William T. Jackson, PhD

B.S., M.I.T. 1993
Ph.D. U.C. Berkeley 1999
Fellowship: Stanford Medical School 2000-2006

Enteroviruses are among the most severe causes of human disease, and recent outbreaks of emerging enteroviruses such as types D68 and 71 have highlighted the need to understand more about these pathogens. Our comparative studies of poliovirus (PV), coxsackievirus B3, and now EV-D68 have shown many commonalities in the life-cycles of these viruses. We have focused our studies on how members of the Enterovirus genus trigger a cellular pathway known as autophagy to promote production of infectious virus.

Autophagy is a constitutive degradative cellular process required for turnover of damaged vesicles, aggregated proteins, and other spent cellular components. During times of stress, including amino acid starvation, organismal development, and infection, autophagy is up-regulated. Autophagic vesicles, thought to be derived from the complex web of viral RNA replication membranes, can be observed during mid-to-late infection.

We and others have demonstrated that viral proteins specifically induce autophagic signaling and autophagosome formation. These autophagosomes acidify, promoting maturation of the viral capsid and release of newly formed infectious viruses, often encased in these cell-derived membranes, from the cell. 

Our lab is dedicated to understanding the generation and regulation of membranes during infection, from the initial RNA replication membranes to the autophagosomes promoting maturation of virions to the single-membraned virus-containing vesicles being released from the cell. Understanding this entire pathway, the latter parts of which have only been identified within the past few years, will provide an understanding of how these viruses replicate, mature, release from cells, and evade immune detection.

Some of our projects include:

• How specific viral non-structural proteins initiate autophagosome formation at the early stages of infection and regulate downstream steps in autophagosome formation, acidic maturation, and virus release. 

• The viral and host requirements for development of viral RNA replication membranes, and the mechanism of formation of autophagosomes from these convoluted membrane structures during infection.

• Regulation of autophagy through novel localization of viral and autophagic proteins.

• How acidic autophagosomes form and promote maturation of the virion by inducing cleavage of the capsid protein VP0 into VP2 and VP4. 

• The multiple roles of the SNARE proteins in regulation virus entry, replication, maturation, and release, including SNAP29, part of a complex that mediates fusion between acidic autophagosomes and lysosomes. SNAP29 is cleaved by the viral 3C protease late in infection, but is required early.  

• The role of another SNARE in the same family, SNAP47, which associates with the endosomal SNARE VAMP7, and is required for normal autophagy and EV-D68 replication. 

• The roles of another SNARE, SNAP23 in redirecting membranes to fuse with the plasma membrane and are released from cells.

• The role and regulation of the neuron-specific SNARE SNAP25 during infection of neuronal cells.

• The role of SARS-CoV-2 proteins in inducing and regulating autophagy.

Picornavirus, Poliovirus, Rhinovirus, Coxsackievirus, Enterovirus D-68, PV, HRV, CVB3, EVD-68, Autophagy, Secretion, Trafficking

A.L. Richards and W.T. Jackson. Intracellular vesicle acidification promotes maturation of infectious poliovirus particles. PLoS Pathogens 2012 Nov;8(11). PMCID: PMC3510256

D.J. Sidjanin, A.K. Park, A. Ronchetti, J.Martins, and W.T. Jackson. TBC1D20 mediates autophagy as a key regulator of autophagosome maturation. Autophagy 2016, Aug 3:1-17

C.A. Quiner and W.T. Jackson. Fragmentation of the Golgi apparatus provides replication membranes for human rhinovirus 1A. Virology 2010 Nov 25 407(2): 185-195

Miller K, McGrath ME, Hu Z, Ariannejad S, Weston S, Frieman M, Jackson WT. Coronavirus interactions with the cellular autophagy machinery. Autophagy. 2020 Dec;16(12):2131-2139. doi: 10.1080/15548627.2020.1817280. Epub 2020 Sep 23. Review. PubMed PMID: 32964796; PubMed Central PMCID: PMC7755319.

