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We study one of the newest family of antiviral cytokines called interferon-lambdas (λs) - but they are more than antivirals!
We study one of the newest family of antiviral cytokines called interferon-lambdas (λs) - but they are more than antivirals!
IFN-lambdas (type III IFNs) have been studied especially for their antiviral action at barrier sites including the liver, gut, lung, placenta, blood-brain barrier, and skin. Type III IFNs are unique in that their specific receptor (IFN-LR1/IL-10RB) has limited distribution, and they have been shown to be induced first without inducing inflammation that is seen with type I IFNs. In mouse models of colitis and allergic asthma, IFN-lambda treatment even significantly dampens inflammation. Our work points to major differences in immune cell responsiveness where many more human immune cell types respond to IFN-lambdas compared to what has been found in mice, and primates encode a soluble version of IFN-LR1 that inhibits IFN-lambda responses (Santer et al. PLOS Pathogens 2020). We are currently focused on identifying how direct interactions of IFN-lambdas with human immune cells induce downstream immunoregulatory pathways. This includes studying fundamental IFN-lambda biology in various cell types and IFN-lambda pathways in inflammatory bowel disease (IBD) patients. We recently published our characterization of the first monoclonal antibody to properly quantify IFN-LR1 levels by flow cytometry (de Weerd et al. JICR 2023), which was awarded a Rosalind Franklin Society Special Award in Science (best paper of the year by a woman or underrepresented minority for the Journal of Interferon and Cytokine Research).
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IFN-λ1 as a COVID-19 therapeutic
IFN-λ1 as a COVID-19 therapeutic
Through our CIHR operating grant-funded collaboration with Dr. Lorne Tyrrell (UAlberta), Dr. Jordan Feld (UHN) and Dr. Adam Gehring (UHN), we have studied how pegylated-IFN-lambda1 treatment of COVID-19 patients (Phase II trial, Lancet Respiratory Medicine) potentially changes peripheral immune cell responses. We published our adaptive immune response data in Nature Communications (link). Targeting the virus as early as possible with IFNs is key, since lower IFN production or IFN autoantibodies are associated with more severe COVID-19 (reviewed here). The TOGETHER Phase III trial was published (link) demonstrating one injection of IFN-lambda1 significantly decreased ER visits and hospitalization compared to placebo, even in a predominantly vaccinated population and with newer virus variants.
IFN-λs regulating immunity in a healthy versus inflamed human gut (ulcerative colitis)
IFN-λs regulating immunity in a healthy versus inflamed human gut (ulcerative colitis)
Funded by Crohn's and Colitis Canada, CIHR and New Frontiers Research Fund- Exploration grant programs, we are aiming to understand how IFN-lambdas uniquely regulate adult and pediatric gut immune responses during homeostasis or during inflammation, such as in ulcerative colitis. This includes identifying if IFN-lambdas could be a future therapeutic target to promote gut health. We collaborate with various clinicians to obtain primary human tissue and blood samples and collaborate with Dr. Simon Hirota (UCalgary) and the Canadian National Organoid Network to expand our knowledge of IFN-lambda biology in humans with the majority of work to date completed in mouse models.
Great type III IFN review articles
Vu V, Mahmood R, Armstrong HK*, Santer DM*. 2024. Crosstalk Between Microbiota, Microbial Metabolites, and Interferons in the Inflammatory Bowel Disease Gut. *co-corresponding authors. Journal of the Canadian Association of Gastroenterology, gwad044, https://doi.org/10.1093/jcag/gwad044
de Weerd NA, Ogungbola O, Liu X, Matthews AY, Ismail A, Vivian JP, Lim SS, Tyrrell DL, Putcha N, Skawinski M, Dickensheets H, Lavoie TB, Donnelly RP, Hertzog PJ, Santer DM. 2023. Characterization of Monoclonal Antibodies to Measure Cell Surface Protein Levels of Human Interferon-Lambda Receptor 1. J Interferon Cytokine Res. 43(9): 403-413. (Rosalind Franklin Society Award)
Armstrong HK, Bording-Jorgensen M, Santer DM, Zhang Z, Valcheva R, Rieger AM, Sung-Ho Kim J, Dijk SI, Mahmood R, Ogungbola O, Jovel J, Moreau F, Gorman H, Dickner R, Jerasi J, Mander IK, Lafleur D, Cheng C, Petrova A, Jeanson TL, Mason A, Sergi CM, Levine A, Chadee K, Armstrong D, Rauscher S, Bernstein CN, Carroll MW, Huynh HQ, Walter J, Madsen KL, Dieleman LA, Wine E. 2023. Unfermented β-fructan fibers fuel inflammation in select inflammatory bowel disease patients. Gastroenterology. 164(2): 228-240.
Santer DM*, Li D*, Ghosheh Y, Zahoor MA, Prajapati D, Hansen BE, Tyrrell DL, Feld JJ, Gehring AJ. 2022. IFN-λ treatment accelerates SARS-CoV-2 clearance despite age-related delays in the induction of T cell immunity. Nat Commun. 13(1): 6992. *co-first authors.
Boulant S, Forero A, Santer DM, Broggi A. 2022. Editorial: Type III interferons: Emerging roles beyond antiviral barrier defense. Front Immunol. 13:1030812.
