Overview
The host innate immune response is the first line of defense against viral infections. Cytosolic sensors in the host cell recognize the incoming virus and stimulate the production of types I and III interferons (IFNs). The same or neighboring cell binds secreted IFNs and triggers the JAK/STAT signaling pathway resulting in the expression of a wide array of IFN-stimulated genes (ISGs). Many of these ISGs are antiviral effectors that target different steps of the viral life cycle, but only some of them have been characterized. A main focus of the Li Lab is to elucidate the mechanisms of antiviral IFNs and ISGs using molecular biology, biochemistry, genome-wide approaches, and stem cell culture systems. We are studying the host and viral determinants that modulate viral infections in the presence of antiviral ISGs in different cell contexts using arthropod-borne alphaviruses as our model system. Several projects in the lab focus on the mechanism of zinc finger antiviral protein (ZAP), a broad-spectrum antiviral ISG that inhibits a broad range of viruses, and how it synergizes with its co-factor, the host E3 ubiquitin ligase TRIM25.
The host innate immune response is the first line of defense against viral infections. Cytosolic sensors in the host cell recognize the incoming virus and stimulate the production of types I and III interferons (IFNs). The same or neighboring cell binds secreted IFNs and triggers the JAK/STAT signaling pathway resulting in the expression of a wide array of IFN-stimulated genes (ISGs). Many of these ISGs are antiviral effectors that target different steps of the viral life cycle, but only some of them have been characterized. A main focus of the Li Lab is to elucidate the mechanisms of antiviral IFNs and ISGs using molecular biology, biochemistry, genome-wide approaches, and stem cell culture systems. We are studying the host and viral determinants that modulate viral infections in the presence of antiviral ISGs in different cell contexts using arthropod-borne alphaviruses as our model system. Several projects in the lab focus on the mechanism of zinc finger antiviral protein (ZAP), a broad-spectrum antiviral ISG that inhibits a broad range of viruses, and how it synergizes with its co-factor, the host E3 ubiquitin ligase TRIM25.
The requirement for TRIM25 in ZAP antiviral activity
How does TRIM25 facilitate viral inhibition by ZAP? Our recent work has shown that the ligase activity of TRIM25 is critical for its inhibition of diverse alphaviruses through viral translation suppression, highlighting the importance of ubiquitination in mediating ZAP antiviral activity. We also found that TRIM25 ubiquitinates key players in translational and nucleic acid metabolic processes, specifically involving stress granule formation, nonsense-mediated mRNA decay, nucleotide synthesis, and translation initiation. Current projects are centered on elucidating the functional consequences of ubiquitination of these TRIM25 substrates in both cellular and antiviral processes. These studies provide new insights into understanding the biological roles of TRIM25 and paves the way forward for identification of novel TRIM substrates at large.
Some of our publications on this topic:
Yang et al, PLoS Pathog 2022
Yang and Li, Frontiers in Immunology 2020
Li et al, PLoS Pathog 2017
How does TRIM25 facilitate viral inhibition by ZAP? Our recent work has shown that the ligase activity of TRIM25 is critical for its inhibition of diverse alphaviruses through viral translation suppression, highlighting the importance of ubiquitination in mediating ZAP antiviral activity. We also found that TRIM25 ubiquitinates key players in translational and nucleic acid metabolic processes, specifically involving stress granule formation, nonsense-mediated mRNA decay, nucleotide synthesis, and translation initiation. Current projects are centered on elucidating the functional consequences of ubiquitination of these TRIM25 substrates in both cellular and antiviral processes. These studies provide new insights into understanding the biological roles of TRIM25 and paves the way forward for identification of novel TRIM substrates at large.
Some of our publications on this topic:
Yang et al, PLoS Pathog 2022
Yang and Li, Frontiers in Immunology 2020
Li et al, PLoS Pathog 2017
ZAP recognition of alphavirus RNA
What determines the specificity of viral RNA binding by ZAP? Our recent work has shown that mutations specifically targeting ZAP CpG-mediated RNA binding negatively impact the ability of ZAP to block viral translation. Most surprisingly, ZAP RNA binding and interaction with its co-factor TRIM25 are negatively correlated, suggesting that these two might be distinct mechanisms driving ZAP antiviral activity. We also found that alphaviruses exhibit differential susceptibility to ZAP, prompting us to hypothesize that the resistant alphaviruses are able to evade or actively antagonize ZAP recognition. Current projects are centered on characterizing the viral determinants that mediate differential susceptibility to ZAP. These studies provide new insights into non-self RNA recognition by the host IFN system and viral antagonism strategies that can lead to increased virulence.
