Wilson Lab - Microbiology

Wilson

Angus Wilson, Ph.D.
Associate Professor, Department of Microbiology
Assistant Dean for Research Laboratory Operations and Facilities
Medical Science Building, Office Rm 210A
550 First Avenue
, New York, NY 10016
Office: (212) 263-0206
Fax: (212) 263-8276
Lab: (212) 263-0238
Lab Fax: (212) 263-8276
Email: angus.wilson@med.nyu.edu

 

 

KEY INTERESTS:

Herpesviruses, herpes simplex virus, Kaposi’s sarcoma-associated herpesvirus, latency, reactivation, transcription, chromatin, epigenetics, pathogenesis, Kaposi’s sarcoma, viruses, gene expression, HCF-1, VP16, RTA, LANA, HSV-1, KSHV, HHV-8, MeCP2, vIRF4

BIOGRAPHIC DETAILS:

Graduate Education

Ph.D. in Molecular Biology in 1990,
King’s College, University of London

Postdoctoral Training:

1991: Cold Spring Harbor Laboratory

Academic Appointments:

1996: Assistant Professor of Microbiology
2004: Associate Professor of Microbiology

Major Responsibilities:

Co-Director, Foundations in Cell & Molecular Biology

Major Honors:

1991: Damon Runyon-Walter Winchell
Cancer Research Foundation Fellow
2001: Lymphoma Research Foundation of America Junior Faculty Fellow

RESEARCH INTERESTS:

Herpesvirus latency: molecular controls and pathogenic consequences

Work in our laboratory aims at understanding how herpesviruses regulate the transition between productive (lytic) replication and a state of long-term persistence known as latency. The ability of these sophisticated to switch from one state to the other is key to their great potential as pathogens, and remarkable success as infectious agents; herpesviruses are found in all vertebrates and even a few invertebrates. During latency, herpesviruses hide in the nucleus of the host cell where they can minimize detection and clearance by host innate and adaptive immune defenses that will otherwise aggressively pursue and eliminate the unwelcome invader. Periodically, a latent virus will reactive and enter the lytic cycle, producing infectious progeny that spreads to new cells and to new hosts. Latent virus is often virtually impossible to clear (“like diamonds, herpes infections are forever”) and discovering how this latent-lytic switch is controlled at a molecular level remains one of the great challenges in virology. There are eight herpesviruses that infect humans and we have projects that study two of these: herpes simplex virus and Kaposi’s sarcoma-associated herpesvirus, each chosen because of their unique and interesting biologies and profound impact on human health.

Project 1. HSV latency in cultured neurons: who’s in control, the virus or the host?

Herpes simplex virus type 1 (HSV-1) and its close-relative HSV-2, establishes latency in the peripheral nervous system and reemerges as painful lesions around the mouth, eyes and genitals. The viral latent genome resides in the neuronal nucleus located in the nerve ganglia, where it is circularized and assembled into chromatin similar to that of the host cell. Silencing of the productive (lytic) cycle genes occurs through epigenetic mechanisms involving histone modifications, but this repressive state can be reversed during reactivation allowing lytic gene transcription. Details of the reactivation process are shrouded in mystery despite decades of careful research in many laboratories. One major reason for this gap in knowledge is the reliance on live-animal infection models that are difficult to manipulate and study. Through a very productive collaboration with colleagues in the laboratories of Drs. Ian Mohr (Department of Microbiology), Pam Roehm (Department of Otolaryngology) and Moses Chao (Molecular Neurobiology Program, Skirball Institute), we have developed a tractable cell culture model for HSV-1 latency/reactivation using primary sympathetic neurons. We are now using this in vitro system to understand the role of the virus-encoded transcription factor VP16 and its cellular cofactor HCF-1 in overcoming epigenetic barriers to reactivation. Our data indicates that VP16 and HCF-1 are initially held in the neuronal cytoplasm but enter the nucleus in cells that support reactivation. We hypothesize that HCF-1 plays critical roles in ejecting repressors including the polycomb group (PcG) repressor complexes from viral chromatin and in establishing an active chromatin state around lytic promoters propelling the program forward. In all likelihood, relocalization of HCF-1 represents a pre-existing process in neurons that has been co-opted by the virus to couple its lifecycle to signaling pathways within the host. Understanding the viral switch will help us understand how neuronal gene expression is modified by intra- and extra-cellular signals.

