Michaela Gack Laboratory

Research

Lab Culture

The Gack Lab, July 2023

The Gack Lab is dedicated to creating a culture of belonging in which people of all backgrounds can thrive in their scientific career and as individuals. We are deeply committed to training the next generation of scientists. In fact, a number of former trainees of the Gack Lab hold faculty positions at prestigious academic institutions, or they have obtained highly desired positions in industry. Another key principle of the Gack Lab culture is intellectual ownership and creative, open discussion of new ideas to advance next-generation approaches for combating infectious diseases and immune-related disorders. 

Overview of Our Research

Our lab has three long term research goals: 

1. Defining the mechanisms by which viral pathogens and immunostimulatory RNA are detected in the host organism to induce innate immune defense responses.  
2. Identifying the strategies employed by viral pathogens (respiratory viruses such as SARS-CoV-2 and influenza, mosquito-transmitted flaviviruses, and certain tumor viruses) to escape cell-intrinsic immune responses.  
3. Identifying and functionally characterizing novel host factors that play important roles in regulating the virus lifecycle.   

We take an integrative approach to addressing these important questions in virology and immunology by complementing gene-targeting and proteomics screens; biochemical, molecular and cell biological techniques; and the ability to generate recombinant viruses using reverse genetics systems.   

This powerful combination of techniques and expertise allows us to examine and unravel the precise mechanisms behind innate immune activation and viral antagonism. A better understanding of how viruses dysregulate the immune system not only provides us with important insights into how the immune system works but also points to possibilities for manipulating immune responses for the development of therapies. This knowledge could also translate into the ability to boost our immune system in a way that is broadly applicable to a wide range of viral pathogens. 

Research Area #1: Innate Immunity and Viral Antagonism

The early detection of viral pathogens by the host depends on a defined repertoire of innate immune receptors that sense nucleic acids or other viral patterns and then activate signaling cascades that result in cytokine-mediated host defense mechanisms. RIG-I and MDA5, members of the RIG-I-like receptor (RLR) family, are key innate immune sensors essential for the detection of a number of clinically relevant viruses including influenza, dengue, Zika and coronaviruses. Furthermore, key molecules in innate immune signaling pathways have repeatedly been shown to be major targets of viral antagonism.  

The Gack Lab has spearheaded the efforts to define the molecular mechanisms of RLR activation through posttranslational modifications. We continue to study the mechanisms by which viruses antagonize or escape innate immunity, which we expect will provide the molecular basis for developing new antivirals and vaccines.  

More recently, we have started to investigate the role of host-derived immunostimulatory RNAs in innate immune activation. While research efforts towards defining the features of viral RNAs required for innate immune activation have been extensive, we are examining the characteristics of cellular immunostimulatory RNAs.  

Lastly, we are also interested in understanding at a molecular level how virus-induced cytoskeleton disturbance triggers antiviral innate immune defenses. 

Research Area #2: TRIM Proteins in Antiviral Defenses

Recent work has demonstrated that the tripartite motif (TRIM) protein family is an important class of molecules in antiviral immunity. More than 70 TRIM proteins exist in humans, and they all share a common domain structure, composed of a RING domain that confers ubiquitin E3 ligase activity, one or two B-boxes, and a coiled-coil domain. Previous work has shown that several TRIM proteins act as antiviral restriction factors either by interacting with specific viral components or through silencing of viral gene expression. Work from our own lab and other groups demonstrated that TRIM proteins can promote innate immune signaling and antiviral cytokine induction, thereby blocking virus replication. Despite the wealth of information about the role of TRIM proteins in direct virus restriction and modulation of cytokine signaling, our knowledge about the role of TRIM proteins in other antiviral defense pathways is still rudimentary. 

Autophagy is a cellular pathway that mediates lysosome-dependent degradation of cytosolic proteins and organelles, and it plays an important role in many biological processes including development and neurodegeneration. More recently, autophagy has also been recognized as an important antimicrobial defense mechanism, whereby intracellular pathogens such as viruses, bacteria and protozoa are trapped within an autophagosome and targeted to the lysosome for destruction.  

The Gack lab is investigating the molecular mechanisms by which TRIM proteins dually regulate autophagy and cytokine responses to effectively block virus infection and limit viral disease. Molecular insight into the mechanisms by which autophagy controls viral infection may catalyze the design of broad-spectrum antiviral agents. 

Research Area #3: Host Modifying Enzymes Regulating Virus Replication

Over the past several decades, the traditional approach to combating viral infectious diseases has been to target the virus itself, in most cases by either blocking virus-encoded enzymes (e.g. proteases, RNA or DNA polymerases) that are required for viral replication, or by preventing the virus from entering host cells. One of the major caveats of these approaches has been the ability of the virus to readily mutate and thereby become resistant to these classical types of antiviral therapies. Moreover, traditional antiviral approaches are designed to target a specific virus, and therefore are ineffective against any new virus that may emerge in the future, and it is impossible to predict what virus will cause the next outbreak or pandemic. Therefore, there is an urgent need to develop new ways for targeting viral pathogens, which will require creative and innovative research.  

The Gack Lab is identifying and characterizing human modifying enzymes (e.g. kinases, acetyltransferases, ubiquitin E3 ligases) that mediate critical posttranslational modifications (PTMs) in viral proteins, thereby regulating their functions in the viral lifecycle. These host enzymes are promising molecular targets for therapy development against a variety of viruses. We are comprehensively mapping the ‘viral PTMome’ to identify the PTMs that are essential for viral replication and pathogenesis, and are also identifying the responsible host modifying enzymes (‘PTMases’).  

