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David A. Leib, Ph.D.

Title(s):
Professor of Microbiology and Immunology
Adjunct Professor of Biology

Department(s):
Microbiology and Immunology

Education:
David Leib received his BSc from The University of Birmingham, UK in 1983 in Biological Sciences. He then received his PhD from The University of Liverpool, UK in 1986 from the Department of Medical Microbiology. He did a postdoctoral fellowship at Harvard University with Dr Priscilla Schaffer from 1987-1990. He was then was appointed to the faculty of Washington University in St Louis where he served as Professor until 2009, before moving to Dartmouth.

Programs:
Immunology Program
Molecular and Cellular Biology Graduate Programs
Molecular Pathogenesis Program

Websites:
Visit the Leib Lab Website at:
http://geiselmed.dartmouth.edu/leib/

Contact Information:

Geisel School of Medicine at Dartmouth
One Medical Center Drive
Borwell Building 630E
Lebanon NH 03756

Office: 603-650-8616
Fax: 603-650-6223
Email: david.a.leib@dartmouth.edu


Professional Interests:

Since its establishment in 1990 my laboratory has studied the pathogenesis and biology of herpes simplex virus (HSV) with an emphasis on studying the interface of the virus and the host. The generation and use of recombinant viruses in a variety of models of infection followed by analysis with functional genomics and cytokine arrays has allowed us to determine the roles of viral and host factors in the outcome of infection. We have developed a number of reagents, techniques, and approaches. These include BACs to rapidly generate recombinant viruses, non-invasive bioluminescence technology to monitor spread and tropism of HSV in real time, and recombinant viruses that are effective as therapeutic vaccines for prevention of recurrent HSV infections (US Patent #5698431). We have also discovered roles for a number of viral genes in the evasion of innate and adaptive immunity, and of autophagy responses, and elucidated roles for host resistance pathways in the control of acute infection.

Herpes simplex virus is a common ocular pathogen causing a variety of diseases ranging from self-limiting dendritic epithelial keratitis, conjunctivitis, and blepharitis to necrotizing stromal keratitis. HSV exhibits two different modes of gene expression during its life cycle. During the replicative phase of infection all of its genes are expressed. During latency, however, viral gene expression is almost completely repressed. Our approach is to manipulate cloned viral genes and then introduce engineered mutations into the viral genome to generate recombinant viruses. We then use these recombinant viruses in vitro and in vivo to allow the study of viral pathogenesis at the molecular level.

VIRION HOST SHUTOFF (VHS), INNATE IMMUNITY AND VIRAL TROPISM
HSV rapidly shuts off protein synthesis in infected cells in part through the virion host shutoff protein or vhs. Vhs is a ribonuclease, inducing rapid destabilization of host mRNAs. We have demonstrated that vhs activity determines the outcome of infection in vivo by virtue of its ability to degrade viral dsRNA, to alter innate immune function, and to promote viral replication in vivo. Our ongoing work is determining how alterations in viral RNA turnover modulated by vhs affect double-stranded RNA sensing, and thereby the induction of the innate immune response. We are using functional genomic analysis in vivo and in vitro to determine the contribution of vhs to the specific alteration of host gene expression and elucidating the structural determinants that govern the immunomodulatory activity of vhs. Finally, using our real-time bioluminescent approaches, we are showing that the tropism of HSV is strongly shaped by innate immunity, with certain pathways being necessary for protection of the CNS, and others for prevention of generalized hematogenous spread.

INTERFACE BETWEEN HSV, XENOPHAGY, AND IMMUNITY
Autophagy is a constitutive cellular process in which cytoplasmic components are sequestered and degraded by the lysosome to generate metabolic precursors, to remove damaged organelles and altered intracellular components. If the autophagic vacuole also engulfs and destroys invading pathogens, the process is known as xenophagy. Three important aspects of the pathogenesis of HSV are being studied. First, we are determining the role of xenophagy in the pathogenesis of HSV-1. Second, we are exploring mechanisms by which viral genes subvert the host innate xenophagy and interferon (IFN)-mediated antiviral responses. Third, we are determining the impact of two HSV proteins on the regulation of xenophagy and antigen presentation. Our work is demonstrating that xenophagy is a critical process for the protection of the host from infection through both innate and adaptive immune responses, and that subversion of xenophagy is a pivotal determinant of HSV pathogenesis.

