Respiratory Syncytial Virus-Induced Activation and Migration of Respiratory Dendritic Cells and Subsequent Antigen Presentation in the Lung-Draining Lymph Node

ABSTRACT In the respiratory tract, different dendritic cell (DC) populations guard a tight balance between tolerance and immunity to infectious or harmless materials to which the airways are continuously exposed. For infectious and noninfectious antigens administered via different routes, different subsets of DC might contribute during the induction of T-cell tolerance and immunity. We studied the impact of primary respiratory syncytial virus (RSV) infection on respiratory DC composition in C57BL/6 mice. We also tracked the migration of respiratory DC to the lymph nodes and studied antigen presentation by lung-derived and lymph node-resident DC to CD4+ and CD8+ T cells. We observed a massive influx of mainly CD103− CD11bhigh CD11c+ conventional DC (cDC) and plasmacytoid DC during the first 7 days of RSV infection, while CD103+ CD11blow CD11c+ cDC disappeared from the lung. The two major subsets of lung tissue DC, CD103+ CD11blow CD11c+ and CD103− CD11bhigh CD11c+ cDC, both transported RSV RNA to the lung-draining lymph node. Furthermore, these lung-derived cDC subsets as well as resident LN DC, which did not contain viral RNA, displayed viral antigen by major histocompatibility complex class I and class II to CD8+ and CD4+ T cells. Taken together, our data indicate that during RSV infections, at least three DC subsets might be involved during the activation of lymph node-homing naïve and memory CD4+ and CD8+ T cells.

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Cytotoxic T cells clear virus but augment lung pathology in mice infected with respiratory syncytial virus.

Journal of Experimental Medicine ◽

10.1084/jem.168.3.1163 ◽

1988 ◽

Vol 168 (3) ◽

pp. 1163-1168 ◽

Cited By ~ 325

Author(s):

M J Cannon ◽

P J Openshaw ◽

B A Askonas

Keyword(s):

T Cells ◽

Respiratory Syncytial Virus ◽

T Cell ◽

Cell Line ◽

Respiratory Disease ◽

Cytotoxic T Cells ◽

Lung Pathology ◽

Class I Mhc ◽

Rsv Infection ◽

Syncytial Virus

We have examined the function of class I MHC-restricted cytotoxic T cells in experimental respiratory syncytial virus (RSV) infection of BALB/c mice by transfer of T cell line MJC-A2 and CTL clone E8a into RSV-infected mice. The T cell line cleared pulmonary RSV infection within 5 d in persistently infected gamma-irradiated mice, but caused acute respiratory disease. This was only seen in infected mice and was often lethal after transfer of greater than 3 x 10(6) CTL. Lower numbers of CTL produced less severe disease but still cleared lung RSV, albeit over a longer time course (up to 10 d). Clearance of lung RSV in immunocompetent mice by the T cell line and CTL clone was again accompanied by acute and sometimes lethal respiratory disease. Bronchoalveolar lavage showed severe lung hemorrhage and frequent neutrophil efflux in mice with CTL-augmented disease.

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Disability-adjusted Life Years for respiratory syncytial virus in children under 2 years

10.21203/rs.3.rs-20260/v3 ◽

2020 ◽

Author(s):

jefferson buendia ◽

Fernando Polack ◽

Juana Patricia Sanchez Villamil

Keyword(s):

Respiratory Syncytial Virus ◽

Statistical Parameter ◽

Epidemiological Surveillance ◽

Years Of Life Lost ◽

Disability Adjusted Life Years ◽

Disability Adjusted Life ◽

Life Years ◽

Rsv Infection ◽

Syncytial Virus ◽

The Impact

Abstract BACKGROUND: Respiratory syncytial virus infection is the leading cause of bronchiolitis in Colombia. There is growing evidence about the impact of Respiratory syncytial virus on society in terms of years of life lost due to this condition. The objective of the present study is to determine the Disability-Adjusted Life Years for respiratory syncytial virus in children under 2 years in ColombiaMETHODS: Data from the national epidemiological surveillance system were used to estimate DALYs, calculated from the sum of years of life lost and years lived with disability due to RSV infection in Colombia. A bootstrapped method with 10000 iterations was used to estimate each statistical parameter using the package DALY calculator in R. RESULTS: In 2019, 260 873 years of life (CI95% 208 180- 347 023) were lost due to RSV bronchiolitis in Colombian children under 2 years. The estimated rate was 20 DALYs / 1000 person-year (95% CI 16 – 27).CONCLUSION: This is the first report estimating the impact of RSV bronchiolitis morbidity and mortality in Colombia. The findings of the present study suggest that the actual burden and cost of bronchiolitis due to RSV is high. Prevention strategies, such as RSV vaccination, to reduce morbidity associated with RSV infection should be encouraged in our country.

