The central aim of Dr Michael Gantier’s research is to define how nucleic acids (DNA and RNA) modulate immune responses. Following on his PhD studies on RNA interference in Dublin (Ireland), he joined the laboratory of Prof Bryan Williams in 2006, to define the interaction of small RNAs with the innate immune system. This led to the discovery of structural determinants of RNAs which underlie their capacity to activate, or inhibit immune responses, resulting in the rational design of molecules with potential therapeutic application in cancer and autoinflammatory diseases. More recently, his laboratory discovered how immune responses could be engaged in damaged cells, with implications in infection, immunity and cancer.
In addition, Dr Gantier made important findings regarding how a class of endogenous small RNAs, known as microRNAs, persist in cells to regulate inflammation. This has led to the identification of microRNA sequence variations, which control microRNA stability and could be used as novel disease biomarkers (for instance helping identifying deleterious BRCA1 mutations in breast cancer).
In 2015, following the award of an ARC Future Fellowship and several NHMRC project grants, he was promoted to lead his own research group in the Hudson Institute of Medical Research.
Pépin G, Nejad C, Thomas BJ, Ferrand J, McArthur K, Bardin PG, Williams BR, Gantier MP (2016) Activation of cGAS-dependent antiviral responses by DNA intercalating agents. Nucleic Acids Res pii: gkw878. [Epub ahead of print] PubMed PMID: 27694309.
Pépin G, Ferrand J, Höning K, Jayasekara WS, Cain JE, Behlke MA, Gough DJ, G Williams BR, Hornung V, Gantier MP (2016) Cre-dependent DNA recombination activates a STING-dependent innate immune response. Nucleic Acids Res 44(11):5356-64. doi: 10.1093/nar/gkw405. PubMed PMID: 27166376; PubMed Central PMCID: PMC4914124.
Sarvestani ST, Stunden HJ, Behlke MA, Forster SC, McCoy CE, Tate MD, Ferrand J, Lennox KA, Latz E, Williams BR, Gantier MP (2015) Sequence-dependent off-target inhibition of TLR7/8 sensing by synthetic microRNA inhibitors. Nucleic Acids Res 43:1177-1188.
This work represents the first demonstration that microRNA inhibitors to be used in the clinic can have detrimental effects on the innate immune system.
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 BR, Gantier MP (2014) Inosine-mediated modulation of RNA sensing by Toll-like receptor 7 (TLR7) and TLR8. J Virol 88:799-810.
This work represents the first demonstration that inosine incorporation into viral RNA can potentiate the innate immune sensing of infected cells by phagocytes’ TLR7/8.
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 19:876-888.
This work identified a novel normalization procedure for the use of miRNA microarrays of cancer samples.
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 40:8048-8058.
This work identified a network of miR-19 targets controlling NF-kappaB-driven inflammation.
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 39:5692-5703.
This work represents the first global analysis of miRNA turnover in mammalian cells. It is in the top 1% of its field based on citations and publication year.
Gantier MP, Irving AT, Kaparakis-Liaskos M, Xu D, Evans VA, Cameron PU, Bourne JA, Ferrero RL, John M, Behlke MA, Williams BR (2010) Genetic modulation of TLR8 response following bacterial phagocytosis. Hum Mutat 31:1069-1079.
This is the first demonstration of a direct role for TLR8 in bacterial sensing and establishes an important genetic modulation of TLR8 function.
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 18:785-795.
This work characterises a microRNA modification amenable to any siRNA, allowing for increased activation of TLR7/8 and antiviral effects.
Gantier MP, Williams BR (2009) siRNA delivery not Toll-free. Nat Biotechnol 27:911-912.
Scientific commentary on a novel strategy to deliver siRNAs.
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 180:2117-2124.
This work was first to demonstrate that TLR7 and TLR8 sense distinct RNA motifs, and that TLR7 plays a role in RNA recognition in macrophages.
Gantier MP, Williams BR (2007) The response of mammalian cells to double-stranded RNA. Cytokine Growth Factor Rev 18:363-371.
This review links the fields of RNA interference and innate immunity around their common substrate: double-stranded RNA.
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.