Understanding host-virus interactions is an essential step in developing safe and effective antimicrobials against existing and newly emerging pathogens. The early detection of invading viruses by the host depends on a limited number of specific receptors that detect viral patterns and activate signaling cascades, thereby triggering interferon (IFN)-mediated antiviral defense mechanisms. Intracellular innate immune receptors, such as RIG-I-like receptors (RLRs) and the intracellular viral DNA sensors cGAS and IFI16, detect a variety of RNA and DNA viruses including influenza virus, measles virus, dengue virus and herpesviruses. In addition, members of the tripartite motif (TRIM) protein family play a major role in the antiviral host response.
Research in the Gack laboratory seeks a better understanding of the cell-intrinsic mechanisms underlying the host innate immune response against viral infections. Another area of our research focuses on the detailed mechanisms by which viral pathogens – influenza viruses, measles virus, dengue virus and herpesviruses – suppress the innate immune system. The Gack laboratory uses an integrative approach that combines RNAi screens and proteomics with molecular, biochemical, and cell-biological approaches as well as viral infection studies including reverse genetics systems for the generation of recombinant mutant viruses.
I) Host regulation of antiviral innate immunity
Tight regulation of innate immune recognition and signaling is essential for an effective antiviral response. Whereas positive regulatory mechanisms are required for the rapid activation of the innate immune response upon viral infection, multiple negative regulatory checkpoints must be in place to prevent excessive production of antiviral and proinflammatory cytokines. Our previous work demonstrated that the interconnection between the cytosolic viral RNA receptor RIG-I and a member of the TRIM protein family, TRIM25, represents a novel class of regulatory pathway that triggers the induction of IFN-mediated host innate immunity against a wide variety of RNA viruses. Current studies are focused on identifying and characterizing novel regulatory molecules in antiviral and proinflammatory host responses. Here, our focus is not only on the RLR pathway but also on other important viral sensing pathways. We anticipate that our studies will provide fundamental insights into the mechanisms of how the innate immune system discriminates between ‘self’ and ‘non-self’, which may have important implications for various infectious and autoimmune diseases.
II) Evasion of host innate immunity by viral pathogens
Among the virus-host interactions that modulate pathogenesis, virus-mediated induction and inhibition of the innate immune response play a critical role. The Gack laboratory uses a variety of biochemical, cell-biological and proteomic approaches to unravel the detailed mechanisms by which viral pathogens escape antiviral innate immunity. Furthermore we have established reverse genetics systems to generate mutant recombinant viruses to determine the physiological relevance of newly identified virus-host interactions for viral pathogenesis in vitro and in vivo. Our previous studies revealed that the non-structural protein 1 (NS1) of human, swine and avian influenza A viruses inhibits the activity of TRIM25, suppressing the K63-linked ubiquitination of RIG-I and thereby antiviral IFN production. These findings unveiled a novel immune evasion mechanism of influenza A viruses and also emphasized the vital role of TRIM25 in modulating viral infections. While our previous work primarily focused on influenza A virus, we are now also interested in understanding how paramyxoviruses, dengue virus, and JC virus manipulate the host antiviral response for their efficient replication.
III) The role of TRIM proteins in antiviral defense
Over the past several years, it has become evident that the TRIM protein family represents a novel class of antiviral molecules involved in innate immunity. To date, more than 80 genes encoding TRIM proteins have been identified in the human genome; however, among the large number of identified TRIM proteins, only a few have been well characterized. Research in the Gack laboratory focuses on identifying and characterizing novel TRIM proteins that play important roles in innate immune responses to viral infections. Furthermore, we are determining the molecular mechanisms of antiviral TRIM proteins, and are also investigating how viral pathogens antagonize the antiviral activities of specific TRIM molecules.