Towers Lab Favorite Publications
Macrocycle-based PROTACs selectively degrade cyclophilin A and inhibit HIV-1 and HCV
Newton LS, Gathmann C, Ridewood S, Smith RJ, Wijaya AJ, Hornsby TW, Morling KL, Annett D, Chiozzi RZ, Reuschl AK, Govasli ML, Tan YY, Thorne LG, Jolly C, Thalassinos K, Ciulli A, Towers GJ, Selwood DL. (2024) Macrocycle-based PROTACs selectively degrade cyclophilin A and inhibit HIV-1 and HCV. Nature Commun. 16:1484
Developed host targeting antivirals which work by degrading host cofactor Cyclophilin A.
Evolution of Enhanced Innate Immune Suppression by SARS-CoV-2 Omicron Subvariants
Reuschl AK, Thorne LG, Whelan MVX, Ragazzini R, Furnon W, Cowton VM, De Lorenzo G, Mesner D, Turner JLE, Dowgier G, Bogoda N, Bonfanti P, Palmarini M, Patel AH, Jolly C, Towers GJ. (2024) Evolution of enhanced innate immune suppression by SARS-CoV-2 Omicron subvariants. Nat Microbiol.9:451-463.
Surprisingly, early Omicrons were poor innate immune evaders but we discovered the Omicron sub-lineages reproduced enhancement of innate immune evasion by antagonist upregulation similar to previous VOCs.
The HIV Capsid Mimics Karyopherin Engagement of FG-Nucleoporins
Dickson CF, Hertel S, Tuckwell AJ, Li N, Ruan J, Al-Izzi SC, Ariotti N, Sierecki E, Gambin Y, Morris RG, Towers GJ, Böcking T, Jacques DA. (2024) The HIV capsid mimics karyopherin engagement of FG-nucleoporins. Nature.626:836-842
Funded by our Wellcome collaborative award, we showed that intact HIV capsids penetrate NPCs by solubilising in the FG matrix permeability barrier, like a huge karyopherin. Quoting David our senior author, HIV capsid doesnt need a karyopherin, it is a karyopherin!
SARS-CoV-2 Variants Evolve Convergent Strategies to Remodel the Host Response
Bouhaddou_M et al, Jolly_C*, Zuliani-Alvarez_L*, Towers_GJ*, Krogan_NJ*. (2023) SARS-CoV-2 variants evolve convergent strategies to remodel the host response. Cell.186:4597-4614.e26.
Followed Thorne_et_al to show that VOCs Beta, Gamma and Delta behaved like Alpha independently evolving upregulated expression of innate immune antagonists N, Orf9b and Orf6 to increase innate immune evasion and improve transmission frequency.
Evasion of cGAS and TRIM5 Defines Pandemic HIV
Zuliani-Alvarez L, Govasli ML, Rasaiyaah J, Monit C, Perry SO, Sumner RP, McAlpine-Scott S, Dickson C, Rifat Faysal KM, Hilditch L, Miles RJ, Bibollet-Ruche F, Hahn BH, Boecking T, Pinotsis N, James LC, Jacques DA, Towers GJ. ( 2022) Evasion of cGAS and TRIM5 defines pandemic HIV. Nat Microbiol.7:1762-1776
Demonstrates how pandemic HIV has uniquely evolved its capsid to avoid TRIM5 and protect its genome from cGAS and TREX1. Structural and evolutionary studies identified specific adaptations and suggested that increasing capsid dynamics permits more exquisite regulation of the timing and location of genome release by cofactors. Thus the pandemic HIV is the best transmitter by best avoiding innate immune activation.
Evolution of Enhanced Innate Immune Evasion by SARS-CoV-2
Thorne_LG et al, Jolly_C*, Towers_GJ*, Krogan_NJ*.(2022) Evolution of enhanced innate immune evasion by SARS-CoV-2. Nature.602:487-495
Demonstrated that the SARS-CoV-2 Alpha evolved to enhance antagonism of human innate immunity by up-regulating the expression of specific innate immune antagonists nucleocapsid, Orf9b and Orf6.
SARS-CoV-2 Sensing by RIG-1 and MDA5 Links Epithelial Infection to Macrophage Inflamation
Thorne_LG, Reuschl_AK, Zuliani-Alvarez_L, Whelan_MVX, Turner_J, Noursadeghi_M, Jolly_C, Towers_GJ.(2021) SARS-CoV-2 sensing by RIG-I and MDA5 links epithelial infection to macrophage inflammation. EMBO_J.40(15):e107826.
At the 1st pandemic UK Microbiology society meeting in June 2020 we were the first lab to have established SARS-CoV-2 replication assays which we used to demonstrate that the cytokines driving disease were downstream of viral RNA sensing and could be produced by infected cells.
HIV-1 uses Dynamic Capsid Pores to Import Nucleotides and Fuel Encapsidated DNA Synthesis
Jacques_DA, McEwan_WA, Hilditch_L, Price_AJ, Towers_GJ, James-LC.(2016) HIV-1 uses dynamic capsid pores to import nucleotides and fuel encapsidated DNA synthesis. Nature.536:349-353
We discovered that HIV capsids form electrostatic channels that transport nucleotides to fuel encapsidated DNA synthesis allowing protection of viral genome from nucleases and DNA sensors. Transformed our understanding of capsid function reiterating the importance of genome protection from innate immunity.
HIV-1 Evades Innate Immune Recognition Through Specific Co-Factor Recruitment
Rasaiyaah J, Tan CP, Fletcher AJ, Price AJ, Blondeau C, Hilditch L, Jacques DA, Selwood DL, James LC, Noursadeghi M, Towers GJ. (2013) HIV-1 evades innate immune recognition through specific co-factor recruitment. Nature.503:402-5
Demonstrated that HIV-1 host cofactors CypA/CPSF6 facilitate innate immune evasion explaining why they are redundant in cell culture, because innate immunity is ineffective. This study transformed our approach to infection experiments, popularised the use of primary macrophages for molecular studies and underlined importance of innate immune evasion for HIV replication.
HIV-1 Capsid-Cyclophilin Interactions Determine Nuclear Import Pathway, Integration Targeting and Replication Efficiency
Schaller T, Ocwieja KE, Rasaiyaah J, Price AJ, Brady TL, Roth SL, Hué S, Fletcher AJ, Lee K, KewalRamani VN, Noursadeghi M, Jenner RG, James LC, Bushman FD, Towers GJ. (2011) HIV-1 Capsid-Cyclophilin Interactions Determine Nuclear Import Pathway, Integration Targeting and Replication Efficiency. PLoS Pathogens.7:e1002439
We demonstrated interaction between HIV capsid and the nuclear pore and how CPSF6/Cyclophilins influence downstream nuclear pore associated cofactor use. Challenged the dogma of cytoplasmic uncoating. Showing how cofactors influence integration targeting rather than infection efficiency, paved the way for Rasaiyaah above.