Jae Jung’s Laboratory and Research Interests
My laboratory is conducting four different areas of research:
1. Virus-Induced Cancer
This section is focused on understanding the molecular mechanisms of gamma herpesvirus-induced cancers by investigating the molecular basis of viral carcinogenesis, the epigenetic regulation of viral gene expression, and the development of organoid and animal models for human diseases.
Gamma-2 herpesvirus: The gamma-2 herpesviruses include Kaposi’s sarcoma associated herpesvirus (KSHV), herpesvirus saimiri (HVS), and murine herpesvirus 68 (MHV68). KSHV is consistently associated with Kaposi’s sarcoma, which is a multifocal vascular tumor of mixed cellular composition and the most common tumor in patients with AIDS. Infection of New World primates with HVS results in rapidly progressing malignant T cell lymphomas. Finally, MHV68, the murine counterpart of KSHV and HVS, can be used in a small animal model to study viral persistent infection. Genomic, biochemical and immunological analyses of individual viral genes in culture and experimental infection of mouse and/or primate with recombinant herpesviruses are used to define their roles in the onset of disease. In addition, we have developed humanized mouse models to study human herpesvirus infection. Using the genetic manipulation of viral genome and primate/mouse models, we investigate viral gene expression, epigenetic regulation, persistence, pathogenesis, and vaccine development.
2. Host-Microbe Standoff
Host: The first step to mounting a protective immune response is the recognition of pathogens by cell surface receptors, called pattern recognition receptors (PRRs), located on professional phagocytes, dendritic cells, and non-immune cells. PRRs include C-type lectin receptors (CLR), Toll-like receptors (TLRs), NOD-like receptors (NLRs), and cytoplasmic nucleic sensors (RIG-I, MDA5, and cGAS). After recognizing specific pathogen-associated molecular patterns, PRRs activate intracellular signaling pathways and stimulate inflammatory mediators. As a consequence, chemokines and cytokines are released and inflammatory cells accumulate at the site of infection. Our focus in this section is to understand PRR-mediated anti-microbial responses with a specific focus on RIG-I/MDA5, NLRP1/3/12, cGAS and their ubiquitination-dependent regulations.
Herpesvirus: To avoid host innate and adaptive immune responses, herpesviruses have evolved elaborate mechanisms to target and modulate different aspects of the host’s immune system. Understanding these herpesvirus-mediated immune evasion tactics is the primary goal of this avenue.
Influenza virus: We study how the host recognizes influenza viral infection with a specific focus on the RIG-I, TRIMs, IFITMs, and IRFs, and how influenza virus escapes host IFN-mediated anti-viral responses with a specific focus on the Influenza virus NS1 gene.
Emerging Pathogens: Dengue virus (DENV), Zika virus (ZIKV), Chikungunya virus (CHIKV) and Severe Fever with Thrombocytopenia virus (SFTSV): Dengue is the most prevalent mosquito-borne viral disease, causing an estimated 200 million infections annually with rapidly growing incidence in the past decade. DENV is a single positive-stranded RNA virus of the Flavivirus family and causes a spectrum of diseases, namely dengue fever, dengue hemorrhagic fever and dengue shock syndrome. ZIKV is closely related to DENV, and transmitted by Aedes mosquitoes. While ZIKV infection causes a mild illness, a recent outbreak strongly indicates that ZIKV infection is a key risk factor for microcephaly. CHIKV is a reemerging family of Alphavirus and causes incapacitating arthralgia. While CHIKV has been present mostly in Asia, Africa and Europe, it was recently introduced to the Americas. SFTSV is an emerging infectious agent that was discovered in China in 2010 and has since spread into other countries in East Asia. SFTSV is a three-segmented negative-stranded RNA virus of the Bunyavirus family and has a fatality rate of 12% and as high as 30% in some areas by causing multiple organ failure, thrombocytopenia, and leukopenia. Understanding how DENV, ZIKV, CHIKV and SFTSV are able to evade host immune system and cause diseases is the main topics of interest. Also, we have a new state-of-art Biosafety Lab 3 (BSL3) with mouse infection facility to study CHIKV and SFTSV.
3. Programmed Cell Death (Apoptosis, Autophagy, Pyroptosis and Necroptosis)
Upon viral infection, infected cells can become the target of host immune responses or can go through a programmed cell death (PCD). Apoptosis has been a primary PCD mechanism for the body to respond to viral infection by sacrificing an infected host cell. Autophagy is an important host innate immune pathway that is a highly regulated homeostatic process wherein worn-out proteins, malfunctioning organelles, and invading pathogens are swept up and degraded by tiny “vacuum cleaners”. This process also plays an effective role in anti-microbial and anti-tumor responses by degrading intracellular viruses and by suppressing cancer cell growth, respectively. Pyroptosis is an inflammatory form of cell death characterized by massive leakage of cytosolic contents to magnify inflammatory response. Necroptosis is a programmed form of necrosis, resulting from cellular damage or infiltration by pathogens. Thus, these PCDs are important innate safeguard mechanisms to protect the organism against harmful microbes and unwanted cancerous cells. Viruses, in turn, have evolved elaborate mechanisms to subvert these PCD processes. This avenue is to understand how the host initiates PCD responses upon tumor development or viral infection and how the virus escapes host intracellular PCD-mediated innate immune controls to establish persistent infection and pathogenesis.
4. Developing Programs
Immune aging and infection: Aging is associated with multiple immune system dysfunctions. An important current direction for immunosenescence research is towards assessing the age-associated modifications of immunity that make the elderly more susceptible towards chronic infections, including herpesvirus, and for acute infections, including influenza virus and SFTS virus. We use premature aging knockout mouse models to study how hosts and viruses interact in an aged animal’s immune system.
Traumatic brain injury (TBI) and infection: We have identified novel tripartite motif 9 (TRIM9) E3 ligase as brain-specific innate immune effector to develop balanced host immune responses against brain injury and viral infection. Specifically, TRIM9 KO mice develops serious brain injury and encephalitis upon traumatic stress, stroke or infection. Using this mouse TBI models, we study the development and permeability of blood brain barrier, neuronal and astrocyte cell death, NF-B-mediated brain inflammation, and viral infection-mediated IFN production.
Vaccine stabilization: Instability of vaccines often emerges as a key challenge during clinical development as well as commercial distribution. To yield stable, efficacious vaccine dosage forms for human use, successful formulation strategies must address a combination of interrelated topics including stabilization of antigens, selection of appropriate adjuvants, and development of stability-indicating analytical methods. Our goal is to develop thermostable vaccines for distribution in developing countries without the need of a cold-chain transport. We are working on polio virus vaccine and will ultimately expand this program to other vaccines that require cold-chain transport.