On Monday, August 26, 2024, Shea Lowery successfully defended her PhD thesis, "Innate Immune and Inflammatory Responses to Coronaviruses." This major achievement in her academic career was celebrated with her mentor, Stanley Perlman, MD, PhD. In the photo, Shea is pictured with Dr. Perlman.
 

Research

Coronavirus infection of both human and mice can result in severe disease, characterized by significant immunopathology that is spurred by an exuberant, yet dysregulated, innate immune response with a poor adaptive response. One mechanism by which coronaviruses generate dysregulated immune responses is by encoding innate immune antagonist genes. Once such gene is a conserved accessory gene within the +1 ORF of nucleocapsid called the internal N gene. This gene is referred to as “I” for mouse hepatitis virus (MHV), ORF9b for severe acute respiratory CoV 1 and 2(SARS-CoV-1/2), and ORF8b for Middle East respiratory syndrome CoV (MERS-CoV). In this thesis I describe a mild innate immune antagonist function for the MHV-JHM strain I protein. I show genetic deletion of JHMV I resulted in a highly attenuated virus both in vitro and in vivo that displayed a post RNA replication/transcription defect that ultimately resulted in fewer infectious virions packaged compared to wild type virus. This was unique to JHM as another MHV virus, A59, did not display the same phenotypes and highlights a previously unappreciated role for CoV accessory proteins. 

SARS-CoV-2 is also excellent at subverting the host immune response, leading to the development of both acute disease, as well as long term disease manifestations called post-acute sequalae of SARS-CoV-2 (PASC). To development effective therapeutics for patients, an animal model that recapitulates PASC symptoms and pathology is required. Our lab developed a mouse-adapted (MA) SARS-CoV-2 (herein MA30) capable of recapitulating acute and PASC COVID-19-like disease. Mice sub-lethally infected with MA30 recover from infection but exhibit extensive cognitive defects and lung damage as long as 100 days post infection (dpi). Immune cell infiltration in the lungs, including T and B cells, monocytes, macrophages, and neutrophils remained elevated long term in the absence of live virus. Furthermore, using a reporter mouse, which labels haematopoietically-derived monocytes and granulocytes, I identified an increased number of inflammatory monocytes and macrophages in the lungs out to 100 dpi. Additionally, the brain showed an increase in T and B cell numbers over time, while innate immune cell numbers remained unchanged. Interestingly, single cell analyses of CD45+ cells in the brains of MA30 infected mice showed increased expression of inflammatory genes in neutrophils, monocytes, and microglia. I found monocyte populations model the gene signature of disease inflammatory macrophages (DIMs) identified in neurological diseases such as Alzheimer’s and Parkinson’s. Additionally, the microglia take on disease associated microglia (DAM) gene signatures, as well as a unique subset of microglia with enhanced ISG expression that only increased in infected animal brains. Overall, these data identify a long-term inflammatory immune response in SARS-CoV-2-infected animals that mimic human neurological diseases and will allow us to better understand long-COVID-like disease and to develop therapeutics.

Background

Shea was born and raised in middle Georgia with her parents, Mike and Lisa, and younger brother, Robby. Though she came from a family of engineers, math was not her strong suit, and she developed a passion for science at a young age. Known as “bug girl” as a child, she dreamed about being an entomologist. She then discovered a love for horses and a desire to be a large animal veterinarian. She eventually settled on becoming a physician her junior year of high school, for who knows what reason. During her senior year literature class, she wrote a paper on the ethics of stem cell research, which sparked her interest in reading and writing research papers, and the science performed to complete them. From that moment, she knew she had to get involved in a research lab in college.

Shea received her Bachelor of Science, majoring in Biology, at Georgia College and State University in 2018. She performed research on bacteriophages for 3 years and presented her work at multiple conferences. While tutoring chemistry and biology, recruiting and training all her friends in her research lab, she realized her dream job was a profession that combined both teaching and research. She completed a research experience for undergraduates (REU) at Texas A&M University, studying human cytomegalovirus. From there, she solidified a plan to pursue molecular virology research and a PhD at the University of Iowa.

At the University of Iowa, Shea taught in multiple areas, including the Virology and Human Disease course, the Bacteria and Human Disease course, and introducing REU students to coronaviruses. She participated in multiple Center for Integration of Research, Teaching, and Learning (CIRTL) courses. In addition, she trained 3 REU students, as well as multiple lab technicians and graduate students. Her teaching prowess earned her the Sarah Pulvermacher Teaching Award in 2021. She has authored 2 manuscripts and contributed to 5 others. Her research passion is viral pathogenesis, and she looks forward to continuing her career as a post-doctoral fellow at Emory University, studying Herpesvirus egress.

When she is not in lab, Shea enjoys time with her husband, Trey, and her daughter, Lexa. She is a voracious reader, gardener, and cook. She will miss the many friends she has made in graduate school and Iowa City’s excellent food!