Elucidating how environmental perturbations determine the duration of enteric viral infection

SUMMARY For many non-integrating RNA viruses, a typical course of infection involves a brief period of peak viral burden followed by rapid resolution. However, the virus or viral products are detected in a subset of individuals for a prolonged period for a growing list of viruses previously considered non-persistent. Prolonged infection may contribute to long-term complications and increased opportunities for transmission. In preliminary data, we developed an animal model of persistent murine astrovirus (MuAstV) infection that we propose to apply towards elucidating how the environment determines the duration of enteric infection. Astroviruses are RNA viruses that are a common cause of self-limiting gastroenteritis in humans following fecal-oral transmission, although like other gut viruses, some individuals display prolonged shedding for unknown reasons. We found that routine cage change procedures induce a stress response characterized by a spike and drop in glucocorticoid levels that leads to rapid clearance of MuAstV infection in mice. In contrast, the virus establishes a robust persistent infection if the mice remain in the same cage for the duration of the experiment. We will first determine how MuAstV establishes a persistent infection in the unperturbed setting, focusing on immune evasion mechanisms of the virus including how goblet cells potentially represent an immune-privileged niche. Then, we will determine how the cage change procedure mediates clearance of MuAstV, especially the role of the glucocorticoid-CD8 T cell axis representing a novel contribution of the stress response to viral dynamics. Cage change routines are an important variable in animal research that are often ignored. Moreover, stress and glucocorticoids are pervasive aspects of human biology. We anticipate identifying fundamental mechanisms involved in how the immune system reacts to stressful environmental perturbations to regulate the duration of viral infections in the gut. This information may inform intervention strategies that can be deployed to diminish the duration of viral infection and window of transmission. Project Number: 1R01AI195722-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Ken Cadwell | Institution: UNIVERSITY OF PENNSYLVANIA, PHILADELPHIA, PA | Award Amount: $627,483 | Activity Code: R01 | Study Section: Viral Dynamics and Transmission Study Section [VDT] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI19572201