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Modelling the household-level impact of a maternal respiratory syncytial virus (RSV) vaccine in a high-income setting

BMC Medicine ◽

10.1186/s12916-020-01783-8 ◽

2020 ◽

Vol 18 (1) ◽

Author(s):

Patricia T. Campbell ◽

Nicholas Geard ◽

Alexandra B. Hogan

Keyword(s):

Respiratory Syncytial Virus ◽

Vaccine Trial ◽

Population Level ◽

High Income ◽

Demographic Model ◽

Model Framework ◽

Substantial Impact ◽

Rsv Infection ◽

Syncytial Virus ◽

The Impact

Abstract Background Respiratory syncytial virus (RSV) infects almost all children by the age of 2 years, with the risk of hospitalisation highest in the first 6 months of life. Development and licensure of a vaccine to prevent severe RSV illness in infants is a public health priority. A recent phase 3 clinical trial estimated the efficacy of maternal vaccination at 39% over the first 90 days of life. Households play a key role in RSV transmission; however, few estimates of population-level RSV vaccine impact account for household structure. Methods We simulated RSV transmission within a stochastic, individual-based model framework, using an existing demographic model, structured by age and household and parameterised with Australian data, as an exemplar of a high-income country. We modelled vaccination by immunising pregnant women and explicitly linked the immune status of each mother-infant pair. We quantified the impact on children for a range of vaccine properties and uptake levels. Results We found that a maternal immunisation strategy would have the most substantial impact in infants younger than 3 months, reducing RSV infection incidence in this age group by 16.6% at 70% vaccination coverage. In children aged 3–6 months, RSV infection was reduced by 5.3%. Over the first 6 months of life, the incidence rate for infants born to unvaccinated mothers was 1.26 times that of infants born to vaccinated mothers. The impact in older age groups was more modest, with evidence of infections being delayed to the second year of life. Conclusions Our findings show that while individual benefit from maternal RSV vaccination could be substantial, population-level reductions may be more modest. Vaccination impact was sensitive to the extent that vaccination prevented infection, highlighting the need for more vaccine trial data.

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Respiratory Syncytial Virus Infection Upregulates NLRC5 and Major Histocompatibility Complex Class I Expression through RIG-I Induction in Airway Epithelial Cells

Journal of Virology ◽

10.1128/jvi.00349-15 ◽

2015 ◽

Vol 89 (15) ◽

pp. 7636-7645 ◽

Cited By ~ 20

Author(s):

Xuancheng Guo ◽

Taixiang Liu ◽

Hengfei Shi ◽

Jingjing Wang ◽

Ping Ji ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

A549 Cells ◽

Class I ◽

Complex Class ◽

Major Histocompatibility ◽

Class I Mhc ◽

Mhc I ◽

Histocompatibility Complex ◽

Rsv Infection ◽

Syncytial Virus

ABSTRACTRespiratory syncytial virus (RSV) is the leading cause of acute respiratory tract viral infection in infants, causing bronchiolitis and pneumonia. The host antiviral response to RSV acts via retinoic acid-inducible gene I (RIG-I). We show here that RSV infection upregulates major histocompatibility complex class I (MHC-I) expression through the induction of NLRC5, a NOD-like, CARD domain-containing intracellular protein that has recently been identified as a class I MHC transactivator (CITA). RSV infection of A549 cells promotes upregulation of NLRC5 via beta interferon (IFN-β) production, since the NLRC5-inducing activity in a conditioned medium from RSV-infected A549 cells was removed by antibody to IFN-β, but not by antibody to IFN-γ. RSV infection resulted in RIG-I upregulation and induction of NLRC5 and MHC-I. Suppression of RIG-I induction significantly blocked NLRC5, as well as MHC-I, upregulation and diminished IRF3 activation. Importantly, Vero cells deficient in interferon production still upregulated MHC-I following introduction of the RSV genome by infection or transfection, further supporting a key role for RIG-I. A model is therefore proposed in which the host upregulates MHC-I expression during RSV infection directly via the induction of RIG-I and NLRC5 expression. Since elevated expression of MHC-I molecules can sensitize host cells to T lymphocyte-mediated cytotoxicity or immunopathologic damage, the results have significant implications for the modification of immunity in RSV disease.IMPORTANCEHuman respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and pneumonia in infants and young children worldwide. Infection early in life is linked to persistent wheezing and allergic asthma in later life, possibly related to upregulation of major histocompatibility class I (MHC-I) on the cell surface, which facilitates cytotoxic T cell activation and antiviral immunity. Here, we show that RSV infection of lung epithelial cells induces expression of RIG-I, resulting in induction of a class I MHC transactivator, NLRC5, and subsequent upregulation of MHC-I. Suppression of RIG-I induction blocked RSV-induced NLRC5 expression and MHC-I upregulation. Increased MHC-I expression may exacerbate the RSV disease condition due to immunopathologic damage, linking the innate immune response to RSV disease.

