Immune responses to respiratory syncytial virus in neonate and adult mononuclear cells: Cytokine expression patterns and role of interferon regulatory factor-1

Persistent Link:
http://hdl.handle.net/10150/280622
Title:
Immune responses to respiratory syncytial virus in neonate and adult mononuclear cells: Cytokine expression patterns and role of interferon regulatory factor-1
Author:
Krishnan, Subramaniam
Issue Date:
2004
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
RSV infections are ubiquitous in children but are most severe in infants in the first few months of life. Innate and adaptive immune responses were assessed to respiratory syncytial virus (RSV) in neonate mononuclear cells (MCs) obtained at birth (prior to any direct and independent exposure) and these responses were compared to those from adult MCs. Our hypothesis was that neonates exhibit innate and/or adaptive immune hyperresponsiveness to RSV. In neonate MCs, inactivated virus invoked large levels of the innate immune cytokines IL-6, TNF-α, and IL-10 and low levels of IFN-γ and IL-12 but no adaptive immune cytokines. Live RSV induced lower levels (compared to inactivated virus) and fewer innate (IL-6, IL-10 and IFN-γ) and no adaptive immune cytokines. In adult MCs, inactivated and live virus invoked cytokines reflecting both innate and adaptive immunity (IL-6, IFN-γ, IL-2, TNF-α and IL-10). Further, NK cells (and not T cells) were the primary source of IFN-γ in neonate MCs, whereas both NK cells and T cells contributed towards IFN-γ in adult MCs to live RSV. RSV-induced proliferation in neonate MCs was not observed, though positive in adult MCs. Taken together, the results indicated that the immune response to live virus at birth was only innate in nature and could be characterized as hyporesponsive (compared to adults), thus contradicting our initial hypothesis. Immune suppression to live RSV in neonate MCs was found to be closely associated with dysregulation between type I (IFN-α) and type II (IFN-γ) IFNs. IFN-α expression in neonate MCs was significantly more than in adult MCs to live RSV. Inhibition of the live RSV-induced IFN-α in neonate MCs led to significant increases in innate (IFN-γ, IL-12, IL-18 and TNF-α) immune cytokine production. Interferon regulatory factor-1 (IRF-1) expression was part of the immune response to live RSV in adult MCs though not in neonate MCs and that the lack of IRF-1 upregulation in neonate MCs was reversed when IFN-α was neutralized. Overall, enhanced IFN-α expression suppressing innate immune cytokine production and IRF-1 expression in neonate MCs may account for the severity of early life RSV-induced illnesses.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Health Sciences, Immunology.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Microbiology and Immunology
Degree Grantor:
University of Arizona
Advisor:
Halonen, Marilyn

Full metadata record

DC FieldValue Language
dc.language.isoen_USen_US
dc.titleImmune responses to respiratory syncytial virus in neonate and adult mononuclear cells: Cytokine expression patterns and role of interferon regulatory factor-1en_US
dc.creatorKrishnan, Subramaniamen_US
dc.contributor.authorKrishnan, Subramaniamen_US
dc.date.issued2004en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractRSV infections are ubiquitous in children but are most severe in infants in the first few months of life. Innate and adaptive immune responses were assessed to respiratory syncytial virus (RSV) in neonate mononuclear cells (MCs) obtained at birth (prior to any direct and independent exposure) and these responses were compared to those from adult MCs. Our hypothesis was that neonates exhibit innate and/or adaptive immune hyperresponsiveness to RSV. In neonate MCs, inactivated virus invoked large levels of the innate immune cytokines IL-6, TNF-α, and IL-10 and low levels of IFN-γ and IL-12 but no adaptive immune cytokines. Live RSV induced lower levels (compared to inactivated virus) and fewer innate (IL-6, IL-10 and IFN-γ) and no adaptive immune cytokines. In adult MCs, inactivated and live virus invoked cytokines reflecting both innate and adaptive immunity (IL-6, IFN-γ, IL-2, TNF-α and IL-10). Further, NK cells (and not T cells) were the primary source of IFN-γ in neonate MCs, whereas both NK cells and T cells contributed towards IFN-γ in adult MCs to live RSV. RSV-induced proliferation in neonate MCs was not observed, though positive in adult MCs. Taken together, the results indicated that the immune response to live virus at birth was only innate in nature and could be characterized as hyporesponsive (compared to adults), thus contradicting our initial hypothesis. Immune suppression to live RSV in neonate MCs was found to be closely associated with dysregulation between type I (IFN-α) and type II (IFN-γ) IFNs. IFN-α expression in neonate MCs was significantly more than in adult MCs to live RSV. Inhibition of the live RSV-induced IFN-α in neonate MCs led to significant increases in innate (IFN-γ, IL-12, IL-18 and TNF-α) immune cytokine production. Interferon regulatory factor-1 (IRF-1) expression was part of the immune response to live RSV in adult MCs though not in neonate MCs and that the lack of IRF-1 upregulation in neonate MCs was reversed when IFN-α was neutralized. Overall, enhanced IFN-α expression suppressing innate immune cytokine production and IRF-1 expression in neonate MCs may account for the severity of early life RSV-induced illnesses.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectHealth Sciences, Immunology.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplineMicrobiology and Immunologyen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorHalonen, Marilynen_US
dc.identifier.proquest3145086en_US
dc.identifier.bibrecord.b47212470en_US
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