RESPIRATORY SYNCYTIAL VIRUS (RSV) INFECTION INDUCES A DYSREGULATED IMMUNE RESPONSE: T AND B CELL INTERACTIONS AND DISEASE SEVERITY

Mucins (MUC) constitute an important component of the inflammatory and innate immune response. However, the expression of these molecules by respiratory viral infections is still largely unknown. Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) are two close-related paramyxoviruses that can cause severe low respiratory tract disease in infants and young children worldwide. Currently, there is not vaccine available for neither virus. In this work, we explored the differential expression of MUC by RSV and hMPV in human epithelial cells. Our data indicate that the MUC expression by RSV and hMPV differs significantly, as we observed a stronger induction of MUC8, MUC15, MUC20, MUC21, and MUC22 by RSV infection while the expression of MUC1, MUC2, and MUC5B was dominated by the infection with hMPV. These results may contribute to the different immune response induced by these two respiratory viruses.

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Crawling with Virus: Translational Insights from a Neonatal Mouse Model on the Pathogenesis of Respiratory Syncytial Virus in Infants

Journal of Virology ◽

10.1128/jvi.01026-15 ◽

2015 ◽

Vol 90 (1) ◽

pp. 2-4 ◽

Cited By ~ 3

Author(s):

Dahui You ◽

Jordy Saravia ◽

David Siefker ◽

Bishwas Shrestha ◽

Stephania A. Cormier

Keyword(s):

Immune Response ◽

Respiratory Syncytial Virus ◽

Mouse Model ◽

Severe Infection ◽

Neonatal Mouse ◽

Cell Type ◽

Human Infants ◽

Rsv Infection ◽

Syncytial Virus ◽

Infant Immune Response

The infant immune response to respiratory syncytial virus (RSV) remains incompletely understood. Here we review the use of a neonatal mouse model of RSV infection to mimic severe infection in human infants. We describe numerous age-specific responses, organized by cell type, observed in RSV-infected neonatal mice and draw comparisons (when possible) to human infants.

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RESPIRATORY SYNCYTIAL VIRUS LUNG INFECTION IN INFANTS: IMMUNOREGULATORY ROLE OF INFECTED ALVEOLAR MACROPHAGES

PEDIATRICS ◽

10.1542/peds.96.2.391 ◽

1995 ◽

Vol 96 (2) ◽

pp. 391-391

Author(s):

Leon S. Greos

Keyword(s):

Immune Response ◽

Respiratory Syncytial Virus ◽

Lung Injury ◽

Alveolar Macrophages ◽

Lung Infection ◽

Local Immune Response ◽

Rsv Infection ◽

Syncytial Virus

Alveolar macrophages are infected by RSV in vivo and coexpress potent immunomodulatory molecules that potentially regulate local immune response or lung injury caused by RSV infection.

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Temporal Dysbiosis of Infant Nasal Microbiota Relative to Respiratory Syncytial Virus Infection

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa577 ◽

2020 ◽

Author(s):

Alex Grier ◽

Ann L Gill ◽

Haeja A Kessler ◽

Anthony Corbett ◽

Sanjukta Bandyopadhyay ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Respiratory Disease ◽

Disease Severity ◽

Temporal Dynamics ◽

Disease Risk ◽

Developmental Trajectory ◽

Microbiota Composition ◽

Rsv Infection ◽

Syncytial Virus ◽

Nasal Microbiota

Abstract Rationale Respiratory Syncytial Virus (RSV) is a leading cause of infant respiratory disease. Infant airway microbiota has been associated with respiratory disease risk and severity. The extent to which interactions between RSV and microbiota occur in the airway, and their impact on respiratory disease susceptibility and severity, are unknown. Objectives Characterize temporal associations between microbiota and RSV infection before, during, and after infants’ first respiratory illness. Methods 16S rRNA microbiota profiling of two infant cohorts in the first year of life: 1) a cross-sectional cohort of 89 RSV infected infants sampled during illness and 102 matched healthy controls, and 2) a matched longitudinal cohort of 12 infants who developed RSV infection and 12 who did not, sampled before, during, and after infection. Results We identified 12 taxa significantly associated with RSV infection. All 12 taxa were differentially abundant during infection, with 8 associated with disease severity. Nasal microbiota composition was more discriminative of healthy vs. infected than of disease severity. Conclusions Our findings elucidate the chronology of nasal microbiota dysbiosis and suggest an altered developmental trajectory associated with RSV infection. Microbial temporal dynamics reveal indicators of disease risk, correlates of illness and severity, and impact of RSV infection on microbiota composition.

