Current Projects
(2) Develop dmLT and LTA1 Adjuvant to promote protective immunity to vaccines. We work on unique Th1/Th17/Th2-promoting vaccine adjuvants dmLT or LTA1 adjuvants to enable generation of mucosal immunity or for mucosally delivered vaccines. Our work with dmLT has continued ever since Dr. Norton’s post-doctoral fellowship with John Clements and with enterotoxigenic E. coli (ETEC), polio, tuberculosis and other vaccines. In addition, our laboratory has also pioneered the use of LTA1 for intranasal use in flu, klebsiella and opioid vaccines. We have also demonstrated improved safety of LTA1 compared with native enterotoxin. Our work continues to promote these adjuvants, supporting existing vaccines in pre-clinica/clinical development, test new formulation to harness the unique properties of these adjuvants, and collaborate with numerous other national and international scientists on this work. As part of this, we aim to freely share LT, dmLT, LTA1 etc. associated proteins with other laboratories.
(3) Investigate the mechanisms of LT-based proteins on development of immunity in vaccines and therapeutics. We recently observed that neither dmLT or LTA1 signal through PKA activation. In addition, we have used active site mutant E112K to prevent the stimulation of immunity and inflammation (as a novel inflammatory bowel disease (IBD) therapeutic), likely through interactions with the host ARF protein. In the ongoing studies, we plan to define how these proteins stimulate immunity, which key signals are involved and which cells. We are using targeted genetic depletion models to perform these studies as well as comparisons with novel mutant LT proteins. This research aims to: (1) provide mechanistic incite that can be used to support dmLT vaccines in clinical trials or pre-clinical studies, (2) understand LT-based protein interaction on immunity to design next generation adjuvants and therapeutics, (3) provide context to how LT protein during ETEC infection shapes memory responses.
(3)Understand factors regulating development of protective immunity. Humans have a wide-variety of responses to infection or vaccination. The drivers of what shapes immunity is not always clear. Many of our pre-clinical studies are limited in their evaluation of host factors that play major roles in vaccine efficacy or immunity to infections, including age, co-morbidities (e.g. diabetes, cancer), and inflammation. Our recent studies with flu have confirmed that both baseline levels of inflammation and diabetes alter responses to flu infection and vaccination (Baudier et al, in preparation). With the SARS-CoV-2 pandemic these knowledge deficiencies are even clearer. We plan to tackle these questions by evaluating human samples for protective immunity to SARS-CoV-2 infection and also investigate this immunity within context of vaccination to influenza, RSV, or SARS-CoV-2 through a NIH funded projects.
Current or Recent Funding Sources:
Adjuvant or ETEC Research: NIH/NIAID: 1R56AI153600-01A1, 1R56AI143937-01A1, 5R01AI125542-04 (PI-Bitoun), 5R01AI114697-05, PATH Vaccine Solutions
Immunity during Infection/Vaccination: NIH 5R01HL061007-16 (PI-Piedimonte); NIH/NCI Seronet: 1U54CA260581-01 Tulane University COVID Antibody and Immunity Network (TUCAIN); LA CaTS/REACHNET
Publications
Combs JA, Monk CH, Harrison MAA, Norton EB, Morris CA, Sullivan DE, Zwezdaryk KJ. Inhibiting cytomegalovirus replication through targeting the host electron transport chain. Antiviral Res. 2021 Aug 11;194:105159. doi: 10.1016/j.antiviral.2021.105159. [Epub ahead of print] PubMed PMID: 34390771.
Schieffelin JS, Norton EB, Kolls JK. What should define a SARS-CoV-2 “breakthrough” infection?. J Clin Invest. 2021 Jun 15;131(12). doi: 10.1172/JCI151186. PubMed PMID: 33974565; PubMed Central PMCID: PMC8203469.
Stone AE, Scheuermann SE, Haile CN, Cuny GD, Velasquez ML, Linhuber JP, Duddupudi AL, Vigliaturo JR, Pravetoni M, Kosten TA, Kosten TR, Norton EB. Fentanyl conjugate vaccine by injected or mucosal delivery with dmLT or LTA1 adjuvants implicates IgA in protection from drug challenge. NPJ Vaccines. 2021 May 13;6(1):69. doi: 10.1038/s41541-021-00329-0. PubMed PMID: 33986280.