Yang JE, Rossignol ED, Chang D, Zaia J, Forrester I, Raja K, Winbigler H, Nicastro D, Jackson WT, Bullitt E. Complexity and ultrastructure of infectious extracellular vesicles from cells infected by non-enveloped virus. Sci Rep. 2020 May 14;10(1):7939. doi: 10.1038/s41598-020-64531-1. PubMed PMID: 32409751; PubMed Central PMCID: PMC7224179.

Rodriguez-Furlan C, Domozych D, Qian W, Enquist PA, Li X, Zhang C, Schenk R, Winbigler HS, Jackson W, Raikhel NV, Hicks GR. Interaction between VPS35 and RABG3f is necessary as a checkpoint to control fusion of late compartments with the vacuole. Proc Natl Acad Sci U S A. 2019 Oct 15;116(42):21291-21301. doi: 10.1073/pnas.1905321116. Epub 2019 Sep 30. PubMed PMID: 31570580; PubMed Central PMCID: PMC6800349.

Han M, Bentley JK, Rajput C, Lei J, Ishikawa T, Jarman CR, Lee J, Goldsmith AM, Jackson WT, Hoenerhoff MJ, Lewis TC, Hershenson MB. Inflammasome activation is required for human rhinovirus-induced airway inflammation in naive and allergen-sensitized mice. Mucosal Immunol. 2019 Jul;12(4):958-968. doi: 10.1038/s41385-019-0172-2. Epub 2019 May 15. PubMed PMID: 31089187; PubMed Central PMCID: PMC6668626.

Shtanko O, Reyes AN, Jackson WT, Davey RA. Autophagy-Associated Proteins Control Ebola Virus Internalization Into Host Cells. J Infect Dis. 2018 Nov 22;218(suppl_5):S346-S354. doi: 10.1093/infdis/jiy294. PubMed PMID: 29947774; PubMed Central PMCID: PMC6249560.

Corona Velazquez AF, Jackson WT. So Many Roads: the Multifaceted Regulation of Autophagy Induction. Mol Cell Biol. 2018 Nov 1;38(21). doi: 10.1128/MCB.00303-18. Print 2018 Nov 1. Review. PubMed PMID: 30126896; PubMed Central PMCID: PMC6189458.

Corona AK, Jackson WT. Finding the Middle Ground for Autophagic Fusion Requirements. Trends Cell Biol. 2018 Nov;28(11):869-881. doi: 10.1016/j.tcb.2018.07.001. Epub 2018 Aug 13. Review. PubMed PMID: 30115558; PubMed Central PMCID: PMC6197918.

Rajput C, Han M, Bentley JK, Lei J, Ishikawa T, Wu Q, Hinde JL, Callear AP, Stillwell TL, Jackson WT, Martin ET, Hershenson MB. Enterovirus D68 infection induces IL-17-dependent neutrophilic airway inflammation and hyperresponsiveness. JCI Insight. 2018 Aug 23;3(16). doi: 10.1172/jci.insight.121882. eCollection 2018 Aug 23. PubMed PMID: 30135310; PubMed Central PMCID: PMC6141171.

Corona AK, Mohamud Y, Jackson WT, Luo H. Oh, SNAP! How enteroviruses redirect autophagic traffic away from degradation. Autophagy. 2018;14(8):1469-1471. doi: 10.1080/15548627.2018.1480849. Epub 2018 Jul 21. PubMed PMID: 30032704; PubMed Central PMCID: PMC6103677.

Corona Velazquez A, Corona AK, Klein KA, Jackson WT. Poliovirus induces autophagic signaling independent of the ULK1 complex. Autophagy. 2018;14(7):1201-1213. doi: 10.1080/15548627.2018.1458805. Epub 2018 Jul 20. PubMed PMID: 29929428; PubMed Central PMCID: PMC6103675.