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The Human Immune Response to Respiratory Syncytial Virus Infection

Clinical Microbiology Reviews ◽

10.1128/cmr.00090-16 ◽

2017 ◽

Vol 30 (2) ◽

pp. 481-502 ◽

Cited By ~ 87

Author(s):

Clark D. Russell ◽

Stefan A. Unger ◽

Marc Walton ◽

Jürgen Schwarze

Keyword(s):

Immune Response ◽

Respiratory Syncytial Virus ◽

T Cell ◽

T Cell Response ◽

Rsv Infection ◽

Human Immune Response ◽

Ifn Γ ◽

Human Immune ◽

Syncytial Virus

SUMMARY Respiratory syncytial virus (RSV) is an important etiological agent of respiratory infections, particularly in children. Much information regarding the immune response to RSV comes from animal models and in vitro studies. Here, we provide a comprehensive description of the human immune response to RSV infection, based on a systematic literature review of research on infected humans. There is an initial strong neutrophil response to RSV infection in humans, which is positively correlated with disease severity and mediated by interleukin-8 (IL-8). Dendritic cells migrate to the lungs as the primary antigen-presenting cell. An initial systemic T-cell lymphopenia is followed by a pulmonary CD8+ T-cell response, mediating viral clearance. Humoral immunity to reinfection is incomplete, but RSV IgG and IgA are protective. B-cell-stimulating factors derived from airway epithelium play a major role in protective antibody generation. Gamma interferon (IFN-γ) has a strongly protective role, and a Th2-biased response may be deleterious. Other cytokines (particularly IL-17A), chemokines (particularly CCL-5 and CCL-3), and local innate immune factors (including cathelicidins and IFN-λ) contribute to pathogenesis. In summary, neutrophilic inflammation is incriminated as a harmful response, whereas CD8+ T cells and IFN-γ have protective roles. These may represent important therapeutic targets to modulate the immunopathogenesis of RSV infection.

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Olfactomedin 4 Serves as a Marker for Disease Severity in Pediatric Respiratory Syncytial Virus (RSV) Infection

PLoS ONE ◽

10.1371/journal.pone.0131927 ◽

2015 ◽

Vol 10 (7) ◽

pp. e0131927 ◽

Cited By ~ 30

Author(s):

H. K. Brand ◽

I. M. L. Ahout ◽

D. de Ridder ◽

A. van Diepen ◽

Y. Li ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Disease Severity ◽

Rsv Infection ◽

Syncytial Virus

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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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Depletion of TAX1BP1 amplifies innate immune responses during respiratory syncytial virus infection

10.1101/2021.06.03.447014 ◽

2021 ◽

Author(s):

Delphyne Descamps ◽

Andressa Peres de Oliveira ◽

Lorène Gonnin ◽

Sarah Madrières ◽

Jenna Fix ◽

...

Keyword(s):