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CD4+T Cells Drive Lung Disease Enhancement Induced by Immunization with Suboptimal Doses of Respiratory Syncytial Virus Fusion Protein in the Mouse Model

Journal of Virology ◽

10.1128/jvi.00695-19 ◽

2019 ◽

Vol 93 (15) ◽

Cited By ~ 3

Author(s):

Kirsten Schneider-Ohrum ◽

Angie Snell Bennett ◽

Gaurav Manohar Rajani ◽

Leigh Hostetler ◽

Sean K. Maynard ◽

...

Keyword(s):

T Cells ◽

Respiratory Syncytial Virus ◽

Mouse Model ◽

Fusion Protein ◽

Lung Disease ◽

Rat Model ◽

Preclinical Models ◽

Cotton Rat ◽

Rsv Infection ◽

Syncytial Virus

ABSTRACTRespiratory syncytial virus (RSV) infection of seronegative children previously immunized with formalin-inactivated (FI) RSV has been associated with serious enhanced respiratory disease (ERD). The phenomenon was reproduced in the cotton rat and the mouse, and both preclinical models have been routinely used to evaluate the safety of new RSV vaccine candidates. More recently, we demonstrated that immunizations with suboptimal doses of the RSV fusion (F) antigen, in its post- or prefusion conformation, and in the presence of a Th1-biasing adjuvant, unexpectedly led to ERD in the cotton rat model. To assess if those observations are specific to the cotton rat and to elucidate the mechanism by which vaccination with low antigen doses can drive ERD post-RSV challenge, we evaluated RSV post-F antigen dose de-escalation in BALB/c mice in the presence of a Th1-biasing adjuvant. While decreasing antigen doses, we observed an increase in lung inflammation associated with an upregulation of proinflammatory cytokines. The amplitude of the lung histopathology was comparable to that of FI-RSV-induced ERD, confirming the observations made in the cotton rat. Importantly, depletion of CD4+T cells prior to viral challenge completely abrogated ERD, preventing proinflammatory cytokine upregulation and the infiltration of T cells, neutrophils, eosinophils, and macrophages into the lung. Overall, low-antigen-dose-induced ERD resembles FI-RSV-induced ERD, except that the former appears in the absence of detectable levels of viral replication and in the context of a Th1-biased immune response. Taken together, our observations reinforce the recent concept that vaccines developed for RSV-naïve individuals should be systematically tested under suboptimal dosing conditions.IMPORTANCERSV poses a significant health care burden and is the leading cause of serious lower-respiratory-tract infections in young children. A formalin-inactivated RSV vaccine developed in the 1960s not only showed a complete lack of efficacy against RSV infection but also induced severe lung disease enhancement in vaccinated children. Since then, establishing safety in preclinical models has been one of the major challenges to RSV vaccine development. We recently observed in the cotton rat model that suboptimal immunizations with RSV fusion protein could induce lung disease enhancement. In the present study, we extended suboptimal dosing evaluation to the mouse model. We confirmed the induction of lung disease enhancement by vaccinations with low antigen doses and dissected the associated immune mechanisms. Our results stress the need to evaluate suboptimal dosing for any new RSV vaccine candidate developed for seronegative infants.