Corona AK, Saulsbery HM, Corona Velazquez AF, Jackson WT. Enteroviruses Remodel Autophagic Trafficking through Regulation of Host SNARE Proteins to Promote Virus Replication and Cell Exit. Cell Rep. 2018 Mar 20;22(12):3304-3314. doi: 10.1016/j.celrep.2018.03.003. PubMed PMID: 29562185; PubMed Central PMCID: PMC5894509.

Jackson WT. The Autophagic Pathway and Enterovirus Infection. In: Jackson WT, Coyne CB, editors. Enteroviruses: Omics, Molecular Biology, and Control 1st ed. Poole, UK: Caister Academic Press; 2018. Chapter 7; p.113-28. 144p.

Jackson WT, Corona Velazquez AF, Corona AK, Saulsbery HS. Enteroviruses resculpt the autophagic landscape to support virus replication and cell exit (Preprint, non-peer reviewed). Cell Reports Sneak Peek. 2017 August.

Sidjanin DJ, Park AK, Ronchetti A, Martins J, Jackson WT. TBC1D20 mediates autophagy as a key regulator of autophagosome maturation. Autophagy. 2016 Oct 2;12(10):1759-1775. doi: 10.1080/15548627.2016.1199300. Epub 2016 Aug 3. PubMed PMID: 27487390; PubMed Central PMCID: PMC5079675.

Klionsky DJ er al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 2016;12(1):1-222. doi: 10.1080/15548627.2015.1100356. PubMed PMID: 26799652; PubMed Central PMCID: PMC4835977.

Rosenthal AK, Gohr CM, Mitton-Fitzgerald E, Grewal R, Ninomiya J, Coyne CB, Jackson WT. Autophagy modulates articular cartilage vesicle formation in primary articular chondrocytes. J Biol Chem. 2015 May 22;290(21):13028-38. doi: 10.1074/jbc.M114.630558. Epub 2015 Apr 13. PubMed PMID: 25869133; PubMed Central PMCID: PMC4505557.

Jackson WT. Viruses and the autophagy pathway. Virology. 2015 May;479-480:450-6. doi: 10.1016/j.virol.2015.03.042. Epub 2015 Apr 6. Review. PubMed PMID: 25858140; PubMed Central PMCID: PMC5917100.

Jackson WT, Swanson M, editors. Autophagy, Infection, and the Immune Response 1st ed. Hoboken NJ: Wiley-Blackwell; 2015. 239p.

Delorme-Axford E, Morosky S, Bomberger J, Stolz DB, Jackson WT, Coyne CB. BPIFB3 regulates autophagy and coxsackievirus B replication through a noncanonical pathway independent of the core initiation machinery. mBio. 2014 Dec 9;5(6):e02147. doi: 10.1128/mBio.02147-14. PubMed PMID: 25491355; PubMed Central PMCID: PMC4324245.

Jackson WT. Dangerous Membranes: Viruses That Subvert Autophagosomes. EBioMedicine. 2014 Dec;1(2-3):97-8. doi: 10.1016/j.ebiom.2014.11.015. eCollection 2014 Dec. PubMed PMID: 26137514; PubMed Central PMCID: PMC4457410.

Jackson WT. Poliovirus-induced changes in cellular membranes throughout infection. Curr Opin Virol. 2014 Dec;9:67-73. doi: 10.1016/j.coviro.2014.09.007. Epub 2014 Oct 11. Review. PubMed PMID: 25310497; PubMed Central PMCID: PMC4267968.

Kim JH, Hong SK, Wu PK, Richards AL, Jackson WT, Park JI. Raf/MEK/ERK can regulate cellular levels of LC3B and SQSTM1/p62 at expression levels. Exp Cell Res. 2014 Oct 1;327(2):340-52. doi: 10.1016/j.yexcr.2014.08.001. Epub 2014 Aug 14. PubMed PMID: 25128814; PubMed Central PMCID: PMC4164593.

Richards AL, Soares-Martins JA, Riddell GT, Jackson WT. Generation of unique poliovirus RNA replication organelles. mBio. 2014 Feb 25;5(2):e00833-13. doi: 10.1128/mBio.00833-13. PubMed PMID: 24570367; PubMed Central PMCID: PMC3940031.

