Lorellin Durnell, a PhD candidate, recently defended her thesis titled “Measles virus infection triggers a DNA-sensing pathway to stimulate antiviral gene expression.” The defense took place on June 7, 2024. Her mentor, Dr. Patrick Sinn, is pictured with her. Congratulations on this acheivement!
Research
Measles virus (MeV) is the most contagious human virus and is a leading cause of vaccine-preventable deaths globally. Due to COVID-19-related impediments to vaccination, including vaccination campaign terminations, the yearly rates of MeV cases are on the rise. However, obvious reasons why MeV is so much more contagious than other airborne viruses are unknown as the genomic and physical structure of the virus is similar to others in the same family.
To understand how MeV spreads in airway epithelial cells, we use well-differentiated primary airway epithelia (HAE) that have been derived from the tracheal and/or bronchus tissue of human donors. We observed that MeV can spread directly cell-to-cell much more efficiently that related viruses and forms infectious foci that our lab has termed infectious centers. Infectious centers are comprised of anywhere between 5-400 cells and are not cytopathic. Interestingly, infectious centers stop growing ~4 days post-infection. Importantly, like the in vivo airways, our HAE model system contains an intact innate immune response. We hypothesized that interferon (IFN) responses limit infectious center growth as IFN is an important modulator of the antivirus response in our airway cells. In our recently published work, we found that MeV causes significant interferon-stimulated gene (ISG) expression in the absence of IFN RNA and protein. Although IFN isn’t increased in infected cells, we do observe mitochondrial-stress transcripts increased suggesting mitochondrial damage may be occurring upon infection, thereby activating the non-canonical, DNA-sensing pathway, cGAS-STING. This alterative pathway might be responsible for ISG expression even in the absence of IFN. Indeed, we observe mitochondrial membrane depolarization within infected cells compared to uninfected cells. cGAS blockade enhanced cell-to-cell spread as well as STING inhibition. Mitochondrial DNA depletion had a similar effect. Upon further investigation , we found the MeV nucleoprotein (N) locates to mitochondria via a mitochondrial localization sequence present in the N-terminus of the protein. Mutation of the N-terminus ablated localization.
This details the fact that MeV is efficient at blocking the IFN response as we detect little to no IFN in HAE with infection with MeV. Although we observe ISG expression, we believe ISG expression is stemming from the cGAS-STING pathway. The ability of MeV to spread cell-to-cell without appreciable IFN activation and activate the cGAS-STING axis may be a key feature of its highly contagious nature.
Background
Lorellin Amanda Durnell was born in St. Louis, Missouri, to Pamela Lawson and Nathan Durnell. She attended grade school in the greater St. Louis area. Her love of science was fostered at a young age when her father took her hunting for fossils or to the local science center. It is most likely during this time that Lorellin became interested in making observations and asking questions about what she could and couldn’t see around her, including microbes.
This curiosity about the organisms around us that we can’t see and how they interact with their host led her to attend the University of Missouri-Columbia to obtain a degree in Biochemistry. While there, she also participated in undergraduate research in two separate labs. She achieved authorship on two papers during her undergraduate studies. But Lorellin knew she wanted to learn more about virology. So, with her bachelor's degree in hand and lab experience under her belt, she sought out a position in Dr. Michael Diamond’s lab as a lab technician at Washington University in St. Louis. Her project aimed to develop antibody-based therapeutics for emerging viral pathogens and ultimately sealed her fate as a virologist.
Lorellin's innate interest in virology drove her to the University of Iowa where she began her dissertation in the laboratory of Dr. Patrick Sinn. Her graduate work primarily focused on understanding innate immune responses to measles virus infection in primary human epithelia. Her research has resulted in one successful first-author publication with one currently in the works. Additionally, she has authored two other papers during her time in Dr. Sinn’s lab. Lastly, her excellent training has provided her with ample opportunities to present at conferences and symposiums around the country. Lorellin will continue pursuing knowledge in Microbiology and Immunology at the University of North Carolina as a post-doctoral scholar.
While in Iowa, Lorellin met and married her best friend and partner, Brandon Bettis. Lorellin and Brandon live together with their three cats, Kol, Templeton, and Dean and all plan to move to North Carolina this summer.
When she’s rarely not in the lab, Lorellin enjoys reading psychological thrillers, forcing her husband to watch scary movies with her, kissing her cats, and hanging out with her best friends, Bri and Cami. She also enjoys fitness including road biking and hiking.