Original Antigenic Sin and Respiratory Syncytial Virus Vaccines

The original antigenic sin (OAS) theory considers the outcome of the first encounter with an antigen. It favors a memory response to the original antigen upon exposure to a similar or related antigen, and includes both positive and negative impacts of past exposure on the memory response to challenge, and, in particular, on vaccine efficacy. This phenomenon is closely linked with imprinting and the hierarchical nature of immune responses to previously encountered antigens. The focus of this commentary centers on the potential role of OAS or immunological imprinting on respiratory syncytial virus memory responses.

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Immune Responses and Disease Enhancement during Respiratory Syncytial Virus Infection

Clinical Microbiology Reviews ◽

10.1128/cmr.18.3.541-555.2005 ◽

2005 ◽

Vol 18 (3) ◽

pp. 541-555 ◽

Cited By ~ 201

Author(s):

Peter J. M. Openshaw ◽

John S. Tregoning

Keyword(s):

Respiratory Syncytial Virus ◽

Animal Models ◽

Immune Responses ◽

Deep Understanding ◽

T Cell Subsets ◽

Chemokine Production ◽

Syncytial Virus ◽

Complex Deposition ◽

Major Factors

SUMMARY Respiratory syncytial virus (RSV) is one of the commonest and most troublesome viruses of infancy. It causes most cases of bronchiolitis, which is associated with wheezing in later childhood. In primary infection, the peak of disease typically coincides with the development of specific T- and B-cell responses, which seem, in large part, to be responsible for disease. Animal models clearly show that a range of immune responses can enhance disease severity, particularly after vaccination with formalin-inactivated RSV. Prior immune sensitization leads to exuberant chemokine production, an excessive cellular influx, and an overabundance of cytokines during RSV challenge. Under different circumstances, specific mediators and T-cell subsets and antibody-antigen immune complex deposition are incriminated as major factors in disease. Animal models of immune enhancement permit a deep understanding of the role of specific immune responses in RSV disease, assist in vaccine design, and indicate which immunomodulatory therapy might be beneficial to children with bronchiolitis.

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The Role of Toll-like receptor 4 in respiratory syncytial virus replication, interferon lambda 1 induction, and chemokine responses

10.1101/404384 ◽

2018 ◽

Author(s):

Lindsay Broadbent ◽

Jonathon D. Coey ◽

Michael D. Shields ◽

Ultan F. Power

Keyword(s):

Respiratory Syncytial Virus ◽

Immune Responses ◽

P38 Mapk ◽

Inflammatory Cytokines ◽

Virus Replication ◽

Growth Kinetics ◽

Rsv Infection ◽

Syncytial Virus ◽

Pro Inflammatory Cytokines

AbstractRespiratory syncytial virus (RSV) infection is the leading cause of severe lower respiratory tract infections (LRTI) in infants worldwide. The immune responses to RSV infection are implicated in RSV pathogenesis but RSV immunopathogenesis in humans remains poorly understood. We previously demonstrated that IFN-λ1 is the principle interferon induced following RSV infection of infants and well-differentiated primary pediatric bronchial epithelial cells (WD-PBECs). Interestingly, RSV F interacts with the TLR4/CD14/MD2 complex to initiate secretion of pro-inflammatory cytokines, while TLR4 stimulation with house dust mite induces IFN-λ1 production. However, the role of TLR4 in RSV infection and concomitant IFN-λ1 induction remains unclear. Using our RSV/WD-PBEC infection model, we found that CLI-095 inhibition of TLR4 resulted in significantly reduced viral growth kinetics, and secretion of IFN-λ1 and pro-inflammatory chemokines. To elucidate specific TLR4 signalling intermediates implicated in virus replication and innate immune responses we selected 4 inhibitors, including LY294002, U0126, SB203580 and JSH-23. SB203580, a p38 MAPK inhibitor, reduced both viral growth kinetics and IFN-λ1 secretion, while JSH-23, an NF-κB inhibitor, reduced IFN-λ1 secretion without affecting virus growth kinetics. Our data indicate that TLR4 plays a role in RSV entry and/or replication and IFN-λ1 induction following RSV infection is mediated, in part, by TLR4 signalling through NF- κB and/or p38 MAPK. Therefore, targeting TLR4 or downstream effector proteins could present novel treatment strategies against RSV.ImportanceThe role of TLR4 in RSV infection and IFN-λ1 induction is controversial. Using our WD-PBEC model, which replicates many hallmarks of RSV infection in vivo, we demonstrated that the TLR4 pathway is involved in both RSV infection and/or replication and the concomitant induction of IFN-λ1 and other pro-inflammatory cytokines. Increasing our understanding of the role of TLR4 in RSV immunopathogenesis may lead to the development of novel RSV therapeutics.

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