A message from Bertram:

I am a Professor in the School of Life Sciences, and a member of the Biodesign Center for Immunotherapy, Vaccines and Virotherapy at Arizona State University.   My research for the past 40 years has involved trying to understand virus host interactions.  Over the years my lab has worked with influenza virus, VSV, reovirus, poxviruses, including monkeypox/mpox virus (MPXV), and more recently coronaviruses, as well as work with the host anti-viral interferon system. Our work with vaccinia virus has led us to develop highly-attenuated, replication-limited vaccine vectors. These vectors have shown enhanced immunogenicity in non-human primates against HIV and immunogenicity and efficacy in mice against SARS-CoV-2.

Ongoing and recently completed projects that I would like to highlight include:

• 2 R01 AI095394-06 (Jacobs, PI) 7/20-6/25. “Monkeypox virus, Interferon, and Necroptosis”.  The Aims of this grant are to characterize monkeypox virus evasion of PAMP sensing of in infected cells and animals. Role, PI.
• Bill and Melinda Gates Foundation, 9/06-9/11 (Supplemental Grants extending through 2015). “Poxvirus T-cell Vaccine Discovery Consortium.”  The Aims of this proposal was to improve poxviruses as T cell vaccine vectors, with the goal of increasing immunogenicity of poxviruses as HIV vaccine vectors.
  Role: Co-PI
• Bill and Melinda Gates Foundation, 9/13-8/16. “A Novel Replication Competent Flavivirus-based HIV Vaccine Platform, i.e. RepliVax®, as a Priming Component for Improving Antibody Response.” The aims of this proposal was to develop replication competent flavivirus-based vectors as potential HIV vaccine candidates, with the goal of improving achievable immunogenicity while retaining safety.
  Role: Co-PI

Citations:

Jentarra GM, Heck MC, Youn JW, Kibler K, Langland JO, Baskin CR, Ananieva O, Chang Y, Jacobs BL.  Vaccinia viruses with mutations in the E3L gene as potential replication-competent, attenuated vaccines: scarification vaccination.  Vaccine 2008, 26(23):2860-72. doi: 10.1016/j.vaccine.2008.03.044. Epub 2008 Apr 8. PMID: 18455281

Denzler KL, Schriewer J, Parker S, Werner C, Hartzler H, Hembrador E, Huynh T, Holechek S, Buller RM, Jacobs BL. “The attenuated NYCBH vaccinia virus deleted for the immune evasion gene, E3L, completely protects mice against heterologous challenge with ectromelia virus.” Vaccine. 2011 Dec 6;29(52):9691-6. doi: 10.1016/j.vaccine.2011.09.108. Epub 2011 Oct 5. PMID: 21983358

Kibler KV, Benedikt Asbach, Beatriz Perdiguero, Juan García-Arriaza, Nicole L. Yates, Robert Parks, Sherry Stanfield-Oakley, Guido Ferrari, David C. Montefiori, Georgia D. Tomaras, Mario Roederer, Kathryn E. Foulds, Donald N. Forthal, Michael S. Seaman, Steve Self, Raphael Gottardo, Sanjay Phogat, James Tartaglia, Susan Barnett, Anthony D. Cristillo, Deborah Weiss, Lindsey Galmin, Song Ding, Jonathan L. Heeney, Mariano Esteban, Ralf Wagner, Giuseppe Pantaleo, Bertram L. Jacobs. “Replication-Competent VICINIUS VIAVAX Platform Yields Improved Immunogenicity to HIV-1 Antigens in Rhesus Macaques Compared to Nonreplicating NYVAC. Journal of Virology,  93, Issue 3 (2019) e01513-18.

Kibler KV, Szczerba M, Lake D, Roeder AJ, Rahman M, Hogue BG, Roy Wong LY, Perlman S, Li Y, Jacobs BL. Intranasal Immunization with a Vaccinia Virus Vaccine Vector Expressing Pre-Fusion Stabilized SARS-CoV-2 Spike Fully Protected Mice against Lethal Challenge with the Heavily Mutated Mouse-Adapted SARS2-N501YMA30 Strain of SARS-CoV-2. Vaccines (Basel). 2022 Jul 23;10(8):1172. doi: 10.3390/vaccines10081172. PMID: 35893821; PMCID: PMC9394475.