Grant Information:

Principal Investigator, NEI RO1 09083 "Viral and host factors in herpetic reactivation", Funded 1992-2016.

Principal Investigator, NEI RO1 10707 "HSV-induced RNA degradation in pathogenesis", Funded 1994-2014.

Director, Project 3, AI098681 “Innate immunity and the HSV lytic/latent balance”. Program Project (D.M. Coen, Harvard Medical School, Director)
NIH NIAID PO1 “Viral and host mechanisms that tilt the HSV lytic/latent balance”. Funded 2013-2018.

Subaward 1R21AI05896-01 “Antagonizing miRNAs in a strategy to cure HSV latency”. Funded 2013-1015.



Courses Taught:

Microbiology (undergraduate), Fundamentals of Virology, Advanced Cellular and Molecular Immunology, Cellular and Molecular Basis of Immunity (graduate school), Immunology and Virology (medical school).


Selected Publications:

 

Rosato PC, Leib DA
Intrinsic innate immunity fails to control herpes simplex virus and vesicular stomatitis virus replication in sensory neurons and fibroblasts.
J Virol 2014 Sep 1; 88(17):9991-10001
PMID: 24942587

Pan D, Flores O, Umbach JL, Pesola JM, Bentley P, Rosato PC, Leib DA, Cullen BR, Coen DM
A neuron-specific host microRNA targets herpes simplex virus-1 ICP0 expression and promotes latency.
Cell Host Microbe 2014 Apr 9; 15(4):446-56
PMID: 24721573

Katzenell S, Chen Y, Parker ZM, Leib DA
The differential interferon responses of two strains of Stat1-deficient mice do not alter susceptibility to HSV-1 and VSV in vivo.
Virology 2014 Feb; 450-451:350-4
PMID: 24503098

Murphy AA, Rosato PC, Parker ZM, Khalenkov A, Leib DA
Synergistic control of herpes simplex virus pathogenesis by IRF-3, and IRF-7 revealed through non-invasive bioluminescence imaging.
Virology 2013 Sep; 444(1-2):71-9
PMID: 23777662

Leib DA
Herpes simplex virus encephalitis: toll-free access to the brain.
Cell Host Microbe 2012 Dec 13; 12(6):731-2
PMID: 23245315

Gobeil PA, Leib DA
Herpes simplex virus γ34.5 interferes with autophagosome maturation and antigen presentation in dendritic cells.
MBio 2012 Oct 16; 3(5):e00267-12
PMID: 23073763

Pasieka TJ, Menachery VD, Rosato PC, Leib DA
Corneal replication is an interferon response-independent bottleneck for virulence of herpes simplex virus 1 in the absence of virion host shutoff.
J Virol 2012 Jul; 86(14):7692-5
PMID: 22553331

Pasieka TJ, Cilloniz C, Carter VS, Rosato P, Katze MG, Leib DA
Functional genomics reveals an essential and specific role for Stat1 in protection of the central nervous system following herpes simplex virus corneal infection.
J Virol 2011 Dec; 85(24):12972-81
PMID: 21994441

Pasieka TJ, Collins L, O'Connor MA, Chen Y, Parker ZM, Berwin BL, Piwnica-Worms DR, Leib DA
Bioluminescent imaging reveals divergent viral pathogenesis in two strains of Stat1-deficient mice, and in αßγ interferon receptor-deficient mice.
PLoS One 2011; 6(9):e24018
PMID: 21915277

Menachery VD, Pasieka TJ, Leib DA
Interferon regulatory factor 3-dependent pathways are critical for control of herpes simplex virus type 1 central nervous system infection.
J Virol 2010 Oct; 84(19):9685-94
PMID: 20660188