Michael D. Robek, PhD
Areas of Study
- Washington University in St. Louis2000PhD
- Case Western Reserve University1994BS
Our primary research interests lie in studying virus-host interactions, focusing on the hepatitis B virus (HBV). Despite the availability of a protective vaccine, an estimated 296 million people worldwide are chronically infected with this virus, and approximately 820,000 people die each year from chronic liver diseases such as cirrhosis and hepatocellular carcinoma that result from HBV infection. Because current therapies for chronic HBV control but rarely cure the infection, there is a critical need for new approaches to treating this disease.
Our research program focuses on two areas that relate to the innate and adaptive immune responses to HBV and other viruses. First, we are characterizing the ability of antiviral and immunomodulatory cytokines to control HBV replication and prevent liver damage. Second, we are studying new methodologies for therapeutic immunization to eliminate HBV from chronically infected individuals. These studies have contributed to our understanding of virus replication and pathogenesis. This research may also impact public health by expanding the repertoire of therapies for HBV beyond those currently employed.
Cytokines in virus replication and pathogenesis
Type III interferons (IFN-l1-4) induce tissue-specific cellular antiviral programs and play critical roles in the immune response to virus infection in the lung, intestine, and liver. To better understand the precise role of IFN-l in innate immunity, we defined the antiviral response induced by these cytokines. We combined clustering and promoter analysis of gene expression data with mechanistic signaling pathway studies to dynamically characterize the transcriptional responses induced by IFN-a/b and IFN-l in hepatocytes (Bolen et al., 2014). This work revealed quantitative gene expression hierarchies and unique signaling kinetics that suggest specific roles for individual IFNs in the intrahepatic immune response and elucidated the mechanism underlying previously observed differences in IFN antiviral activity. We next defined the molecular mechanism by which IFN-l receptor expression is regulated. We found that the cellular histone deacetylase repression machinery mediates transcriptional silencing of the unique IFN-l receptor IFNLR1 subunit in a tissue-specific manner (Ding et al., 2014). In recent work, we found that the host IFN response, particularly IFN-l, significantly impacts the safety and immunogenicity of a replicating virus-based vaccine platform (Marchese et al., 2020).
In ongoing research, we are further defining the impact of cytokines on the immune response to HBV. CD4+ T cells are an important component of the host response to HBV (Bailey et al., 2023), and the liver has a tolerogenic environment due in part to the presence of cytokines with immunosuppressive activity (IL-10 and TGF-b) that regulate T cell function and proliferation. IL-10 is an immunosuppressive cytokine produced by T cells, B cells, and Kupffer cells in the liver. TGF-b is a profibrogenic cytokine expressed by leukocytes and stromal cells. In current studies, we are using a mouse model of chronic HBV infection to better understand the mechanistic role of these cytokines in HBV persistence and immune-mediated control.
Therapeutic immunization for chronic HBV infection
A strong multi-specific T cell response is generated to HBV in adults who become acutely infected but usually clear the virus. In contrast, in newborns and young children who typically become chronically infected, the T cell response is much weaker in magnitude and is directed toward fewer viral antigens. Because it can eliminate the virus but sometimes fails, the human immune system is an attractive target for therapeutic manipulation. Immunotherapies, including therapeutic vaccination, are promising new tactics for curing chronic HBV infection. Unfortunately, the current HBV vaccine does not eliminate the virus in those already infected. We are working to develop new therapeutic vaccine approaches for chronic HBV and found that vesicular stomatitis virus (VSV)-based vaccine vectors expressing the HBV surface envelope glycoprotein elicit functional immune responses in immunotolerant mouse models of chronic HBV infection (Cobleigh et al., 2013; Moshkani et al., 2019).
In addition to VSV, we are also developing an alphavirus replicon-derived HBV therapeutic vaccine vector based on an earlier finding that infectious “virus-like vesicles” (VLVs) are produced in cells transfected with a DNA-launched Semliki Forest virus (SFV) RNA replicon encoding a single structural protein (VSV-G) and an HBV antigen (Reynolds et al., 2015). We tested the immunogenicity and efficacy of VLV vaccine vectors in normal mice and mouse models of acute and chronic HBV replication (Chiale et al., 2019; Chiale and Yarovinsky et al., 2020). As this VLV vector system allows us to develop new therapeutic vaccines to treat chronic HBV infection, we are further enhancing this platform's immunogenicity and anti-HBV efficacy. We are also performing mechanistic studies to determine how therapeutic vaccines based on viral vectors successfully activate immune responses to HBV in the immune-tolerant environment of chronic HBV infection (Chiale et al., 2021).
Bailey, J.T., S. Moshkani, C. Rexhouse, J.L. Cimino, and M.D. Robek. 2023. CD4+ T cells reverse surface antigen persistence in a mouse model of HBV replication. Microbiol Spectr, 10:e0344723.
Chiale, C., A.M. Marchese, Y. Furuya, and M.D. Robek. 2021. Virus-based vaccine vectors with distinct replication mechanisms differentially infect and activate dendritic cells. npj Vaccines, 6:138.
Chiale C., T.O. Yarovinsky, S.W. Mason, B.R. Madina, M. Menon, M.M. Krady, S. Moshkani, A. Chattopadhyay Pal, B. Almassian, J.K. Rose, M.D. Robek, and V. Nakaar. 2020. Modified alphavirus-vesiculovirus hybrid vaccine vectors for homologous prime-boost immunotherapy of chronic hepatitis B. Vaccines (Basel), 8:279.
Marchese, M., C. Chiale, S. Moshkani, and M.D. Robek. 2020. Mechanisms of innate immune activation by a hybrid alphavirus–rhabdovirus vaccine platform. J Interferon Cytokine Res, 40:92-105.
Chiale C., S. Moshkani, J.K. Rose, and M.D. Robek. 2019. Heterologous prime-boost immunization with vesiculovirus-based vectors expressing HBV Core antigen induces CD8(+) T cell responses in naïve and persistently infected mice and protects from challenge. Antiviral Res, 168:156-167.
Moshkani S., C. Chiale, S.M. Lang, J.K. Rose, and M.D. Robek. 2019. A highly attenuated vesicular stomatitis virus-based vaccine platform controls hepatitis B virus replication in mouse models of hepatitis B. J Virol, 93: e01586-18.
Reynolds T.D., L. Buonocore, N.F. Rose, J.K. Rose, and M.D. Robek. 2015. Virus-Like Vesicle-Based Therapeutic Vaccine Vectors for Chronic Hepatitis B Virus Infection. J Virol, 89:10407-15.
Bolen, C.R., S. Ding, M.D. Robek*, and S.H. Kleinstein*. 2014. Dynamic expression profiling of type I and type III interferon-stimulated hepatocytes reveals a stable hierarchy of gene expression. Hepatology, 59:1262-1272 *Equal contribution.
Ding, S., W. Khoury-Hanold, A. Iwasaki, and M.D. Robek. 2014. Epigenetic reprogramming of the type III interferon response potentiates antiviral activity and suppresses tumor growth. PLOS Biology, 12(1) e1001758
Cobleigh M.A., X. Wei, and M.D. Robek. 2013. A vesicular stomatitis virus-based therapeutic vaccine generates a functional CD8 T cell response to hepatitis B virus in transgenic mice. J Virol, 87:2969-2973
View Michael D. Robek's articles on the National Institute of Health's PubMed website.