Positions, Scientific Appointments, and Honors:

Positions and Scientific Appointments

Aug. 2010-Present — Chair, ASU Institutional Biosafety Committee

Sept. 2006-Present —  Editorial Board Member, Journal of Virology

Aug. 1996-Present — Professor, School of Life Sciences, Member, Biodesign Center for Immunotherapy, 

Vaccines and Virotherapy, Arizona State University

Honors:

April 2007 — Governor’s Innovator of the Year in Academia Awardee

June 2009 — Southwest Center for HIV/AIDS Humanitarian Award

Feb. 2019 — Fellow, American Association for the Advancement of Science

July 2019-2021 — American Society for Microbiology Distinguished Lecturer

Jan. 2022 — Senior Member, National Academy of Inventors

Contributions to Science:

1. Discovery of the VACV interferon resistance gene. In the late 80s little was known about how viruses could evolve resistance to the host anti-viral interferon system.  We were the first to isolate and characterize an interferon resistance gene from vaccinia virus, the E3L gene.  We showed that the E3L-encoded gene product bound to dsRNA, and contained a domain that had homology to other proteins that bound dsRNA.  We mapped dsRNA-binding to this domain, and showed that this domain was both necessary and sufficient for interferon resistance of vaccinia virus, at least in some cells in culture.  This was the first work to show that a dsRNA-binding protein could in fact lead to interferon-resistance.  The original mutant of vaccinia virus, VACVΔE3L, then lead to isolation of other interferon resistance genes from herpes viruses, rotaviruses and reovirus. This work led to our more recent work to characterize the N-terminal Z-NA binding domain of E3L.

   Chang, H. W., J. C. Watson and B. L. Jacobs. “The E3l Gene of Vaccinia Virus Encodes an Inhibitor of the Interferon-Induced, Double-Stranded Rna-Dependent Protein Kinase.” Proc Natl Acad Sci U S A 89, no. 11 (1992): 4825-9.

   Arndt WD, Cotsmire S, Trainor K, Harrington H, Hauns K, Kibler KV, Huynh TP, Jacobs BL. “Evasion of the Innate Immune Type I Interferon System by Monkeypox Virus.” J Virol. 2015 Oct;89(20):10489-99. doi: 10.1128/JVI.00304-15. Epub 2015 Aug 5. PMID: 26246580

   Arndt, W. D., S. D. White, B. P. Johnson, T. Huynh, J. Liao, H. Harrington, S. Cotsmire, K. V. Kibler, J. Langland, and B. L. Jacobs. 2016. Monkeypox virus induces the synthesis of less dsRNA than vaccinia virus, and is more resistant to the anti-poxvirus drug, IBT, than vaccinia virus. Virology 497:125-135.

   Szczerba M, Subramanian S, Trainor K, McCaughan M, Kibler KV, Jacobs BL. “Small Hero with Great Powers: Vaccinia Virus E3 Protein and Evasion of the Type I IFN Response.” Biomedicines. 2022 Jan 22;10(2):235. doi: 10.3390/biomedicines10020235. PMID: 35203445

2. Characterization of Z-NA binding proteins. In addition to a conserved C-terminal domain that we originally demonstrated bound to dsRNA, E3L-encoded proteins contain a conserved N-terminal domain.  When we first started to characterize this domain, there were no homologues in the database, and mutant viruses lacking this domain had no phenotype in cells in culture.  We initially showed that while this domain was dispensable for replication and interferon resistance in most cells in culture, virus lacking this domain was highly attenuated in the mouse model.  Concurrently Alex Rich’s lab showed that ADAR contains a domain with homology to the N-terminus of E3 protein, and that the ADAR domain binds to Z-form nucleic acid.  In collaboration with the Rich lab, we showed that the ADAR Z-DNA binding domain could functionally replace the N-terminus of E3L in the murine pathogenesis model, and that pathogenesis correlated with binding to Z-DNA.  To this day, this model is the best model to investigate the function of a Z-DNA binding domain in biology.  We have used this model to understand the role of the Z-DNA binding domain in pathogenesis.  Mutant virus lacking the N-terminal Z-DNA binding domain is highly attenuated.  Pathogenesis was fully restored in a type I interferon receptor (IFNAR) knock out mouse.  Mutant virus lacking the N-terminus was also interferon sensitive in MEFs in culture.  Interferon resistance was fully restored in PKR knock-out MEFs and after knock-down of PKR, demonstrating that the N-terminus is critical for fully inhibiting the interferon-inducible PKR pathway.  These mutants are also susceptible to IFN-inducible necroptosis in murine L929 cells. Induction of necroptosis is dependent on expression of the IFN-inducible protein, DAI (aka DLM and ZBP1).  Both DAI and E3 protein contain consensus Z-DNA binding domains, and function of both E3 and DAI correlates with their ability to bind Z-DNA in vitro.  Thus, we believe that DAI and E3 compete for binding to a virus-induced Z-NA.  Both DAI and E3 bind to stress-granules, and we have recently shown that expression of DAI in oxidatively stressed cells leads to necroptotic death.

