Graduate Program Information
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Assistant Professor of Biochemistry and Biophysics
Ph.D. University of Chicago 2001

Viral mechanisms of metabolic network manipulation

Viruses are obligate parasites that depend on the metabolic resources provided by the host to supply the energy and biochemical building blocks necessary for virion production. Many anti-viral compounds, such as nucleotide analogs, target viral utilization of macro-molecular precursors and have proven to be clinically successful. Despite these successes, very little is known about the mechanisms governing viral manipulation of the small molecule metabolic network. Our laboratory’s goal is to elucidate these mechanisms and thereby identify potential anti-viral therapeutic targets.

Currently our work focuses on human cytomegalovirus (HCMV), a herpes virus, which is the leading cause of congenital viral infection, resulting in central nervous system damage in the majority of symptomatic newborns. HCMV infection also poses a serious health risk to immunosuppressed individuals, such as the elderly, and patients receiving immunosuppressive chemotherapy, including cancer patients, transplant recipients, and AIDS patients.

In order to elucidate virally-induced changes to the metabolic network, we utilize liquid chromatography/ tandem mass spectrometry (LC-MS/MS) to measure the concentrations of specific metabolite pools. Utilizing this technology, we can measure the concentrations of a wide variety of metabolites in tissue culture, covering a large proportion of metabolite chemical diversity.

In addition to measuring metabolite concentrations, we also measure the rate of molecular conversion from one metabolite to another, i.e. metabolic flux. The speed of metabolic flux is crucial to understanding metabolic network behavior and how it is affected by a cellular perturbation, e.g. viral infection. We measure metabolic flux by feeding cells with stable-isotope-labeled nutrient, e.g. ¹³C glucose, which because of its heavier composition (as compared to ¹²C) produces a unique mass signature. As ¹³C incorporates into the metabolic network it can be distinguished from ¹²C metabolites by mass spectrometry. By measuring the speed of ¹³C incorporation into various metabolite pools we can estimate metabolic flux values and how they are affected by various perturbations such as viral infection.

We have found that HCMV infection activates several metabolic pathways including various aspects of central carbon metabolism and nucleotide biosynthesis. Inhibition of certain virally-up-regulated pathways has been found to block normal viral replication. In addition to screening for metabolic pathways important for viral infection, we utilize genetic techniques such as bacterial artificial chromosome based mutagenesis and retroviral transduction to identify the viral and host cell factors responsible for virally-induced metabolic changes. Increased understanding of the mechanisms of viral metabolic manipulation and the role they play during viral infection will continue to illuminate potential therapeutic avenues.

Recent Publications

Munger J, Bennett BD, Parikh A, Feng XJ, McArdle J, Rabitz HA, Shenk T, Rabinowitz JD (2008) Systems-level metabolic flux profiling identifies fatty acid synthesis as a target for antiviral therapy. Nat Biotechnol, 26:1179-86

Munger J, Bajad SU, Coller HA, Shenk T, Rabinowitz JD (2006) Dynamics of the cellular metabolome during human cytomegalovirus infection. PLoS Pathog, 2:e132

Munger J, Yu D, Shenk T (2006) UL26-deficient human cytomegalovirus produces virions with hypophosphorylated pp28 tegument protein that is unstable within newly infected cells. J Virol, 80:3541-8

Benetti L, Munger J, Roizman B (2003) The herpes simplex virus 1 US3 protein kinase blocks caspase-dependent double cleavage and activation of the proapoptotic protein BAD. J Virol, 77:6567-73

Munger J, Hagglund R, Roizman B (2003) Infected cell protein No. 22 is subject to proteolytic cleavage by caspases activated by a mutant that induces apoptosis. Virology, 305:364-70

Munger J, Zhou G, Roizman B (2003) Cell death on demand: Herpes simplex viruses and apoptosis. In C. D. OíConnor (ed.), Microbial Subversion of Host Cells, Cambridge University Press, Cambridge, 229-245

Hagglund R, Munger J, Poon AP, Roizman B (2002) U(S)3 protein kinase of herpes simplex virus 1 blocks caspase 3 activation induced by the products of U(S)1.5 and U(L)13 genes and modulates expression of transduced U(S)1.5 open reading frame in a cell type-specific manner. J Virol, 76:743-54

Munger J, Chee AV, Roizman B (2001) The U(S)3 protein kinase blocks apoptosis induced by the d120 mutant of herpes simplex virus 1 at a premitochondrial stage. J Virol, 75:5491-7

Munger J, Roizman B (2001) The US3 protein kinase of herpes simplex virus 1 mediates the posttranslational modification of BAD and prevents BAD-induced programmed cell death in the absence of other viral proteins. Proc Natl Acad Sci U S A, 98:10410-5

Galvan V, Brandimarti R, Munger J, Roizman B (2000) Bcl-2 blocks a caspase-dependent pathway of apoptosis activated by herpes simplex virus 1 infection in HEp-2 cells. J Virol, 74:1931-8

Graduate students in my laboratory work toward a Ph.D. degree in the following program[s]:

Ph.D. in Biochemistry
Ph.D. in Microbiology and Immunology

Ph.D. candidates in my laboratory may also be affiliated with these programs:

Contact Information

E-Mail: joshua_munger@urmc.rochester.edu

Joshua Munger
Department of Biochemistry and Biophysics
University of Rochester School of Medicine and Dentistry
601 Elmwood Ave, Box 712
Rochester, New York 14642

Office: Medical Center G-6806
Telephone: (585) 273-4800; Fax: (585) 275-6007