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An In vitro Model to Study Immune Responses of Human Peripheral Blood Mononuclear Cells to Human Respiratory Syncytial Virus Infection
Published on: December 10, 2013
The CD4 T cell response to respiratory syncytial virus infection
Allison F Christiaansen1, Cory J Knudson, Kayla A Weiss
1Department of Microbiology, University of Iowa, 51 Newton Road, 3-532 BSB, Iowa City, IA, 52242, USA.
Insights
Respiratory syncytial virus (RSV) infection causes severe infant lung disease. Future vaccines must balance immune responses to prevent severe illness and vaccine-enhanced disease.
Area of Science:
- Immunology
- Virology
- Pediatrics
Background:
- Respiratory syncytial virus (RSV) causes severe lower respiratory tract infections and bronchiolitis in infants globally.
- RSV-induced inflammation, driven by Th2, Th9, and Th17 cytokines, significantly contributes to disease severity.
- Both primary infection and prior vaccination (FI-RSV) can lead to severe outcomes, with Th2 responses implicated in vaccine-enhanced disease.
Purpose of the Study:
- To investigate the role of T helper cell responses and cytokines in RSV-induced disease and vaccine responses.
- To understand the balance between inflammatory and regulatory immune mechanisms in RSV infection.
- To inform the development of future RSV vaccines that elicit protective and regulated immune responses.
Main Methods:
- Analysis of cytokine profiles (IL-9, IL-13, IL-17, IL-10) in infants with severe RSV infection.
- Utilizing a murine model of RSV infection to study CD4 T cell responses and disease pathogenesis.
- Examining the impact of prior formalin-inactivated RSV (FI-RSV) vaccination on subsequent RSV challenge in animal models.
Main Results:
- Elevated Th2, Th9, and Th17 cytokines correlate with severe RSV disease in infants and a murine model.
- CD4 T cell production of IL-9, IL-13, and IL-17 exacerbates RSV-induced lung disease in mice.
- Regulatory mechanisms involving CD4 regulatory T cells and IL-10 appear protective against RSV disease, with IL-10 polymorphisms linked to susceptibility.
- Formalin-inactivated RSV vaccination leads to enhanced disease upon subsequent natural infection, mediated by Th2 responses.
Conclusions:
- A balanced CD4 T cell response is crucial for effective viral clearance and immune regulation in RSV infection.
- Future RSV vaccines should aim to induce protective immunity while avoiding the exacerbation of disease seen with Th2-biased responses.
- Understanding the interplay between inflammation and regulation is key to developing safe and effective RSV vaccines.
Abstract:
Respiratory syncytial virus (RSV) can induce severe lower respiratory tract infections in infants and is the leading cause of bronchiolitis in children worldwide. RSV-induced inflammation is believed to contribute substantially to the severity of disease. T helper (Th)2-, Th9-, and Th17-related cytokines are all observed in infants hospitalized following a severe RSV infection. These cytokines cause an influx of inflammatory cells, resulting in mucus production and reduced lung function. Consistent with the data from RSV-infected infants, CD4 T cell production of Interleukin (IL)-9, IL-13, and IL-17 has all been shown to contribute to RSV-induced disease in a murine model of RSV infection. Conversely, murine studies indicate that the combined actions of regulatory factors such as CD4 regulatory T cells and IL-10 inhibit the inflammatory cytokine response and limit RSV-induced disease. In support of this, IL-10 polymorphisms are associated with susceptibility to severe disease in infants. Insufficient regulation and excess inflammation not only impact disease following primary RSV infection it can also have a major impact following vaccination. Prior immunization with a formalin-inactivated (FI-RSV) vaccine resulted in enhanced disease in infants following a natural RSV infection. A Th2 CD4 T cell response has been implicated to be a major contributor in mediating vaccine-enhanced disease. Thus, future RSV vaccines must induce a balanced CD4 T cell response in order to facilitate viral clearance while inducing proper regulation of the immune response.
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