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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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Characterization of a Novel Respiratory Syncytial Virus-Specific Human Cytotoxic T-Lymphocyte Epitope

Journal of Virology ◽

10.1128/jvi.74.16.7694-7697.2000 ◽

2000 ◽

Vol 74 (16) ◽

pp. 7694-7697 ◽

Cited By ~ 41

Author(s):

Philip J. R. Goulder ◽

Franziska Lechner ◽

Paul Klenerman ◽

Kenneth McIntosh ◽

Bruce D. Walker

Keyword(s):

T Cells ◽

Respiratory Syncytial Virus ◽

T Lymphocyte ◽

Cytotoxic T Lymphocyte ◽

Rsv Infection ◽

Syncytial Virus ◽

Restricted Epitope

ABSTRACT Respiratory syncytial virus (RSV) infection is a major cause of morbidity in childhood worldwide. The first human RSV-specific cytotoxic T-lymphocyte epitope to be defined is described. This HLA B7-restricted epitope in nucleoprotein (NP) was detectable in four healthy, B7-positive adult subjects using B7-RSV-NP tetrameric complexes to stain CD8+ T cells.

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Disability-adjusted Life Years for respiratory syncytial virus in Colombian children.

10.21203/rs.3.rs-20260/v1 ◽

2020 ◽

Author(s):

jefferson buendia ◽

Fernando Polack ◽

Juana Patricia Sanchez Villamil

Keyword(s):

Respiratory Syncytial Virus ◽

Statistical Parameter ◽

Epidemiological Surveillance ◽

Years Of Life Lost ◽

Disability Adjusted Life Years ◽

Disability Adjusted Life ◽

Life Years ◽

Rsv Infection ◽

Syncytial Virus ◽

The Impact

Abstract BACKGROUND Respiratory syncytial virus infection is the leading cause of bronchiolitis worldwide. However, little is known about the real impact of bronchiolitis on society in terms of years of life lost due to this condition. The objective of the present study is to determine the Disability-Adjusted Life Years (1) in ColombiaMETHODS Data from the national epidemiological surveillance system were used to estimate DALYs, calculated from the sum of years of life lost and years lived with disability due to RSV infection in Colombia. A bootstrapped method with 10000 iterations was used to estimate each statistical parameter using the package DALY calculator in R.RESULTS In 2019, 260 873 years of life (IC 95% 208 180–347 023) were lost due to RSV bronchiolitis in Colombian children under 2 years. The estimated rate was 20 DALYs / 1000 person-year (95% CI 16–27).CONCLUSION This is the first report estimating the impact of RSV bronchiolitis morbidity and mortality in Colombia. The findings of the present study suggest that the actual burden and cost of bronchiolitis due to RSV is high. Prevention strategies to reduce morbidity associated with RSV infection should be encouraged in our country.

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Disability-adjusted Life Years for respiratory syncytial virus in children under 2 years

10.21203/rs.3.rs-20260/v5 ◽

2020 ◽

Author(s):

Juana Patricia Sanchez Villamil ◽

Fernando Polack ◽

jefferson buendia

Keyword(s):

Respiratory Syncytial Virus ◽

Statistical Parameter ◽

Epidemiological Surveillance ◽

Years Of Life Lost ◽

Disability Adjusted Life Years ◽

Disability Adjusted Life ◽

Life Years ◽

Rsv Infection ◽

Syncytial Virus ◽

The Impact

Abstract BACKGROUND : Respiratory syncytial virus infection is the leading cause of bronchiolitis in Colombia. There is growing evidence about the impact of Respiratory syncytial virus on society in terms of years of life lost due to this condition. The objective of the present study is to determine the Disability-Adjusted Life Years for respiratory syncytial virus in children under 2 years in Colombia METHODS : Data from the national epidemiological surveillance system were used to estimate DALYs, calculated from the sum of years of life lost and years lived with disability due to RSV infection in Colombia. A bootstrapped method with 10000 iterations was used to estimate each statistical parameter using the package DALY calculator in R. RESULTS : In 2019, 260 873 years of life (CI95% 208 180- 347 023) were lost due to RSV bronchiolitis in Colombian children under 2 years. The estimated rate was 20 DALYs / 1000 person-year (95% CI 16 – 27). CONCLUSION : This is the first report estimating the impact of RSV bronchiolitis morbidity and mortality in Colombia. The findings of the present study suggest that the actual burden and cost of bronchiolitis due to RSV is high. Prevention strategies, such as RSV vaccination, to reduce morbidity associated with RSV infection should be encouraged in our country.

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