Dissertation
Antiviral gene stimulation during measles virus infection of primary human airway epithelial cells
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Summer 2024
DOI: 10.25820/etd.007631
Abstract
Measles virus (MeV) is the most contagious human virus and is a leading cause of vaccine-preventable deaths, globally. Unfortunately, yearly rates of MeV cases are on the rise due to vaccination campaign terminations during the COVID-19 pandemic. There is no known reason why MeV is much more contagious than other airborne viruses, as the genomic and physical structure of MeV is similar to other viruses in the same family. As MeV is a respiratory virus and primarily infects the upper respiratory tract, we study infection of primary human airway epithelia (HAE), which are derived from the tracheal and/or bronchus tissue of human donors. Upon MeV infection of HAE, we observe that MeV spreads directly cell-to-cell more efficiently in HAE than related viruses, forming infectious foci, termed “infectious centers. While MeV infection of immortalized cells leads to syncytium formation and rapid cell death, in HAE, infectious centers stop growing ~5 days post-infection and cells remain viable. Unlike some immortalized cells, HAE have an intact innate immune response. Thus, we hypothesized that interferon (IFN) responses limit infectious center growth as IFN is an important modulator of the antiviral response in HAE.
Surprisingly, we found that MeV causes significant interferon-stimulated gene (ISG) expression in the absence of IFN RNA and protein. Although the expression of IFNs is not increased in infected cells, we did observe increases in mitochondrial-stress transcripts, implying mitochondrial damage may be occurring upon infection. Mitochondrial stress activates the non-canonical DNA-sensing pathway cGAS-STING, and this alternative pathway may explain ISG expression in the absence of IFN. Indeed, we observed mitochondrial damage, evidenced by superoxide and mitochondrial membrane depolarization within infectious centers. Upon further investigation of how mitochondrial damage may be occurring, we found the MeV nucleoprotein (N) locates to mitochondria via a mitochondrial localization sequence that, when mutated, no longer targets mitochondria.
In this thesis, we investigate how MeV spreads cell-to-cell without appreciable IFN activation and stimulates the cGAS-STING axis. MeV’s unique innate immune signaling profile may be a key feature in explaining its highly contagious nature.
Details
- Title: Subtitle
- Antiviral gene stimulation during measles virus infection of primary human airway epithelial cells
- Creators
- Lorellin A Durnell-Bettis
- Contributors
- Patrick L Sinn (Advisor)Richard J Roller (Committee Member)Jack T Stapleton (Committee Member)Ziying Yan (Committee Member)Jessica M Tucker (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Biomedical Science (Microbiology)
- Date degree season
- Summer 2024
- Publisher
- University of Iowa
- DOI
- 10.25820/etd.007631
- Number of pages
- xiii, 123 pages
- Copyright
- Copyright 2024 Lorellin Amanda Durnell-Bettis
- Language
- English
- Date submitted
- 07/02/2024
- Description illustrations
- illustrations, tables, graphs
- Description bibliographic
- Includes bibliographical references (pages 111-123).
- Public Abstract (ETD)
- Measles virus (MeV) is the most infectious human virus and poses a significant global health threat. However, we do not understand what unique characteristics contribute to MeV’s contagious nature. Further, MeV cases are on the rise as it remains a top killer of children under the age of 5. Therefore, there is still a need to understand what factors may make MeV transmit more efficiently so we can not only stop the spread of MeV but also be more equipped to handle pandemic-potentiating emerging viruses. One quality that makes MeV unique is that it spreads cell-to-cell in the airways much more efficiently than other viruses but how MeV does this is a knowledge gap in the field. We found that MeV combats the immune response much better compared to related viruses, like respiratory syncytial virus, which does not spread cell-to-cell like MeV. We also found that MeV activates pathways normally associated with DNA virus infection. This is a novel observation for MeV, which has an RNA genome. We believe that the ability of MeV to spread cell-to-cell, antagonize the innate immune response, and activate alternative, novel pathways may be contributing reasons why MeV is so much more contagious that other respiratory viruses.
- Academic Unit
- Biomedical Science Program
- Record Identifier
- 9984698152802771
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