Lab focus: nucleic acids in immune responses

Most people will know about DNA, and perhaps a little about RNA. DNA and RNA constitute a class of molecules referred to as nucleic acids, which are essential to all forms of life known to date. They contain and access the genetic information that controls which cells do what in our bodies. Critically, because they are present in every form of life including bacteria and viruses, they are also essential for our immune system to detect infections.

Nucleic acids are the root cause of toxic inflammation in chronic diseases like lupus, or acute sepsis. Understanding how this operates is essential to identify potential drugs targeting inflammation driven by nucleic acids, aiming at providing novel therapeutic avenues to treat these diseases.

With several new nucleic acids-based therapies now approved for use in humans and to be widely rolled out in populations (as with inclisiran), understanding how synthetic nucleic acids can influence normal immune responses is important. This can also present new strategies to treat tumours, where immune responses are altered.

Finally, nucleic acids circulating in the blood present many advantages for disease detection and prognosis.

Our group has made significant findings relevant to these themes – for instance describing how acriflavine, a century old antiseptic that binds DNA, can also induce immune responses protective against viruses.

Current research projects

• In line with our findings on acriflavine, we are now working to understand how cellular damage recruits immune responses and how nucleic acids are involved. We are investigating the development of molecules that can be quickly repurposed as anti-inflammatory drugs to prevent chronic inflammation and sepsis (for instance to be used in the context of COVID-19 infections).
• Relying on more than 10 years’ expertise in synthetic nucleic acids, we are also studying how such synthetic molecules could be designed to modulate immune responses, in cancer and auto-immune diseases.
• Finally, we are also working to define the role of microRNAs in the regulation of infection and immunity. We have a specific focus on mechanisms regulating microRNA stability, and how this knowledge can be used to create novel biomarkers of auto-inflammation and cancer.

If you are looking for a great workplace to carry out an honours, PhD or Masters project, please contact us to see how our lab could help you make a lasting impact in your next scientific endeavour.

e: michael.gantier@hudson.org.au

Research Group

• Dr Samantha Jayasekara, Research Support Staff
• Sumaiah Al-Asmari, PhD Student
• Arwaf Alharbi, PhD Student
• Alexandra McAllan, PhD Student
• Refaya Rezwan, PhD Student
• Tomalika Ullah, PhD Student
• Rayann Andrade, Honours Student
• Erandi Rupasinghe, Honours Student

Selected publications

• Valentin R, Wong C, Alharbi AS, Pradeloux S, Morros MP, Lennox KA, Ellyard JI, Garcin AJ, Ullah TR, Kusuma GD, Pépin G, Li HM, Pearson JS, Ferrand J, Lim R, Veedu RN, Morand EF, Vinuesa CG, Behlke MA, Gantier MP. Sequence-dependent inhibition of cGAS and TLR9 DNA sensing by 2′-O-methyl gapmer oligonucleotides. Nucleic Acids Res. 2021 Jun 21;49(11):6082-6099. doi: 10.1093/nar/gkab451. PMID: 34057477

• Alharbi AS, Garcin AJ, Lennox KA, Pradeloux S, Wong C, Straub S, Valentin R, Pépin G, Li HM, Nold MF, Nold-Petry CA, Behlke MA, Gantier MP. Rational design of antisense oligonucleotides modulating the activity of TLR7/8 agonists. Nucleic Acids Res. 2020 Jul 27;48(13):7052-7065. doi: 10.1093/nar/gkaa523. PMID: 32544249

• Pépin G, De Nardo D, Rootes CL, Ullah TR, Al-Asmari SS, Balka KR, Li HM, Quinn KM, Moghaddas F, Chappaz S, Kile BT, Morand EF, Masters SL, Stewart CR, Williams BRG, Gantier MP (2020) Connexin-Dependent Transfer of cGAMP to Phagocytes Modulates Antiviral Responses. mBio. 2020 Jan 28;11(1):e03187-19. doi: 10.1128/mBio.03187-19. PMID: 31992625; PMCID: PMC6989113.

• Pillman KA, Goodall GJ, Bracken CP, Gantier MP (2019) miRNA length variation during macrophage stimulation confounds the interpretation of results: implications for miRNA quantification by RT-qPCR. RNA. 2019 Feb;25(2):232-238. doi: 10.1261/rna.069047.118. Epub 2018 Nov 28. PMID: 30487268; PMCID: PMC6348984.