Jackson WT. Autophagy as a broad antiviral at the placental interface. Autophagy. 2013 Dec;9(12):1905-7. doi: 10.4161/auto.26819. Epub 2013 Oct 16. PubMed PMID: 24145384.

Tam JS, Jackson WT, Hunter D, Proud D, Grayson MH. Rhinovirus specific IgE can be detected in human sera. J Allergy Clin Immunol. 2013 Nov;132(5):1241-3. doi: 10.1016/j.jaci.2013.07.011. Epub 2013 Aug 30. PubMed PMID: 23992751; PubMed Central PMCID: PMC5429026.

Richards AL, Jackson WT. How positive-strand RNA viruses benefit from autophagosome maturation. J Virol. 2013 Sep;87(18):9966-72. doi: 10.1128/JVI.00460-13. Epub 2013 Jun 12. Review. PubMed PMID: 23760248; PubMed Central PMCID: PMC3754026.

Richards AL, Jackson WT. Behind closed membranes: the secret lives of picornaviruses?. PLoS Pathog. 2013;9(5):e1003262. doi: 10.1371/journal.ppat.1003262. Epub 2013 May 2. Review. PubMed PMID: 23658516; PubMed Central PMCID: PMC3642085.

Richards AL, Jackson WT. That which does not degrade you makes you stronger: infectivity of poliovirus depends on vesicle acidification. Autophagy. 2013 May;9(5):806-7. doi: 10.4161/auto.23962. Epub 2013 Feb 25. PubMed PMID: 23439228; PubMed Central PMCID: PMC3669197.

Richards AL, Jackson WT. Intracellular vesicle acidification promotes maturation of infectious poliovirus particles. PLoS Pathog. 2012;8(11):e1003046. doi: 10.1371/journal.ppat.1003046. Epub 2012 Nov 29. PubMed PMID: 23209416; PubMed Central PMCID: PMC3510256.

Klionsky DJ, et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy. 2012 Apr;8(4):445-544. doi: 10.4161/auto.19496. PubMed PMID: 22966490; PubMed Central PMCID: PMC3404883.

Klein KA, Jackson WT. Human rhinovirus 2 induces the autophagic pathway and replicates more efficiently in autophagic cells. J Virol. 2011 Sep;85(18):9651-4. doi: 10.1128/JVI.00316-11. Epub 2011 Jul 13. PubMed PMID: 21752910; PubMed Central PMCID: PMC3165776.

Klein KA, Jackson WT. Picornavirus subversion of the autophagy pathway. Viruses. 2011 Sep;3(9):1549-61. doi: 10.3390/v3091549. Epub 2011 Aug 26. Review. PubMed PMID: 21994795; PubMed Central PMCID: PMC3187694.

Quiner CA, Jackson WT. Fragmentation of the Golgi apparatus provides replication membranes for human rhinovirus 1A. Virology. 2010 Nov 25;407(2):185-95. doi: 10.1016/j.virol.2010.08.012. Epub 2010 Sep 9. PubMed PMID: 20825962; PubMed Central PMCID: PMC7111317.

Parameswaran P, Sklan E, Wilkins C, Burgon T, Samuel MA, Lu R, Ansel KM, Heissmeyer V, Einav S, Jackson W, Doukas T, Paranjape S, Polacek C, dos Santos FB, Jalili R, Babrzadeh F, Gharizadeh B, Grimm D, Kay M, Koike S, Sarnow P, Ronaghi M, Ding SW, Harris E, Chow M, Diamond MS, Kirkegaard K, Glenn JS, Fire AZ. Six RNA viruses and forty-one hosts: viral small RNAs and modulation of small RNA repertoires in vertebrate and invertebrate systems. PLoS Pathog. 2010 Feb 12;6(2):e1000764. doi: 10.1371/journal.ppat.1000764. PubMed PMID: 20169186; PubMed Central PMCID: PMC2820531.