Some of our publications on this topic:
Nguyen et al, Viruses 2023
Yang and Nguyen et al, Frontiers in Cellular and Infection Microbiology 2022
What determines the specificity of viral RNA binding by ZAP? Our recent work has shown that mutations specifically targeting ZAP CpG-mediated RNA binding negatively impact the ability of ZAP to block viral translation. Most surprisingly, ZAP RNA binding and interaction with its co-factor TRIM25 are negatively correlated, suggesting that these two might be distinct mechanisms driving ZAP antiviral activity. We also found that alphaviruses exhibit differential susceptibility to ZAP, prompting us to hypothesize that the resistant alphaviruses are able to evade or actively antagonize ZAP recognition. Current projects are centered on characterizing the viral determinants that mediate differential susceptibility to ZAP. These studies provide new insights into non-self RNA recognition by the host IFN system and viral antagonism strategies that can lead to increased virulence.
Some of our publications on this topic:
Nguyen et al, Viruses 2023
Yang and Nguyen et al, Frontiers in Cellular and Infection Microbiology 2022
The role of host factors in viral neuroinvasion
What modulates viral neuroinvasion? Many alphaviruses and flaviviruses are neurotropic and can enter the central nervous system to cause neurological diseases. Studies by our group and others have uncovered surprising roles for IFNs (types I and III) and ISGs in preserving blood-brain barrier integrity in mice infected with neurotropic viruses. However, the pro-barrier function of IFNs and their downstream pathways are not well characterized. In addition, using a stem cell derived blood-brain barrier model on a dish, we have recently shown that a neuroinvasive strain of Sindbis virus, the prototype alphavirus, can efficiently infect the brain microvascular endothelial cells while a non-neuroinvasive strain cannot. This supports direct infection of the barrier cells as a potential route of neuroinvasion, although the host processes involved are unclear. Current projects are centered on identifying host factors and processes that modulate viral invasion into the central nervous system. These studies are highly relevant and timely as long-term neurological sequelae following acute viral infections, such as long COVID-19, are more prevalent than we previously thought.
Some of our publications on this topic:
Cheng et al, Cell Reports 2022
Li et al, JEM 2016
What modulates viral neuroinvasion? Many alphaviruses and flaviviruses are neurotropic and can enter the central nervous system to cause neurological diseases. Studies by our group and others have uncovered surprising roles for IFNs (types I and III) and ISGs in preserving blood-brain barrier integrity in mice infected with neurotropic viruses. However, the pro-barrier function of IFNs and their downstream pathways are not well characterized. In addition, using a stem cell derived blood-brain barrier model on a dish, we have recently shown that a neuroinvasive strain of Sindbis virus, the prototype alphavirus, can efficiently infect the brain microvascular endothelial cells while a non-neuroinvasive strain cannot. This supports direct infection of the barrier cells as a potential route of neuroinvasion, although the host processes involved are unclear. Current projects are centered on identifying host factors and processes that modulate viral invasion into the central nervous system. These studies are highly relevant and timely as long-term neurological sequelae following acute viral infections, such as long COVID-19, are more prevalent than we previously thought.
Some of our publications on this topic:
Cheng et al, Cell Reports 2022
Li et al, JEM 2016
Development of novel antiviral therapeutics
Viruses such as SARS-CoV-2 have evolved diverse strategies to co-opt cellular processes and suppress the host innate immune response to further its replication in the host cell. Can we target these cellular processes or viral encoded activities to block infection? We are currently working with other groups in bioengineering and drug discovery to design and test small molecule inhibitors with specific or pan antiviral activity.
Some of our publications on this topic:
Campagna et al, Arch Clin Biomed Res 2022
Viruses such as SARS-CoV-2 have evolved diverse strategies to co-opt cellular processes and suppress the host innate immune response to further its replication in the host cell. Can we target these cellular processes or viral encoded activities to block infection? We are currently working with other groups in bioengineering and drug discovery to design and test small molecule inhibitors with specific or pan antiviral activity.
Some of our publications on this topic:
Campagna et al, Arch Clin Biomed Res 2022
