Utilizing a novel hamster model to determine neurologic and behavioral abnormalities of offspring from mothers infected with SARS-CoV-2 - PROJECT SUMMARY A novel coronavirus, severe acute respiratory syndrome 2 (SARS-CoV-2), emerged in 2019 and led to the worldwide COVID-19 pandemic with over 773 million human infections and 7 million deaths by the end of 2023. Four years later, the full implications of this pandemic remain unclear. Though the acute syndrome has been extensively characterized, more cryptic complications such as long-COVID and neuro-PASC demonstrate that this illness still requires intensive study. Additionally, maternal infection has been linked to negative fetal outcomes including stillbirth. Recent studies implicate SARS-CoV-2 in neurologic aberrations of offspring born to infected mothers. It is crucial that these clinical findings are confirmed through laboratory studies to interrogate the mechanism of any such impacts. A proactive approach to this issue can help alleviate the societal impact of a large influx of children potentially exhibiting neurodevelopmental issues as a result of gestational COVID-19 exposure. As such, the objective of this study is to develop the golden Syrian hamster model to examine the role of maternal infection. The hamster model has been used to great effect in characterizing COVID-19 variants as it does not require adapted virus, demonstrates human-like illness and pathology, and is capable of transmission. Additionally, our group has shown its functional role in a common neuro-PASC sign of illness, anosmia. Utilizing classical virology, molecular biology, histopathology, and extensive neuroimaging, we also expect to gain insight into the mechanisms involved. We further plan on utilizing behavioral studies that we have adapted for hamsters to determine long-term neurodevelopment impacts on the offspring. We will accomplish this through two aims. In Specific Aim 1, we will focus on the impact of maternal infection in utero. Initial studies will focus on the direct effects of maternal infection on the female reproductive tract and developing fetus. Additionally, we will determine which tissues are capable of being productively infected and whether vertical transmission occurs. We will also determine the inflammatory state of the placenta and fetus. Our multidisciplinary team will do an in-depth analysis on neurodevelopment to identify any acute fetal neurologic aberrations resulting from maternal infection. In Specific Aim 2, we will explore the behavioral and neurologic implications of maternal infection on the resulting offspring. We have optimized tests for depression, muscle weakness, and cognition/memory in the golden Syrian hamster model. We expect that even in the absence of acute fetal abnormality or vertical transmission, the inflammatory state of the infected dams will cause detrimental long-term neurological impacts in the resulting pups analogous to those reported in human offspring. In addition to the behavioral testing, we will perform extensive histopathologic analysis, neuroimaging, and c-Fos straining to assess the impact of maternal infection. The proposed studies will generate a novel maternal-fetal hamster model of COVID-19. Our results can be utilized to better prepare public health entities to the long-term societal impacts of COVID-19 maternal infection and to provide a powerful tool to the research community for mechanistic and interventional studies.