• Ferrand J, Croft NP, Pépin G, Diener KR, Wu D, Mangan NE, Pedersen J, Behlke MA, Hayball JD, Purcell AW, Ferrero RL, Gantier MP (2018) The Use of CRISPR/Cas9 Gene Editing to Confirm Congenic Contaminations in Host-Pathogen Interaction Studies. Front Cell Infect Microbiol. 2018 Mar 19;8:87. doi: 10.3389/fcimb.2018.00087. PMID: 29616197; PMCID: PMC5867302.

• Pepin G, Nejad C, Thomas BJ, Ferrand J, McArthur K, Bardin PG, Williams BR, Gantier MP (2017) Activation of cGAS-dependent antiviral responses by DNA intercalating agents. Nucleic Acids Res 45:198-205.

• Pepin G, Ferrand J, Honing K, Jayasekara WS, Cain JE, Behlke MA, Gough DJ, Williams BRG, Hornung V, Gantier MP (2016) Cre-dependent DNA recombination activates a STING-dependent innate immune response. Nucleic Acids Res 44:5356-5364.

• Sarvestani ST, Stunden HJ, Behlke MA, Forster SC, McCoy CE, Tate MD, Ferrand J, Lennox KA, Latz E, Williams BRG, Gantier MP (2015) Sequence-dependent off-target inhibition of TLR7/8 sensing by synthetic microRNA inhibitors. Nucleic Acids Res 43(2):1177-1188.

• Sarvestani ST, Tate MD, Moffat JM, Jacobi AM, Behlke MA, Miller AR, Beckham SA, McCoy CE, Chen W, Mintern JD, O’Keeffe M, John M, Williams BRG, Gantier MP (2014) Inosine-Mediated Modulation of RNA Sensing by TLR7/8. J Virol 88(2):799-810.

• Wu D, Hu Y, Tong S, Williams BR, Smyth GK, Gantier MP (2013) The use of miRNA microarrays for the analysis of cancer samples with global miRNA decrease. RNA 19:876-88.

• Gantier MP, Stunden HJ, McCoy CE, Behlke MA, Wang D, Kaparakis-Liaskos M, Sarvestani ST, Yang YH, Xu D, Corr SC, Morand EF, Williams BR (2012) A miR-19 regulon that controls NF-kappaB signaling. Nucleic Acids Res 40:8048-58.

• Gantier MP, McCoy CE, Rusinova I, Saulep D, Wang D, Xu D, Irving AT, Behlke MA, Hertzog PJ, Mackay F, Williams BR (2011) Analysis of microRNA turnover in mammalian cells following Dicer1 ablation. Nucleic Acids Res 39:5692-703.

• Gantier MP, Tong S, Behlke MA, Irving AT, Lappas M, Nilsson UW, Latz E, McMillan NA, Williams BR (2010) Rational design of immunostimulatory siRNAs. Mol Ther 18:785-95.

• Gantier MP, Irving AT, Kaparakis-Liaskos M, Xu D, Evans WA, Cameron PU, Bourne JA, Ferrero RL, John M, Behlke MA, Williams BR (2010) Genetic modulation of TLR8 response following bacterial phagocytosis. Human Mutation 31:1069-79.

• Gantier MP, Tong S, Behlke MA, Xu D, Phipps S, Foster PS, Williams BR (2008) TLR7 is involved in sequence-specific sensing of single-stranded RNAs in human macrophages. J Immunol 180:2117-24.

• Pépin G, Nejad C, Ferrand J, Thomas BJ, Stunden HJ, Sanij E, Foo CH, Stewart CR, Cain JE, Bardin PG, Williams BRG, Gantier MP (2017) Topoisomerase 1 Inhibition Promotes Cyclic GMP-AMP Synthase-Dependent Antiviral Responses. MBio 8(5):e01611-17

• Nejad C, Pillman KA, Siddle KJ, Pepin G, Änkö ML, McCoy CE, Beilharz T, Quintana-Murci L, Goodall GJ, Bracken CP, Gantier MP (2017) miR-222 isoforms are differentially regulated by type-I interferon. RNA pii: rna.064550.117. doi: 10.1261/rna.064550.117.