Huang Z, Ning B, Yang HS, Youngquist BM, Niu A, Lyon CJ, Beddingfield BJ, Fears AC, Monk CH, Murrell AE, Bilton SJ, Linhuber JP, Norton EB, Dietrich ML, Yee JK, Lai W, Scott JW, Yin XM, Rappaport J, Robinson JE, Saba NS, Roy CJ, Zwezdaryk KJ, Zhao Z, Hu TY. Sensitive tracking of circulating viral RNA through all stages of SARS-CoV-2 infection. J Clin Invest. 2021 Feb 9;. doi: 10.1172/JCI146031. [Epub ahead of print] PubMed PMID: 33561010.
Motyka NI, Stewart SR, Hollifield IE, Kyllo TR, Mansfield JA, Norton EB, Clements JD, Bitoun JP. Elevated Extracellular cGMP Produced after Exposure to Enterotoxigenic Escherichia coli (ETEC) Heat-Stable Toxin (ST) Induces Epithelial IL-33 Release and Alters Intestinal Immunity. Infect Immun. 2021 Jan 11;. doi: 10.1128/IAI.00707-20. [Epub ahead of print] PubMed PMID: 33431701.
Baudier RL, Zwezdaryk KJ, Czarny-Ratajczak M, Kodroff LH, Sullivan DE, Norton EB. Unique Transcriptome Changes in Peripheral B Cells Revealed by Comparing Age Groups From Naive or Vaccinated Mice, Including snoRNA and Cdkn2a. J Gerontol A Biol Sci Med Sci. 2020 Nov 13;75(12):2326-2332. doi: 10.1093/gerona/glaa165. PubMed PMID: 32609344; PubMed Central PMCID: PMC7759738.
Liu S, Liu F, Zhang B, Yan P, Rowan BG, Abdel-Mageed AB, Steele C, Jazwinski SM, Moroz K, Norton EB, Wang A, Myers L, Sartor O, Zhang Q. CD4+ T helper 17 cell response of aged mice promotes prostate cancer cell migration and invasion. 2020 Jul;80(10):764-776. doi: 10.1002/pros.23990. Epub 2020 May 1. PubMed PMID: 32356608; PubMed Central PMCID: PMC7310589.
Valli E, Baudier RL, Harriett AJ, Norton EB. LTA1 and dmLT enterotoxin-based proteins activate antigen-presenting cells independent of PKA and despite distinct cell entry mechanisms. PLoS One. 2020;15(1):e0227047. doi: 10.1371/journal.pone.0227047. eCollection 2020. PubMed PMID: 31929548; PubMed Central PMCID: PMC6957164.
Combs JA, Norton EB, Saifudeen ZR, Bentrup KHZ, Katakam PV, Morris CA, Myers L, Kaur A, Sullivan DE, Zwezdaryk KJ. Human Cytomegalovirus Alters Host Cell Mitochondrial Function during Acute Infection. J Virol. 2020 Jan 6;94(2). doi: 10.1128/JVI.01183-19. Print 2020 Jan 6. PubMed PMID: 31694945; PubMed Central PMCID: PMC6955246.
Valli E, Harriett AJ, Nowakowska MK, Baudier RL, Provosty WB, McSween Z, Lawson LB, Nakanishi Y, Norton EB. LTA1 is a safe, intranasal enterotoxin-based adjuvant that improves vaccine protection against influenza in young, old and B-cell-depleted (μMT) mice. Sci Rep. 2019 Oct 22;9(1):15128. doi: 10.1038/s41598-019-51356-w. PubMed PMID: 31641151; PubMed Central PMCID: PMC6805908.
Maciel M Jr, Bauer D, Baudier RL, Bitoun J, Clements JD, Poole ST, Smith MA, Kaminski RW, Savarino SJ, Norton EB. Intradermal or Sublingual Delivery and Heat-Labile Enterotoxin Proteins Shape Immunologic Responses to a CFA/I Fimbria-Derived Subunit Antigen Vaccine against Enterotoxigenic Escherichia coli. Infect Immun. 2019 Nov;87(11). doi: 10.1128/IAI.00460-19. Print 2019 Nov. PubMed PMID: 31427449; PubMed Central PMCID: PMC6803349.
Norton EB. Altered responses to pneumococcal vaccination in an elderly diabetic Japanese vaccine trial: The risk of concurrent vaccination strategies. J Diabetes Complications. 2019 Mar;33(3):189-190. doi: 10.1016/j.jdiacomp.2018.12.007. Epub 2018 Dec 21. PubMed PMID: 30651178.