Immune Response ◽

Respiratory Syncytial Virus ◽

Antiviral Response ◽

Innate Immune ◽

Cellular Proteins ◽

Separation Mechanism ◽

Efficient Treatment ◽

Rsv Infection ◽

Syncytial Virus ◽

Host Antiviral Response

Respiratory syncytial virus (RSV) is the main cause of acute respiratory infections in young children, and also has a major impact in the elderly and immunocompromised people. In the absence of vaccine or efficient treatment, a better understanding of RSV interactions with the host antiviral response during infection is needed. Previous studies revealed that cytoplasmic inclusion bodies (IBs) where viral replication and transcription occur could play a major role in the control of innate immunity during infection by recruiting cellular proteins involved in the host antiviral response. We recently showed that the morphogenesis of IBs relies on a liquid-liquid phase separation mechanism depending on the interaction between viral nucleoprotein (N) and phosphoprotein (P). These scaffold proteins are expected to play a central role in the recruitment of cellular proteins to IBs. Here, we performed a yeast two-hybrid screen using RSV N protein as a bait, and identified the cellular protein TAX1BP1 as a potential partner of N. This interaction was validated by pulldown and immunoprecipitation assays. We showed that TAX1BP1 suppression has only a limited impact on RSV infection in cell cultures. On the contrary, in vivo experiments showed that RSV replication is decreased in TAX1BP1KO mice, whereas the production of inflammatory and antiviral cytokines is enhanced. In vitro infection of either wild-type or TAX1BP1KO alveolar macrophages confirmed that the innate immune response to RSV infection is enhanced in the absence of TAX1BP1. Altogether, our results suggest that RSV could hijack TAX1BP1 to restrain the host immune response during infection.

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The specific features of the developing T cell compartment of the neonatal lung are a determinant of respiratory syncytial virus immunopathogenesis

PLoS Pathogens ◽

10.1371/journal.ppat.1009529 ◽

2021 ◽

Vol 17 (4) ◽

pp. e1009529

Author(s):

Thomas Démoulins ◽

Melanie Brügger ◽

Beatrice Zumkehr ◽

Blandina I. Oliveira Esteves ◽

Kemal Mehinagic ◽

...

Keyword(s):

T Cells ◽

Respiratory Syncytial Virus ◽

T Cell ◽

Disease Severity ◽

Early Life ◽

Cell Compartment ◽

Neonatal Lung ◽

Rsv Infection ◽

Syncytial Virus

The human respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract infections in infants, possibly due to the properties of the immature neonatal pulmonary immune system. Using the newborn lamb, a classical model of human lung development and a translational model of RSV infection, we aimed to explore the role of cell-mediated immunity in RSV disease during early life. Remarkably, in healthy conditions, the developing T cell compartment of the neonatal lung showed major differences to that seen in the mature adult lung. The most striking observation being a high baseline frequency of bronchoalveolar IL-4-producing CD4 and CD8 T cells, which declined progressively over developmental age. RSV infection exacerbated this pro-type 2 environment in the bronchoalveolar space, rather than inducing a type 2 response per se. Moreover, regulatory T cell suppressive functions occurred very early to dampen this pro-type 2 environment, rather than shutting them down afterwards, while γδ T cells dropped and failed to produce IL-17. Importantly, RSV disease severity was related to the magnitude of those unconventional bronchoalveolar T cell responses. These findings provide novel insights in the mechanisms of RSV immunopathogenesis in early life, and constitute a major step for the understanding of RSV disease severity.

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Association of Viral Load With Disease Severity in Outpatient Children With Respiratory Syncytial Virus Infection

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa076 ◽

2020 ◽

Vol 222 (2) ◽

pp. 298-304 ◽

Cited By ~ 3

Author(s):

Erika Uusitupa ◽

Matti Waris ◽

Terho Heikkinen

Keyword(s):

Viral Load ◽

Respiratory Syncytial Virus ◽

Disease Severity ◽

Respiratory Infections ◽

Respiratory Illness ◽

Lower Viral Load ◽

Primary Analysis ◽

Rsv Infection ◽

Syncytial Virus ◽

Outpatient Children

Abstract Background There are scarce data on whether viral load affects the severity of respiratory syncytial virus (RSV) disease in outpatient children. Methods We analyzed the association between viral load and disease severity among children who participated in a prospective cohort study of respiratory infections. The children were examined and nasal swabs for the detection of RSV were obtained during each respiratory illness. Quantification of RSV load was based on the cycle threshold (Ct) value. For the primary analysis, the children were divided into 2 groups: higher (Ct < 27) and lower viral load (Ct ≥ 27). Results Among 201 episodes of RSV infection, children with higher viral load had significantly longer median durations of rhinitis (8 vs 6 days; P = .0008), cough (8 vs 6 days; P = .034), fever (2 vs 1 days; P = .018), and any symptom (10 vs 8 days; P = .024) than those with lower viral load. There were statistically significant negative correlations between the Ct values and durations of all measured symptoms. Conclusions Our findings support the concept that viral load drives the severity of RSV disease in children. Reducing the viral load by RSV antivirals might provide substantial benefits to outpatient children.

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