-0171 nebulization for 3 or 5 consecutive days.Colostrum-deprived newborn lambs were infected with hRSV-M37 before being treated by daily nebulization with either ALX-0171 or placebo. Two different treatment regimens were examined: day 1–5 or day 3–5 post-infection. Lambs were monitored daily for general well-being and clinical parameters. Respiratory tissues and bronchoalveolar lavage fluid were collected at day 6 post-inoculation for the quantification of viral lesions, lung viral titers, viral antigen and lung histopathology.Administration by inhalation of ALX-0171 was well-tolerated in these hRSV-infected newborn lambs. Robust antiviral effects and positive effects on hRSV-induced lung lesions and reduction in symptoms of illness were noted. These effects were still apparent when treatment start was delayed and coincided with peak viral loads (day 3 post-infection) and at a time point when signs of RSV disease were apparent. The latter design is expected to have high translational value for planned clinical trials. These results are indicative of the therapeutic potential of ALX-0171 in infants.

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Section: Discussionsupporting

confidence: 76%

Delivery of ALX-0171 by inhalation greatly reduces respiratory syncytial virus disease in newborn lambs

Mora

Detalle

Gallup

et al. 2018

mAbs

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“…Our study also confirms the previous suggestion that ciliated cells are the target of RSV infection [2,3]. Our study collected evidence using electron and confocal microscopy from RSV-infected and uninfected ciliated epithelium.…”

Section: Basal Cell Cultures Infected With Rsv Increase Secretion Of supporting

confidence: 79%

“…Recent evidence suggests that the virus initiates infection by targeting human ciliated epithelium lining the nasopharynx [2][3][4]. We have previously shown that nasal brush biopsies from hospitalised infants with bronchiolitis exhibited significant disruption of the ciliated epithelium during RSV infection, with recovery taking many weeks [5].…”

Section: Introductionmentioning

confidence: 99%

Ciliary dyskinesia is an early feature of respiratory syncytial virus infection

et al. 2013

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Respiratory syncytial virus is a major cause of respiratory disease. There are conflicting accounts of the response of human epithelial cells to respiratory syncytial virus and a lack of data on its effect on ciliary function. Our aim was to study the early stages of respiratory syncytial virus infection of primary human basal and ciliated cultures.Using high speed videomicroscopy, we found that ciliary beat frequency was unaffected by respiratory syncytial virus infection over 72 h; however, ciliary dyskinesia significantly increased within 24 h of infection (p,0.05). Transmission electron microscopy revealed that ultrastructural abnormalities were confined to ciliated cells, including increased cilia loss and mitochondrial damage. Confocal immunofluorescence microscopy showed that respiratory syncytial virus antigen gradually spread from the cell surface to the ciliary tip of infected cells over 3 days. Interestingly, ciliated cultures secreted fewer viruses than basal (progenitor) cell cultures and produced a chemokine response focused on recruitment of neutrophils.This study highlights differences in infection models and underscores the need to explore further the role of ciliated cells in the establishment of respiratory syncytial virus infection.Increased ciliary dyskinesia combined with ciliary loss and epithelial damage is likely to result in reduced mucociliary clearance early in the infective process. @ERSpublications Increased ciliary dyskinesia with ciliary loss and epithelial damage can result in reduced mucociliary clearance

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“…Among these are three surface glycoproteins, the G glycoprotein, the F protein, and the small hydrophobic (SH) protein (1). The G protein is responsible for attachment with host cells, which are predominantly ciliated airway epithelial cells (7,8). Fusion of the viral and cellular membranes is facilitated by the RSV F protein, as is fusion between the membranes of infected cells with adjacent cells, which result in large, multinucleated syncytia.…”

mentioning

confidence: 99%

Antibody-Induced Internalization of the Human Respiratory Syncytial Virus Fusion Protein

Leemans

Schryver

Gucht

et al. 2017

J Virol

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Respiratory syncytial virus (RSV) infections remain a major cause of respiratory disease and hospitalizations among infants. Infection recurs frequently and establishes a weak and short-lived immunity. To date, RSV immunoprophylaxis and vaccine research is mainly focused on the RSV fusion (F) protein, but a vaccine remains elusive. The RSV F protein is a highly conserved surface glycoprotein and is the main target of neutralizing antibodies induced by natural infection. Here, we analyzed an internalization process of antigen-antibody complexes after binding of RSV-specific antibodies to RSV antigens expressed on the surface of infected cells. The RSV F protein and attachment (G) protein were found to be internalized in both infected and transfected cells after the addition of either RSV-specific polyclonal antibodies (PAbs) or RSV glycoprotein-specific monoclonal antibodies (MAbs), as determined by indirect immunofluorescence staining and flow-cytometric analysis. Internalization experiments with different cell lines, well-differentiated primary bronchial epithelial cells (WD-PBECs), and RSV isolates suggest that antibody internalization can be considered a general feature of RSV. More specifically for RSV F, the mechanism of internalization was shown to be clathrin dependent. All RSV F-targeted MAbs tested, regardless of their epitopes, induced internalization of RSV F. No differences could be observed between the different MAbs, indicating that RSV F internalization was epitope independent. Since this process can be either antiviral, by affecting virus assembly and production, or beneficial for the virus, by limiting the efficacy of antibodies and effector mechanism, further research is required to determine the extent to which this occurs in vivo and how this might impact RSV replication.IMPORTANCE Current research into the development of new immunoprophylaxis and vaccines is mainly focused on the RSV F protein since, among others, RSV F-specific antibodies are able to protect infants from severe disease, if administered prophylactically. However, antibody responses established after natural RSV infections are poorly protective against reinfection, and high levels of antibodies do not always correlate with protection. Therefore, RSV might be capable of interfering, at least partially, with antibody-induced neutralization. In this study, a process through which surface-expressed RSV F proteins are internalized after interaction with RSVspecific antibodies is described. One the one hand, this antigen-antibody complex internalization could result in an antiviral effect, since it may interfere with virus par-

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In vitro modeling of respiratory syncytial virus infection of pediatric bronchial epithelium, the primary target of infection in vivo

Cited by 174 publications

References 41 publications

Delivery of ALX-0171 by inhalation greatly reduces respiratory syncytial virus disease in newborn lambs

Delivery of ALX-0171 by inhalation greatly reduces respiratory syncytial virus disease in newborn lambs

Ciliary dyskinesia is an early feature of respiratory syncytial virus infection

Antibody-Induced Internalization of the Human Respiratory Syncytial Virus Fusion Protein

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