Prof. Dr.
Ulrike Protzer
Prof. Dr.
Ulrike Protzer
Research background
Hepatitis viruses establish acute and chronic infections that can culminate in liver cirrhosis and hepatocellular carcinoma. Hepatitis B virus (HBV), an enveloped DNA virus, persists in hepatocytes through complex interactions between its genome and host cellular pathways, while related hepatitis viruses such as hepatitis C and hepatitis delta viruses, both RNA viruses, further illustrate the diversity of viral strategies targeting the liver. How HBV is regulated within infected cells, how immune mediators or metabolic signals influence replication and persistence of viral nucleic acids and how an infection is cured remain central questions in virology because HBV causes more than one million deaths per year.
The research of Ulrike Protzer focuses on elucidating the molecular interplay between HBV and its host hepatocyte. Her work employs advanced infection systems to dissect all steps of HBV replication and to identify cellular pathways controlling viral gene expression and genome maintenance. In addition, she investigates how viral factors modulate immune responses and metabolic signaling and how chronic infection contributes to hepatocarcinogenesis. By translating mechanistic insights into immunotherapeutics and targeted antiviral strategies using nucleic acids and evaluating them in preclinical models, this research advances efforts toward achieving a cure for chronic hepatitis B.
Research fields
Publications
Activation of CD4 T cells during prime immunization determines the success of a therapeutic hepatitis B vaccine in HBV-carrier mouse models.
J Hepatol. · 2023
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We recently developed a heterologous therapeutic vaccination scheme (TherVacB) comprising a particulate protein prime followed by a modified vaccinia-virus Ankara (MVA)-vector boost for the treatment of HBV. However, the key determinants required to overcome HBV-specific immune tolerance remain unclear. Herein, we aimed to study new combination adjuvants and unravel factors that are essential for the antiviral efficacy of TherVacB.
Three exposures to the spike protein of SARS-CoV-2 by either infection or vaccination elicit superior neutralizing immunity to all variants of concern.
Nat Med. · 2022
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Infection-neutralizing antibody responses after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or coronavirus disease 2019 vaccination are an essential component of antiviral immunity. Antibody-mediated protection is challenged by the emergence of SARS-CoV-2 variants of concern (VoCs) with immune escape properties, such as omicron (B.1.1.529), which is rapidly spreading worldwide. Here we report neutralizing antibody dynamics in a longitudinal cohort of coronavirus disease 2019 convalescent and infection-naive individuals vaccinated with mRNA BNT162b2 by quantifying SARS-CoV-2 spike protein antibodies and determining their avidity and neutralization capacity in serum. Using live-virus neutralization assays, we show that a superior infection-neutralizing capacity against all VoCs, including omicron, developed after either two vaccinations in convalescents or a third vaccination or breakthrough infection of twice-vaccinated, naive individuals. These three consecutive spike antigen exposures resulted in an increasing neutralization capacity per anti-spike antibody unit and were paralleled by stepwise increases in antibody avidity. We conclude that an infection-plus-vaccination-induced hybrid immunity or a triple immunization can induce high-quality antibodies with superior neutralization capacity against VoCs, including omicron.
Knockdown of Virus Antigen Expression Increases Therapeutic Vaccine Efficacy in High-Titer Hepatitis B Virus Carrier Mice.
Gastroenterology. · 2020
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Hepatitis B virus (HBV) infection persists because the virus-specific immune response is dysfunctional. Therapeutic vaccines might be used to end immune tolerance to the virus in patients with chronic infection, but these have not been effective in patients so far. In patients with chronic HBV infection, high levels of virus antigens might prevent induction of HBV-specific immune responses. We investigated whether knocking down expression levels of HBV antigens in liver might increase the efficacy of HBV vaccines in mice.
Interferon-γ and Tumor Necrosis Factor-α Produced by T Cells Reduce the HBV Persistence Form, cccDNA, Without Cytolysis.
Gastroenterology. · 2016
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Viral clearance involves immune cell cytolysis of infected cells. However, studies of hepatitis B virus (HBV) infection in chimpanzees have indicated that cytokines released by T cells also can promote viral clearance via noncytolytic processes. We investigated the noncytolytic mechanisms by which T cells eliminate HBV from infected hepatocytes.
Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA.
Science. · 2014
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Current antiviral agents can control but not eliminate hepatitis B virus (HBV), because HBV establishes a stable nuclear covalently closed circular DNA (cccDNA). Interferon-α treatment can clear HBV but is limited by systemic side effects. We describe how interferon-α can induce specific degradation of the nuclear viral DNA without hepatotoxicity and propose lymphotoxin-β receptor activation as a therapeutic alternative. Interferon-α and lymphotoxin-β receptor activation up-regulated APOBEC3A and APOBEC3B cytidine deaminases, respectively, in HBV-infected cells, primary hepatocytes, and human liver needle biopsies. HBV core protein mediated the interaction with nuclear cccDNA, resulting in cytidine deamination, apurinic/apyrimidinic site formation, and finally cccDNA degradation that prevented HBV reactivation. Genomic DNA was not affected. Thus, inducing nuclear deaminases-for example, by lymphotoxin-β receptor activation-allows the development of new therapeutics that, in combination with existing antivirals, may cure hepatitis B.