   Kim, Y. G., M. Muralinath, T. Brandt, M. Pearcy, K. Hauns, K. Lowenhaupt, B. L. Jacobs and A. Rich. “A Role for Z-DNA Binding in Vaccinia Virus Pathogenesis.” Proc Natl Acad Sci U S A 100, no. 12 (2003): 6974-9.

   Koehler H, Cotsmire, S., Langland, J., Kibler, K.V., Kalman, D., Upton, J.W., Mocarski, E.S. and Jacobs, B.L. 2017. Inhibition of DAI-dependent necroptosis by the Z-DNA binding domain of the vaccinia virus innate immune evasion protein, E3. PNAS doi:10.1073/pnas.1700999114.

   Koehler HS, Jacobs BL. Subversion of Programed Cell Death by Poxviruses. Curr Top Microbiol Immunol. 2021 Jan 29:10.1007/82_2020_229. doi: 10.1007/82_2020_229. Epub ahead of print. PMID: 33507400; PMCID: PMC8319220.

   Koehler, H., Cotsmire, S., Zhang, T., Balachandran, S., Upton, J., Langland, J., Kalman, D., Jacobs, B., Mocarski, E. Vaccinia virus E3 prevents sensing of Z-RNA to block ZBP1-dependent necroptosis.  Cell Host Microbe. 2021 Aug 11;29(8):1266-1276.e5. doi: 10.1016/j.chom.2021.05.009. Epub 2021 Jun 29. PMID: 34192517

3. VACV pro-inflammatory signal transduction. Since dsRNA is a key player in host anti-viral signaling, in addition to activating host anti-viral enzymes, such as PKR and OAS, we have investigated induction of pro-inflammatory signaling by VACV and VACV containing key mutations in E3L.  wtVACV fails to signal through IRF3, NF-kB or the MAP kinase pathways.  Virus deleted of E3L signals efficiently through all three pathways. Virus lacking either the dsRNA-binding domain or the Z-NA binding domain signal through the MAP kinase pathway, indicating that both domains are required to inhibit MAP kinase signaling.  NF-kB signaling was inhibited in virus expressing a dsRNA-binding domain, but not in virus expressing a Z-NA binding domain, indicating that binding to dsRNA is essential to inhibit the NF-kB pathway. Neither mutants lacking the Z-NA binding domain, nor mutants lacking the dsRNA-binding domain led to IRF phosphorylation.  Our most recent data suggests that there is a third domain, between the N-terminal Z-NA binding domain and the C-terminal dsRNA-binding domain that can inhibit activation of the IRF3 pathway.  We have recently shown that heat inactivated vaccinia virus potently leads to activation of IRF3 and induction of type I interferon, but not to signaling through the NF-kB or MAP kinase pathways.

   Langland, J. O., J. M. Cameron, M. C. Heck, J. K. Jancovich and B. L. Jacobs. “Inhibition of PKR by RNA and DNA Viruses.” Virus Res 119, no. 1 (2006): 100-10.

   Langland, J. O., J. C. Kash, V. Carter, M. J. Thomas, M. G. Katze and B. L. Jacobs. “Suppression of Proinflammatory Signal Transduction and Gene Expression by the Dual Nucleic Acid Binding Domains of the Vaccinia Virus E3l Proteins.” J Virol 80, no. 20 (2006): 10083-95.

4. Replication competent, highly attenuated vaccine vectors. VACV lacking the N-terminal Z-NA-binding domain of E3L has a very interesting phenotype.  These mutants replicate to wt levels at the initial site of inoculation, but fail to spread from the site of inoculation (either the nose or the skin), and are therefore highly attenuated.  We thought that this phenotype, replication competent, but highly attenuated, would have desirable properties as a vaccine vector.  In fact, these mutants are potent vaccine vectors despite being highly attenuated.  We brought this concept of a highly attenuated, replication competent vector to the Poxvirus T-cell Vaccine Discovery Consortium (PTVDC) in 2005 and have developed a putative HIV vaccine, based on this concept.  The vector developed in this Consortium is attenuated by approximately 4 logs compared to the current smallpox vaccine, yet induces potent T cell and antibody responses in vaccinated NHPs. We have recently shown that this vector has potential as a heat stable, easy to administer SARS-CoV-2 vaccine.

