Molecular analysis of mother-to-child transmission of hepatitis B virus

Hepatitis B virus (HBV) can cause severe liver diseases including cirrhosis and hepatocellular carcinoma (HCC). There are approximately 254 million people in the world that are chronically infected by this virus, resulting in more than 1 million deaths every year. Most chronic HBV carriers acquired the virus early in life from their infected mothers. In contrast to the mother-to-child transmission (a.k.a. vertical transmission), patients who acquired HBV from unrelated individuals (a.k.a. horizontal transmission) usually developed self-limited acute infection. The goal of our research is to understand how HBV and its antigens in the mother affect anti-HBV immunity of her children to promote chronic HBV infection in the latter. HBV has a very narrow host range, which has greatly hampered its research. We have developed a mouse model to study how HBV in the mother affects anti-HBV immunity of her children. By crossing female hemizygous HBV transgenic mice to male naïve mice, we obtained non-transgenic mouse pups. When the HBV genomic DNA was introduced into the liver of these non- transgenic mouse pups by hydrodynamic injection, HBV persistently replicated in these mice for up to 28 weeks. In contrast, HBV was not able to persist in control mice born to non-transgenic dams and was cleared from the mice within 4 weeks after the DNA injection. Our further studies indicated that maternal HBV could educate fetal Kupffer cells (i.e., hepatic macrophages) of the offspring in utero. These Kupffer cells would then undergo M2- like anti-inflammatory polarization to suppress HBV-specific CD8+ T cells after birth, resulting in HBV persistence in the offspring. In contrast, Kupffer cells of the offspring that were not exposed to maternal HBV in utero would undergo the M1-like proinflammatory polarization to promote HBV clearance. During this grant period, we will continue to investigate how maternal HBV and its antigens affect offspring immunity against HBV. Specifically, we will identify maternal HBV factors that promote and support HBV replication in the offspring and their effects on anti-HBV immunity of the offspring. We will also examine the molecular mechanism by which HBV and its antigens use to cross the placental barrier to education fetal immunity. As our preliminary studies suggested that maternal HBV antigens could genetically reprogram fetal Kupffer cells to result in their distinct anti-inflammatory response to HBV after birth, we will also determine the molecular mechanism of this reprogramming. Our proposed studies will provide important information for us to understand how HBV and its antigens in the mother affects anti-HBV immunity of her children to promote HBV replication and persistence after its mother-to-child transmission. This information will be important for the development of novel treatments for chronic HBV patients. Project Number: 1R01AI189583-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: J.-H. James Ou | Institution: UNIVERSITY OF SOUTHERN CALIFORNIA, Los Angeles, CA | Award Amount: $621,698 | Activity Code: R01 | Study Section: Pregnancy and Neonatology Study Section[PN] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI18958301