This powerful approach, combined with collaborative studies aimed at designing and testing chemical inhibitors to block the enzymes that regulate critical viral PTMs, is expected to provide unique mechanistic insight into host control of virus replication, and may also lay the groundwork for developing new antivirals for a range of emerging viral infectious diseases. 

Selected Publications

View publications for Michaela Gack, PhD
(Disclaimer: This search is powered by PubMed, a service of the U.S. National Library of Medicine. PubMed is a third-party website with no affiliation with Cleveland Clinic.)

• Serman, T., Chiang, C., Liu, G., Sayyad, Z., Pandey, S., Volcic, M., Lee, H., Muppala, S., Acharya, D., Goins, C., Stauffer, S.R., Sparrer, K.M.J., and Gack, M.U. (2023). Acetylation of the NS3 helicase by KAT5-gamma is essential for flavivirus replication. Cell Host Microbe, 2023 Jul 14; S1931-3128(23)00264-0. doi: 10.1016/j.chom.2023.06.013
  
  
• Zhu, J., Chiang, C., Gack, M.U. Viral evasion of the interferon response at a glance. Journal of Cell Science 2023 Jun 15;136(12):jcs260682. doi: 10.1242/jcs.260682.  
  
  
• Khan, D., Terenzi, F., Liu, G., Ghosh, P.K., Ye, F., Nguyen, K., China, A., Ramachandiran, I., Chakraborty, S., Stefan, J., Khan, K., Vasu, K., Dong, F., Willard, B., Karn, J., Gack, M.U., Fox, P.L. A viral pan-end RNA element and host complex define a SARS-CoV-2 regulon. Nature Communications 2023 Jun 9;14(1):3385. doi: 10.1038/s41467-023-39091-3
  
  
• Naesens, L., Haerynck, F., Gack. M.U. The RNA polymerase III-RIG-I axis in antiviral immunity and inflammation. Trends in Immunology 2023 Jun;44(6):435-449. doi: 10.1016/j.it.2023.04.002.  
  
  
• Chen, D.Y., Chin, C.V., Kenney, D., Tavares, A.H., Khan, N., Conway, H.L., Liu, G., Choudhary, M.C., Gertje H.P., O'Connell AK, Adams S, Kotton DN, Herrmann A, Ensser A, Connor, J.H., Bosmann, M., Li, J.Z., Gack, M.U., Baker, S.C., Kirchdoerfer, R.N., Kataria, Y., Crossland, N.A., Douam, F., Saeed, M. Spike and nsp6 are key determinants of SARS-CoV-2 Omicron BA.1 attenuation. Nature 2023 Mar;615(7950):143-150. doi: 10.1038/s41586-023-05697-2.  
  
  
• Naesens, L., Muppala, S., Acharya, D., Nemegeer, J., Bogaert, D., Lee, J.H., Staes, K., Debacker, V., De Bleser, P., De Bruyne, M., De Baere, E., van Gent, M., Liu, G., Lambrecht, B.N., Staal, J., Kerre, T., Beyaert, R., Maelfait, J., Tavernier, S.J., Gack, M.U.*, Haerynck, F.*. GTF3A mutations predispose to herpes simplex encephalitis by disrupting biogenesis of the host-derived RIG-I ligand RNA5SP141. Science Immunology 2022 Nov 25;7(77):eabq4531. doi: 10.1126/sciimmunol.abq4531.                                *co-corresponding authors 
  
  
• Acharya, D., Reis, R., Volcic, M., Liu, G., Wang, M.K., Chia, B.S., Nchioua, R., Groß, R., Münch, J,, Kirchhoff, F., Sparrer, K.M.J.*, Gack, M.U.* Actin cytoskeleton remodeling primes RIG-I-like receptor activation. Cell 2022 Sep 15;185(19):3588-3602.e21. doi: 10.1016/j.cell.2022.08.011. 
  
  
• Liu, G., Gack, M.U. Insights into pandemic respiratory viruses: manipulation of the antiviral interferon response by SARS-CoV-2 and influenza A virus. Current Opinion in Immunology 2022 Oct;78:102252. doi: 10.1016/j.coi.2022.102252. 
  
  
• van Gent, M., Reich, A., Velu, S.E., and Gack, M.U. (2021) Nonsense-mediated decay controls the reactivation of the oncogenic herpesviruses EBV and KSHV. PLoS Biology 2021 Feb 17;19(2):e3001097. 
  
  
• Liu, G., Lee, J.H., Parker, Z.M., Acharya, D., Chiang, J.J., van Gent, M., Riedl, W., Davis-Gardner, M.E., Wies, E., Chiang, C., and Gack, M.U. (2021). ISG15-dependent activation of the sensor MDA5 is antagonized by the SARS-CoV-2 papain-like protease to evade host innate immunity. Nature Microbiology 2021 Mar 16. doi: 10.1038/s41564-021-00884-1. 
  
  
• Liu, G. & Gack, M.U. (2020). Distinct and orchestrated functions of RNA sensors in innate immunity. Immunity 52, July 14, 2020 
  
  
• Rehwinkel, J. & Gack, M.U. RIG-I-like receptors: their regulation and roles in RNA sensing. Nature Reviews Immunology 2020 Sep;20(9):537-551. doi: 10.1038/s41577-020-0288-3. 
  
  
• Acharya, D., Liu, G. and Gack, M.U. (2020). Dysregulation of type I interferon responses in COVID-19. Nature Reviews Immunology 2020 Jul;20(7):397-398.