David A. Leib, PHD
Professor of Microbiology and Immunology
Adjunct Professor of Biology
Microbiology and Immunology
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.
Molecular and Cellular Biology Graduate Programs
Molecular Pathogenesis Program
Visit the Leib Lab Website at:
Geisel School of Medicine at Dartmouth
One Medical Center Drive
Borwell Building 630E
Lebanon NH 03756
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.
MODULATION OF INNATE IMMUNITY
The ability of HSV to evade innate immunity is critical to its success as a pathogen. A number of projects in the lab are focused on the molecular basis of immune evasion and determining the precise genes and domains that are involved. In particular, we are studying the g34.5 of HSV which has multiple cellular binding partners that collectively serve to control the interferon response, global translation rates, autophagy and egress from the cell. g34.5 is therefore a highly versatile and potent determinant of virulence.
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. We have also recently shown that autophagy represents a target for therapy against the blinding sequelae of ocular HSV infection. Our current work is therefore focused on determining the therapeutic effects of modulation of autophagy on inflammatory disease.
Principal Investigator, NEI RO1 09083 "Viral and host factors in herpetic reactivation", Funded 1992-2016.
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.
Microbiology (undergraduate), Fundamentals of Virology, Advanced Cellular and Molecular Immunology, Cellular and Molecular Basis of Immunity (graduate school), Immunology and Virology (medical school).
Immune- and Nonimmune-Compartment-Specific Interferon Responses Are Critical Determinants of Herpes Simplex Virus-Induced Generalized Infections and Acute Liver Failure.
Neuronal IFN signaling is dispensable for the establishment of HSV-1 latency.
Herpes Simplex Virus and Interferon Signaling Induce Novel Autophagic Clusters in Sensory Neurons.
Dendritic Cell Autophagy Contributes to Herpes Simplex Virus-Driven Stromal Keratitis and Immunopathology.
Role of the DNA Sensor STING in Protection from Lethal Infection following Corneal and Intracerebral Challenge with Herpes Simplex Virus 1.
Neurons versus herpes simplex virus: the innate immune interactions that contribute to a host-pathogen standoff.
Neuronal Interferon Signaling Is Required for Protection against Herpes Simplex Virus Replication and Pathogenesis.
Intrinsic innate immunity fails to control herpes simplex virus and vesicular stomatitis virus replication in sensory neurons and fibroblasts.
A neuron-specific host microRNA targets herpes simplex virus-1 ICP0 expression and promotes latency.
The differential interferon responses of two strains of Stat1-deficient mice do not alter susceptibility to HSV-1 and VSV in vivo.