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CHARACTERIZATION AND IMMUNOMODULATION OF THE INFANT IMMUNE RESPONSE TO RESPIRATORY SYNCYTIAL VIRUS

Eichinger, Katherine/ KM (2019) CHARACTERIZATION AND IMMUNOMODULATION OF THE INFANT IMMUNE RESPONSE TO RESPIRATORY SYNCYTIAL VIRUS. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Respiratory syncytial virus (RSV) is a single-stranded, negative sense RNA virus that is the leading viral cause of serious respiratory tract infections in infants and young children worldwide. The virus is highly infectious and a majority of children are infected during their first RSV season. Decades of research has provided critical information detailing mechanisms of viral pathogenesis and host immune subversion however, a regretfully incomplete understanding of the infant RSV immune response still exists. Generally, infants are heavily reliant on innate immunity to respond to pathogens and they divert normal, pro-inflammatory responses to allergy-inducing innate immune responses, making them particularly vulnerable to intracellular pathogens like RSV. While this diversion can protect infants from over-exuberant immunopathology, allergic responses can potentiate mucus production and airway obstruction acutely as well as increase the predisposition towards atopy and asthma later in life. Clinical observations have noted an inverse relationship between increased pro-inflammatory RSV immune responses and reduced RSV disease severity in children, but the acute and long-term effects of pro-inflammatory immunomodulation during primary, infant RSV infection are not well understood. In this dissertation, we hypothesized that pro-inflammatory immunomodulation during primary infant RSV infection alters acute and memory RSV immune responses.
We demonstrate that both innate and adaptive infant RSV immunity is less robust when compared to adult responses. Alveolar macrophages (AMs), critical innate immune cells, were less activated and had fewer differentially expressed genes (DEGs) in response to RSV infection than adults. Administration of the pro-inflammatory cytokine, interferon gamma (IFNγ), during primary RSV infection reduced viral titers, increased AM activation, and increased RSV-specific CD8+ T cell responses. Not only did IFNγ treatment have an effect on primary RSV immune responses, it also increased RSV-specific memory CD8+ T cell responses, reduced airway hyperresponsiveness, and contributed to signals of innate trained immunity upon secondary infection. We also demonstrated that passive immunization with RSV-neutralizing maternal antibodies resulted in heightened innate immune activation and increased mucus production. Our data suggests that immunomodulation of the primary infant RSV immune response can have beneficial acute and long-term effects but must be properly balanced to avoid immunopathology.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Eichinger, Katherine/ KMkme46@pitt.eduKME460000-0002-0968-8513
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairEmpey, Kerry/ KMkme33@pitt.edukme33
Committee MemberEmpey, Philip/ PEpempey@pitt.eduPEMPEY
Committee MemberAlcorn, John/ JFjfa9@pitt.edujfa9
Committee MemberGibbs, Robert/ RBgibbsr@pitt.edugibbsr
Committee MemberPeebles, R. Stokes/ RSstokes.peebles@vanderbilt.edu
Date: 3 April 2019
Date Type: Publication
Defense Date: 18 March 2019
Approval Date: 3 April 2019
Submission Date: 1 April 2019
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 241
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Antibodies, Immunization, Infant, Interferon, Lung, RSV
Date Deposited: 03 Apr 2019 15:30
Last Modified: 03 Apr 2019 15:30
URI: http://d-scholarship.pitt.edu/id/eprint/36198

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