Clements JD, Norton EB. The Mucosal Vaccine Adjuvant LT(R192G/L211A) or dmLT. mSphere. 2018;3(4). Epub 2018/07/27. doi: 10.1128/mSphere.00215-18. PubMed PMID: 30045966.
Norton, E. B., Branco, L.M. Clements, J.D. Evaluating the A-subunit of the heat-labile toxin (LT) as an immunogen and a protective antigen against enterotoxigenic Escherichia coli (ETEC). PLoS One. 2015 Aug 25;10(8):e0136302. doi: 10.1371/journal.pone.0136302. eCollection 2015. PMID: 26305793
Norton E. B., Bauer D.L., Weldon W.C., Oberste M.S., Lawson L.B., Clements J.D. The novel adjuvant dmLT promotes dose sparing, mucosal immunity and longevity of antibody responses to the inactivated polio vaccine in a murine model. Vaccine. 2015;33(16):1909-15. doi: 10.1016/j.vaccine.2015.02.069. PubMed PMID: 25765967.
Read, L.T., Hahn, R.W., Thompson, C.C., Bauer, D.L., Norton, E.B., Clements, J.D. Simultaneous exposure to Escherichia coli heat-labile and heat-stable enterotoxins increases fluid secretion and alters cyclic nucleotide and cytokine production by intestinal epithelial cells. Infect Immun. 2014; 82(12):5308-16. PMID: 25483682
White, J.A., Blum, J.S., Hosken, N.A., Marshak, J.O., Duncan, L., Zhu, C., Norton, E.B., Clements, J.D., Koelle D.M., Chen, D., Lal, M. Serum and mucosal antibody responses to inactivated polio vaccine after sublingual immunization using a thermoresponsive gel delivery system. Hum Vaccin Immunother. 2014 Nov:10(12). PMID: 25483682.
Tomchuck, S.L., Norton, E.B., Garry, R.F., Bunnell, B.A., Morris, C.A., Freytag, L.C., Clements, J.D. Mesenchymal Stem Cells as a Novel Vaccine Platform. Front Cell Infect Microbiol. 2012 Nov 2: 140. PMID: 23162801.
Norton, E. B., L. B. Lawson, Mahdi, Z., Freytag, L.C., Clements, J.D. The A-subunit of Escherichia coli heat-labile enterotoxin functions as a mucosal adjuvant and promotes IgG2a, IgA and Th17 responses to vaccine antigens. Infect Immun. 2012 Jul;80(7):2426-35. PMID: 22526674
Lawson, L.B., Norton, E.B., Clements, J.D. Defending the Mucosa: Adjuvant and Carrier Formulations for Mucosal Immunity. Curr Opin Immunol. 2011 Jun;23(3):414-20. PMID: 21511452.
Cross R.W., Betancourt, A.M., Schur, M.J., Norton, E.B., Roy D, et al. Impact of Primary Influenza Infection on the Immune Response to Secondary Bacterial Infection in Aged Mice. Symposium on viral respiratory disease surveillance. Influenza and Other Respiratory Viruses.2011 May. (Suppl. 1), 195–201.
Norton, E. B., L. B. Lawson, Freytag, L. C., Clements, J.D. 2011. Characterization of a Mutant Escherichia coli Heat-labile Toxin, R192G/L211A, as a Safe and Effective Oral Adjuvant. Clin Vaccine Immunol. 2011 Apr;18(4):546-51. PMID: 21288994.
Norton, E., Clements, J, Voss, T., Freytag, L. Prophylactic Administration of Bacterially Derived Immunomodulators Improves the Outcome of Influenza Virus Infection in a Murine Model. J Virol. 2010 Mar; 84(6):2983-95. PMID: 20053748
Norton, E.B. Evaluation of Vaccine Adjuvants as Immunomodulators in Pulmonary Disease. Dissertation Thesis. 2009.
Norton, E., Archibald, L. K., Nwanyanwu, O. C., Kazembe, P. N., Dobbie, H., Reller B.R., Jarvis, W. R Jason, J. Clinical Predictors of Bloodstream Infections and Mortality in Hospitalized Malawian Children. Pediatr Infect Dis J. 2004 Feb;23(2):145-51. Discussion 151-5. PMID: 14872181
Jason, J., Archibald, L. K., Nwanyanwu, O. C., Kazembe, P. N., Chatt, J. A., Norton, E., Dobbie, H., Jarvis, W. R. Clinical and Immune Impact of Mycobacterium bovis BCG Vaccination Scarring. Infect Immun. 2002 Nov;70(11):6188-95.
For more information, visit Dr. Norton’s MyBibliography page.