Dissertation
Altered innate immune response to influenza virus infection in the neonate
Doctor of Philosophy (Ph.D.), Drexel University
Jul 2020
DOI:
https://doi.org/10.17918/00001395
Abstract
Respiratory viral infections contribute substantially to global infant mortality and disproportionately affect preterm neonates. This mortality is often attributed to the immunological immaturity of the newborn. Newborn immune responses are qualitatively and quantitatively distinct from those of adults. Neonates are ineligible for current influenza vaccines as they fail to develop effective antibody responses. Therefore, there is a critical need for developing antiviral therapeutic interventions for this extremely vulnerable population. Using our clinically relevant neonatal murine model of influenza virus infection, neonates exhibit high mortality and viral load early in influenza infection coupled with delayed innate immune transcriptional responses in the lung compared to adults. Administration of a probiotic, Lactobacillus rhamnosus GG (LGG), serves as an effective immune modulator during influenza viral infection, which improves neonatal mouse survival by calibrating innate antiviral responses, specifically type I interferons (IFN I). Uncontrolled production of IFN I, which controls viral replication, may also result in the production of pathogenic reactive oxygen species (ROS). Infants are particularly susceptible to ROS because of decreased production of antioxidants, such as superoxide dismutase 3 (SOD3). Furthermore, neonates demonstrate increased pathology under oxidative stress conditions. Neonatal infected lung epithelial cells and immune cells have an increased production of ROS in response to IFN I. The recruitment of the most potent ROS-producing immune cell, the neutrophil, is controlled by neonatal TLR 2 and ablation of this receptor or treatment with an antioxidant improves survival in neonates. Our research identifies modifiable risk factors which can be used to develop antiviral therapeutics in this currently understudied population.
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Details
- Title
- Altered innate immune response to influenza virus infection in the neonate
- Creators
- Ogan Kartal Kumova
- Contributors
- Alison Carey (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xix, 354 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Microbiology and Immunology; College of Medicine; Drexel University
- Other Identifier
- 991014695135104721