   Jentarra GM, Heck MC, Youn JW, Kibler K, Langland JO, Baskin CR, Ananieva O, Chang Y, Jacobs BL.  Vaccinia viruses with mutations in the E3L gene as potential replication-competent, attenuated vaccines: scarification vaccination.  Vaccine 2008, 26(23):2860-72. doi: 10.1016/j.vaccine.2008.03.044. Epub 2008 Apr 8. PMID: 18455281

   Denzler KL, Schriewer J, Parker S, Werner C, Hartzler H, Hembrador E, Huynh T, Holechek S, Buller RM, Jacobs BL. “The attenuated NYCBH vaccinia virus deleted for the immune evasion gene, E3L, completely protects mice against heterologous challenge with ectromelia virus.” Vaccine. 2011 Dec 6;29(52):9691-6. doi: 10.1016/j.vaccine.2011.09.108. Epub 2011 Oct 5. PMID: 21983358

   Kibler KV, Benedikt Asbach, Beatriz Perdiguero, Juan García-Arriaza, Nicole L. Yates, Robert Parks, Sherry Stanfield-Oakley, Guido Ferrari, David C. Montefiori, Georgia D. Tomaras, Mario Roederer, Kathryn E. Foulds, Donald N. Forthal, Michael S. Seaman, Steve Self, Raphael Gottardo, Sanjay Phogat, James Tartaglia, Susan Barnett, Anthony D. Cristillo, Deborah Weiss, Lindsey Galmin, Song Ding, Jonathan L. Heeney, Mariano Esteban, Ralf Wagner, Giuseppe Pantaleo, Bertram L. Jacobs. “Replication-Competent VICINIUS VIAVAX Platform Yields Improved Immunogenicity to HIV-1 Antigens in Rhesus Macaques Compared to Nonreplicating NYVAC. Journal of Virology,  93, Issue 3 (2019) e01513-18.

   Kibler KV, Szczerba M, Lake D, Roeder AJ, Rahman M, Hogue BG, Roy Wong LY, Perlman S, Li Y, Jacobs BL. Intranasal Immunization with a Vaccinia Virus Vaccine Vector Expressing Pre-Fusion Stabilized SARS-CoV-2 Spike Fully Protected Mice against Lethal Challenge with the Heavily Mutated Mouse-Adapted SARS2-N501YMA30 Strain of SARS-CoV-2. Vaccines (Basel). 2022 Jul 23;10(8):1172. doi: 10.3390/vaccines10081172. PMID: 35893821; PMCID: PMC9394475.

5. Herbal anti-virals. My long term collaborator, Jeff Langland, initially found a reference from the 1800’s that the Micmac native Americans had a cure for smallpox: a hot aqueous extract (tea) from the carnivorous plant Sarracenia pupurea. We obtained an extract from S. purpurea and showed that it had potent anti-vaccinia virus, anti-monkeypox virus and potent anti-variola virus activity (the later in collaboration with Inger Damon at the CDC). The extract inhibited poxvirus early gene expression, at a step subsequent to binding and uptake. The extract inhibited transcription from purified cores, indicating that it is a potent inhibitor of early transcription. Further characterization showed that this extract had anti-papovavirus activity (against SV-40), anti-herpes virus activity (against HSV-1, HSV-2, VZV, EBV, and equine herpesvirus), and anti-HIV activity. The extract could also induce cell death in HPV-transformed SiHa cells. The extract potently inhibits activation of the host cyclin-dependent kinase (CDK) system, which we believe explains its broad anti-viral activity, since many viruses utilize the host CDKs for viral DNA synthesis and transcription.

   Arndt, W., C. Mitnik, K. L. Denzler, S. White, R. Waters, B. L. Jacobs, Y. Rochon, V. A. Olson, I. K. Damon and J. O. Langland. “In Vitro Characterization of a Nineteenth-Century Therapy for Smallpox.” PLoS One 7, no. 3 (2012): e32610.

   Ferreira, V., Ruiz, G., Jacobs, B.L., Denzler, K., Waters, R., Chamberlain, R., Proefrock, K.J., and Langland, J.O. (2015). Treatment of Verruca Vulgaris (common warts) with a synergistic botanical blend: case report. Nat. Doc. News and Review (in press).

   Ferreira, V., Jacobs, B.L., Denzler, K., Waters, R., Chamberlain, R., Proefrock, K.J., and Langland, J.O. (2015). Treatment of Herpes Zoster with botanical interventions: case report. Medicine Case Reports and Study Protocols 2(1):p e0058, January 2021. | DOI: 10.1097/MD9.0000000000000058.

Complete list of publications: https://www.ncbi.nlm.nih.gov/myncbi/bertram.jacobs.1/bibliography/public/