Taylor MP, Jackson WT. Viruses and arrested autophagosome development. Autophagy. 2009 Aug;5(6):870-1. doi: 10.4161/auto.9046. Epub 2009 Aug 19. PubMed PMID: 19502808.

Taylor MP, Burgon TB, Kirkegaard K, Jackson WT. Role of microtubules in extracellular release of poliovirus. J Virol. 2009 Jul;83(13):6599-609. doi: 10.1128/JVI.01819-08. Epub 2009 Apr 15. PubMed PMID: 19369338; PubMed Central PMCID: PMC2698579.

Klionsky DJ, et al. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy. 2008 Feb;4(2):151-75. doi: 10.4161/auto.5338. Epub 2007 Nov 21. Review. PubMed PMID: 18188003; PubMed Central PMCID: PMC2654259.

Jackson WT, Martin GS. Transcription of the Schizosaccharomyces pombe gene cdc18+: roles of MCB elements and the DSC1 complex. Gene. 2006 Mar 15;369:100-8. doi: 10.1016/j.gene.2005.10.039. Epub 2006 Feb 7. PubMed PMID: 16460890.

Kirkegaard K, Jackson WT. Topology of double-membraned vesicles and the opportunity for non-lytic release of cytoplasm. Autophagy. 2005 Oct-Dec;1(3):182-4. doi: 10.4161/auto.1.3.2065. Epub 2005 Oct 30. PubMed PMID: 16874042.

Jackson WT, Giddings TH Jr, Taylor MP, Mulinyawe S, Rabinovitch M, Kopito RR, Kirkegaard K. Subversion of cellular autophagosomal machinery by RNA viruses. PLoS Biol. 2005 May;3(5):e156. doi: 10.1371/journal.pbio.0030156. Epub 2005 Apr 26. PubMed PMID: 15884975; PubMed Central PMCID: PMC1084330.

Kirkegaard K, Taylor MP, Jackson WT. Cellular autophagy: surrender, avoidance and subversion by microorganisms. Nat Rev Microbiol. 2004 Apr;2(4):301-14. doi: 10.1038/nrmicro865. Review. PubMed PMID: 15031729; PubMed Central PMCID: PMC7097095.

When a picornavirus moves into a cell, it does so with the goal of turning the cell into a virus factory. Most of the normal functions of a cell are shut down and the cell's resources are diverted to the service of the virus. Most dramatically, the cell's innards are rearranged to the point that they become irreversibly damaged and unrecognizable. The virus uses the rearranged cell membranes to set up genetic "copying centers" where the genetic material of the virus is replicated. Our lab studies the large variety of tricks employed by these viruses to rearrange cell membranes.

For example, poliovirus triggers a "starvation response" so that the cell generates double-membraned structures called autophagosomes. Autophagosomes typically act as recycling centers, gathering up cellular contents and chewing them up so the starving cell has the raw materials to build new proteins. Poliovirus, however, uses these recycling centers produce infectious virus particles.

We have found that some common cold viruses use this same strategy. However, we also found that one particular common cold virus, Rhinovirus 1A, uses a different trick. It causes the Golgi apparatus, which is used by the cells to sort newly made proteins, to break up into round "vesicles" which provide a base for virus genome factories.

We also study the emerging pathogen Enterovirus D-68 (EVD-68), a respiratory pathogen of chidren which may be associated with acute flaccid myelitis and Guillain-Barré syndrome. Our previous work on poliovirus and rhinovirus has allowed us to quickly assess the intracellular life cycle of this under-studied virus. EVD-68 also induces autophagosomes and regulates this cellular pathway in novel ways.

What's surprising is that, to a virologist, poliovirus, EVD-68, and Rhinovirus 1A are close cousins, and both need to rearrange cell membranes to produce progeny viruses. However, each regulates cellular membrane formation in a unique way. How do each of their strategies work? Is there some common element among these viruses we could use to target therapeutics and eventually develop a cure for EVD-68, CVB3, and the common cold? These questions currently drive our research.