"Viruses are the best Cell Biologists."
Viruses interact with host cells in ways that uniquely reveal the general aspects of their molecular and cellular structure and function. This makes viruses great tools to study the underlying mechanisms of disease caused by malfunction of cellular or molecular machinery.
Oncogenic viruses not only genetically code molecules to cause cancer, but also strategically utilize host molecules for its survival and cancer development. Many of these viral targeting proteins turn out to be tumor suppressors that are important to many different cancer types.
Thus, understanding how oncogenic viruses cause cancer, will not only benefit the treatment of viral related cancers, but also have therapeutic potentials to all types of cancers.
Kaposi’s sarcoma associated herpesvirus
Kaposi’s sarcoma associated herpesvirus (KSHV) is the etiological agent for several malignancies in the human population including Kaposi’s sarcoma (KS), multicentric Castleman’s disease (MCD), and primary effusion lymphoma (PEL). Although innate immunity is critical for comprehensive antiviral responses to clear viral infections and limit viral tumor proliferation, exactly how the innate immune system senses tumor viruses, such as KSHV, is not well understood at the molecular level. By investigating the interplay between the innate immune system, KSHV, and KSHV-associated cancers, this will help us develop better therapies to treat not only KSHV related malignancies, but also broaden our knowledge with respect to other viral cancers.
The cGAS-STING DNA sensing pathway
As the first line of host defense, the innate immune system utilizes germline-encoded receptors named Pattern-Recognition Receptors (PRRs) to detect invading pathogens. PRRs recognize conserved molecular structures of pathogens known as Pathogen-Associated Molecular Patterns (PAMPs) to initiate immune responses that counteract pathogen infection. The immuno-stimulatory feature of exogenous nucleic acids, such as viral DNA and RNA, has been known for more than half a century, but the mechanism by which they function as an immune stimulant has remained unclear for a long time.
The most well-known DNA sensing pathway was revealed during the past decade, the cGAS-STING DNA sensing pathway. Briefly, cGAS binds to cytosolic double-stranded DNA (dsDNA) from pathogens (bacteria or viruses) or hosts in a sequence-independent and length-dependent manner. Following the binding of dsDNA, cGAS catalyzes the production of a second messenger known as cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) in the presence of GTP and ATP, which subsequently binds to the adaptor protein STING on the endoplasmic reticulum (ER) membrane. STING then undergoes a dramatic trafficking process from the ER to the Golgi complex, to perinuclear compartments and eventually degraded after forming large punctate structures. Before degradation, STING recruits TANK binding kinase 1 (TBK1) and activates transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor-κB (NF-κB), which then translocate into the nucleus to induce the transcriptional activation of type I interferons (IFNs) and other inflammatory cytokines, thus establishing an antiviral state in infected and uninfected neighboring host cells. Numerous DNA viruses have been reported to activate the cGAS–STING pathway.
KSHV regulates the cGAS-STING pathway
We have found that the DNA sensing cGAS-STING pathway is responsible for triggering innate immune responses upon KSHV primary infection and lytic replication. However, the fact that KSHV is capable of establishing lifelong infection in the presence of cGAS-STING signaling suggests that KSHV encodes viral regulators to modulate the cGAS-STING pathway to facilitate its viral transmission and its lifelong persistence in the human population. These potential viral regulators were successfully identified by our screening system, but their roles in KSHV infection, as well as KSHV cancer development, are still subjected to further investigation
Utilizing molecular biology as well as bioinformatics tools, our lab seeks to extend our knowledge of how these viral proteins regulate the cGAS-STING pathway and how to develop potential KSHV cancer therapy by targeting these viral proteins. Specifically, we are focusing on:
1) Exploring detailed mechanisms of cGAS-STING signaling regulation by KSHV viral proteins
2) Exploring the role of KSHV viral proteins on KSHV pathogenesis in vitro and in vivo
3) Screening for novel cGAS-STING pathway agonists, and testing their efficacy using PEL based xenograft mouse model
KSHV research is full of possibility
We are also actively exploring other signaling pathways that are involved in KSHV infection and KSHV cancer progression. Particularly, we aim to identify viral regulators that are responsible for modulating some of these pathways, and further study their mechanism and roles in KSHV cancer development. Our long-term goals are to better understand KSHV cancers and developing potential KSHV cancer treatments or vaccines.