Project 2. Molecular basis of latency and reactivation in KSHV

The challenges that face latent Kaposi’s sarcoma-associated herpesvirus (KSHV) are very different from HSV in that the virus persist in a rapidly dividing endothelial or lymphocytic cell and that it chooses to modify its environment through extensive reprogramming of cellular gene expression and through the effusive production of extracellular signaling molecules (cytokines and chemokines). Because KSHV promotes the survival and proliferation of infected cells it can form tumors in immunocompromised people, such as organ transplant recipients or those with HIV/AIDS. These tumors are disfiguring and can be life-threatening. Our interests have focused on two viral transcription factors that serve as major regulators of the latency and lytic programs: LANA and RTA. LANA is expressed in all infected cells and manipulates viral and cellular gene expression, enables the viral DNA genome to replicate in synchrony with the host and also physically tethers the viral genome to host chromosomes ensuring passage through cell divisions. Recent projects in the lab have explored the chromosome tethering function of LANA and the control of LANA expression. RTA is only expressed in cells undergoing reactivation and like the HSV initiator protein VP16, RTA is needed to propel the lytic transcription program forward. Our recent studies have focused on identifying viral promoters that respond to RTA with the goal of understanding how these different genes are expressed in an ordered fashion. This has led to the identification of factors that cooperate with RTA to confer promoter- and presumably context-specific activity, so-called co-regulators. Our studies concentrate on two examples, the cellular co-regulator CSL (RBPJk, CBF-1), an endpoint of the Notch signaling pathway and the viral co-regulator vIRF4, an interferon regulatory factor (IRF) homologue that was captured from the cell at some relatively recent point in the evolution of the rhadinovirus family that includes KSHV. We are interested to discover the significance of these factors for the virus. Does KSHV manipulate Notch signaling during reactivation? Why has KSHV selected, incorporated and then modified a master regulator of the antiviral response? These and other studies emphasize the very tight intertwining of virus and host control processes and perhaps helps to explain why herpesviruses can persist for long intervals in a host.

PUBLICATIONS:

Control of viral latency in neurons by axonal mTOR signaling and the 4E-BP translation repressor.
M. Kobayashi, A. C. Wilson, M. V. Chao, I. Mohr.
Genes Dev. 26, 1527­1532 (2012). PMID: 22802527

Transient reversal of episome silencing precedes VP16-dependent transcription during reactivation of latent HSV-1 in neurons.
Kim JY, Mandarino A, Chao MV, Mohr I, Wilson AC.
PLoS Pathog. 2012 8(2):e1002540.
PMID: 22383875

A primary neuron culture system for the study of herpes simplex virus latency and reactivation.
Kobayashi M, Kim JY, Camarena V, Roehm PC, Chao MV, Wilson AC, Mohr I.
J Vis Exp. 2012 62. pii: 3823. doi: 10.3791/3823.
PMID: 22491318

Cooperation between viral interferon regulatory factor 4 and RTA to activate a subset of Kaposi's sarcoma-associated herpesvirus lytic promoters.
Xi X, Persson LM, O'Brien MW, Mohr I, Wilson AC.
J Virol. 2012 86(2):1021-33.
PMID: 22090118

Nature and duration of growth factor signaling through receptor tyrosine kinases regulates HSV-1 latency in neurons.
Camarena V, Kobayashi M, Kim JY, Roehm P, Perez R, Gardner J, Wilson AC, Mohr I, Chao MV
Cell Host Microbe. 2010 Oct 21;8(4):320-30
PMID: 20951966

The latency-associated nuclear antigen interacts with MeCP2 and nucleosomes through separate domains.
Matsumura S, Persson LM, Wong L, Wilson AC.
J Virol. 2010 84(5):2318-30.
PMID: 20032179

Wide-scale use of Notch signaling factor CSL/RBP-Jkappa in RTA-mediated activation of Kaposi's sarcoma-associated herpesvirus lytic genes.
Persson LM, Wilson AC.
J Virol. 2010 84(3):1334-47.
PMID: 19906914

Activation of host translational control pathways by a viral developmental switch.
Arias C, Walsh D, Harbell J, Wilson AC, Mohr I.
PLoS Pathog. 2009 5(3):e1000334.
PMID: 19300492

Association of C-terminal ubiquitin hydrolase BRCA1-associated protein 1 with cell cycle regulator host cell factor 1.
Misaghi S, Ottosen S, Izrael-Tomasevic A, Arnott D, Lamkanfi M, Lee J, Liu J, O'Rourke K, Dixit VM, Wilson AC.
Mol Cell Biol. 2009 29(8):2181-92.
PMID: 19188440

Setting the stage for S phase.
Wilson AC.
Mol Cell. 2007 20;27(2):176-7.
PMID: 17643366

Transcripts encoding K12, v-FLIP, v-cyclin, and the microRNA cluster of Kaposi's sarcoma-associated herpesvirus originate from a common promoter.
Pearce M, Matsumura S, Wilson AC.
J Virol. 2005 79(22):14457-64.
PMID: 16254382

Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen induces a strong bend on binding to terminal repeat DNA.
Wong LY, Wilson AC.
J Virol. 2005 79(21):13829-36.
PMID: 16227305

Activation of the Kaposi's sarcoma-associated herpesvirus major latency locus by the lytic switch protein RTA (ORF50).
Matsumura S, Fujita Y, Gomez E, Tanese N, Wilson AC.
J Virol. 2005 79(13):8493-505.
PMID: 15956592

Transcriptional activation by the Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen is facilitated by an N-terminal chromatin-binding motif.
Wong LY, Matchett GA, Wilson AC.
J Virol. 2004 78(18):10074-85.
PMID: 15331740

 

LAB MEMBERS:

Xiangmei Xi, Ph.D. – Postdoc (co-mentored with Dr. Ian Mohr)
Ju Youn Kim – Graduate Student
Michael O’Brien – Masters Student