Virus infection causes various types of diseases in humans, and the innate immune responses serve as the first line of defense against viruses. Virus infection causes rapid induction of antiviral and inflammatory genes in the infected cells, leading to the establishment of an antiviral state in the host. Virus infection is recognized by the pattern-recognition receptors, which activate the transcription factors IRF3 and NF-kB, to induce antiviral genes, e.g., interferons (IFNs). IFNs further amplify the response by inducing IFN-stimulated genes (ISGs), which specifically inhibit the steps of the viral life cycle. Recently we performed a high throughput screen to isolate novel ISGs against virus replication. Our screen revealed TDRD7, a novel ISG that inhibits virus-induced autophagy to suppress virus replication. It has become increasingly clear that in addition to viral load, virus-induced inflammation is a major determinant of viral pathogenesis. Our studies revealed that IRF3 inhibits viral inflammation by inhibiting NF-kB, the major transcription factor responsible for inflammatory gene induction. We used various cell types to show that IRF3 deficiency caused enhanced NF-kB activation and inflammatory responses. IRF3 deficiency causes susceptibility to viral diseases, and both ISG-inducing and anti-inflammatory functions contribute to the protection. Targeting these pathways may help reveal new therapeutics that can be applied to treat viral infection.
- Audience will learn how innate immune response provides antiviral protection.
- The audience can use the knowledge to enrich their teaching and research.
- Novel therapeutics can be developed in the future.
Chattopadhyay laboratory is interested in studying how the interferon system protects against virus infection. In this context, Dr. Chattopadhyay has been studying how a key transcription factor Interferon Regulatory Factor 3 (IRF3), functions to inhibit viral replication in vitro and in vivo. IRF3, upon activation by virus infection, transcriptionally induces many antiviral genes, such as interferons and interferon-stimulated genes (ISGs). The protein products of these ISGs inhibit specific stages of the viral life cycle, thereby inhibiting virus replication. Because a single ISG cannot inhibit all viruses, it is important to investigate virus-specific ISGs. Using high throughput screening approaches, Dr. Chattopadhyay began to identify new viral restriction mechanisms. In the future, these mechanisms will be tested in vivo using appropriate viral pathogenesis models.
A major accomplishment of Dr. Chattopadhyay’s research has been the discovery of a non-transcriptional pathway of IRF3 to kill the virus-infected cells. IRF3 does not require its transcriptional activity in this pathway, but upon binding with the pro-apoptotic protein BAX, it triggers a direct apoptotic response in the virus-infected cells. Specific protein components are required to trigger this pathway by virus-induced RIG-I activation. This pathway is required for antiviral protection; the absence of this pathway leads to viral persistence. Dr. Chattopadhyay’s recent studies illuminated that ubiquitination of IRF3 triggers the apoptotic pathway. Moreover, in the absence of induced antiviral genes, the apoptotic pathway can protect mice against respiratory viral pathogenesis. Using newly-generated knock-in mice, Dr. Chattopadhyay’s studies demonstrated that the apoptotic function of IRF3 provides antiviral protection in the absence of its transcriptional activity. Because the viruses often shut off the host protein synthesis machinery, it is critical to provide antiviral defense even in the absence of induced antiviral genes.
The ongoing projects in Dr. Chattopadhyay’s laboratory involve the finer details of both the transcriptional and non-transcriptional pathways. Major questions will be how the host selectively uses these pathways in specific cells and protect against viral and non-viral diseases.
Dr. Chattopadhyay received his PhD from the Indian Institute of Technology Delhi and did his postdoctoral fellowship at Cleveland Clinic under Dr. Ganes Sen. He then worked as a Project Staff and Assistant Professor at Cleveland Clinic Lerner College of Medicine. Dr. Chattopadhyay joined the Department of Medical Microbiology and Immunology in April of 2016.