Dunsmore G, Perez Rosero E, Shahbaz S, Santer DM, Jovel J, Lacy P, Houston S and Elahi S. 2021. Neutrophils promote T cell activation in HIV-infection through the regulated release of CD44 bound cell surface Galectin-9. PLOS Biology. 19(8): e3001387.
Feld JJ, Kandel C, Biondi MJ, Kozak RA, Zahoor MA, Lemieux C, Borgia SM, Boggild AK, Powis J, McCready J, Tan DHS, Chan T, Coburn B, Kumar D, Humar A, Chan A, O’Neil B, Noureldin S, Booth J, Hong R, Smookler D, Aleyadeh W, Patel A, Barber B, Casey J, Hiebert R, Mistry H, Choong I, Hislop C, Santer DM, Tyrrell DL, Glenn JS, Gehring AJ, Janssen HLA, Hansen B. 2021. Peginterferon-lambda for the treatment of COVID-19 in outpatients. Lancet Resp. Med. 9 (5): 498-510.
Onabajo OO, Banday AR, Stanifer ML, Yan W, Obajemu A, Santer DM, Florez-Vargas O, Piontkivska H, Vargas JM, Ring TJ, Kee C, Doldan P, Tyrrell DL, Mendoza JL, Boulant S, Prokunina-Olsson L. 2020. Interferons and viruses induce a novel truncated ACE2 isoform and not the full-length SARS-CoV-2 receptor. Nat Genet. 52(12):1283-1293.
Santer DM, Minty GES, Golec D, Lu J, May J, Namdar A, Shah J, Elahi S, Proud D, Joyce M, Tyrrell DLJ, Houghton M. 2020. Differential expression of IFN-lambda receptor 1 splice variants determines the magnitude of the antiviral response induced by IFN-lambda 3 in human immune cells. PLoS Pathog. 16(4):e1008515. (co-corresponding author); Recommended as a significant paper by Faculty Opinions
Prokunina-Olsson L, Alphonse N, Dickenson RE, Durbin JE, Glenn JS, Hartmann R, Kotenko SV, Lazear HM, O'Brien TR, Odendall C, Onabajo OO, Piontkivska H, Santer DM, Reich NC, Wack A, Zanoni I. 2020. COVID-19 and emerging viral infections: The case for interferon lambda. J Exp Med. 217(5). e20200653.
Santer DM, Minty GES, Mohamed A, Baldwin L, Bhat R, Joyce M, Egli A, Tyrrell DLJ, Houghton M. 2017. A novel method for detection of IFN-lambda 3 binding to cells for quantifying IFN-lambda receptor expression. J Immunol Methods. 445:15-22. (co-corresponding author)
Syedbasha M, Linnik J, Santer D, O'Shea D, Barakat K, Joyce M, Khanna N, Tyrrell DL, Houghton M, Egli A. 2016. An ELISA based binding and competition method to rapidly determine ligand-receptor interactions. J Vis Exp. 14;(109). doi: 10.3791/53575.
Egli A, Santer DM, O'Shea D, Barakat K, Syedbasha M, Vollmer M, Baluch A, Bhat R, Groenendyk J, Joyce MA, Lisboa LF, Thomas BS, Battegay M, Khanna N, Mueller T, Tyrrell DL, Houghton M, Humar A, Kumar D. 2014. IL-28B is a Key Regulator of B- and T-Cell Vaccine Responses against Influenza. PLoS Pathog. 10(12): e1004556.
Egli A, Levin A, Santer DM, Joyce M, O’Shea D, Thomas B, Lisboa LF, Barakat K, Bhat R, Fischer K, Houghton M, Tyrrell DL, Kumar D, Humar A. 2014. Immunomodulatory function of interleukin-28B during primary infection with Cytomegalovirus. J Infect Dis. 210(5):717-727.
Santer DM, Ma MM, Hockman D, Landi A, Tyrrell DL, Houghton M. 2013. Enhanced activation of memory, but not naïve, B cells in chronic hepatitis C virus-infected patients with cryoglobulinemia and advanced liver fibrosis. PLoS One. 8(6): e68308.
Elkon KB and Santer DM. 2012. Complement, interferon and lupus. Curr Opin Immunol. 24(6):665-670.
Santer DM, Wiedeman AE, Teal TH, Ghosh P, Elkon KB. 2012. Plasmacytoid dendritic cells and C1q differentially regulate inflammatory gene induction by lupus immune complexes. J Immunol. 188(2):902-915.
Santer DM, Hall BE, George TC, Liu CL, Utz PJ, Arkwright PD, Elkon KB. 2010. C1q deficiency leads to the defective suppression of IFN-alpha in response to nucleoprotein containing immune complexes. J Immunol. 185(8):4738-4749. (highlighted in J Immunol ‘In This Issue’ and evaluated as a must-read paper on Faculty of 1000)
Santer DM, Yoshio T, Minota S, Möller T, Elkon KB. 2009. Potent Induction of IFN-alpha and chemokines by autoantibodies in the cerebrospinal fluid of patients with neuropsychiatric lupus. J Immunol. 182(2):1192-1201.
Schoenborn JR, Dorschner MO, Sekimata M, Santer DM, Shnyreva M, Fitzpatrick DR, Stamatoyannopoulos JA, Wilson CB. 2007. Comprehensive epigenetic profiling identifies multiple distal regulatory elements directing transcription of the gene encoding interferon-gamma. Nat Immunol. 8(7):732-742.
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