Peter J. McGuire, M.D.

Investigator

Medical Genomics and Metabolic Genetics Branch

Head

Metabolism, Infection and Immunity Section

Education

B.A. Villanova University, 1993

M.S. New York Medical College, 1998

M.B.B.Ch. Royal College of Surgeons in Ireland, 2003

Contact Info

BG 10 RM 7N260
10 CENTER DR 1646
BETHESDA MD 20892-1646

Biography

Dr. Peter McGuire received his bachelor's in psychology from Villanova University, a master's. in microbiology and immunology from New York Medical College, and an M.B.B.Ch. (with honors, and equivalent with an M.D.) from the Royal College of Surgeons in Ireland. After completing a combined residency in pediatrics and medical genetics at Mount Sinai Medical Center, he was awarded a fellowship in biochemical genetics from the American College of Medical Genetics and Genzyme. After completing his training, he remained as a junior faculty member in the Program for Inherited Metabolic Diseases at Mount Sinai. Dr. McGuire is board certified in Pediatrics, Clinical Genetics and Biochemical Genetics.

In 2010, Dr. McGuire moved to the National Institutes of Health (NIH) to join the Physician Scientist Development Program to accelerate his translational research program. He was appointed to the position of tenure track Investigator in 2016. Throughout his career, Dr. McGuire has been focused on improving the care of patients with disorders of mitochondrial metabolism. By combining his training in immunology and biochemical genetics, he fashioned a translational research program to understand the interplay between mitochondrial metabolism and the immune system.

His NIH Clinical Center protocol, the NIH MINI Study, is the first organized effort to study immune function in patients with disorders of mitochondrial metabolism, which aims to demonstrate that these patients can be informative regarding the role of mitochondria in immune cell function.

Scientific Summary

The Metabolism, Infection and Immunity Section (MINIS) studies the interplay between metabolism and the immune system through a translational research program involving patients with inborn errors of mitochondrial metabolism. The group studies two aspects of immunometabolism: 1) the effects of immune system activation on end-organ mitochondrial metabolism; and 2) the role of mitochondria in immune cell function.

Immune system activation and end-organ mitochondrial metabolism

The focus of the group's research on immune system activation and end-organ metabolism is based on the clinical observation that infection is a major cause of metabolic decompensation and associated morbidity and mortality in patients with mitochondrial disease. The MINIS uses animal models, combined with infectious organisms or immune activators, to yield insights into the metabolic perturbations seen in disorders of mitochondrial metabolism and to identify potential targets for intervention. Metabolic perturbations are demonstrated using metabolomics, mRNA profiling, proteomics, enzymology and in vivo metabolic imaging with MR spectroscopy.

Kupffer cell depletion studies have highlighted their role as a major node in this immune reaction

Figure 1: The liver is a metabolic and immunologic organ. Signals such as cytokines, virus, PAMPs and DAMPs activate Kupffer cells in the liver. Interferons (e.g. IFNα) and inflammatory cytokines (e.g. IL-1, IL-6, TNFα) produced systemically or locally mediate changes in metabolic reserve and precipitate or exacerbate metabolic decompensation. Kupffer cell depletion studies have highlighted their role as a major node in this immune reaction.]

The group also studies intermediary metabolism and immune cell function. Immune cells drastically alter their metabolic programming during activation and differentiation. The deficiencies present in patients with mitochondrial disease may affect these processes. In order to describe the interactions between intermediary metabolism and immune system function, the group developed a clinical protocol in the National Institutes of Health (NIH) Clinical Center, called the NIH MINI Study: Metabolism Infection and Immunity in IEM (NIH Clinical Trial NCT01780168).

Role of mitochondria in immune cell function

Figure 2: Human mitochondrial morbidity map as a guide for identifying mitochondrial disease patients that may have defects in innate or adaptive immune responses. Cartoon provides a list of known mtDNA or nDNA-encoded mitochondrial disease-associated genes, and in which key mitochondrial function that gene product is known to play a role: (A) mitochondrial calcium transport, mitochondrial membrane (B) fission and (C) fusion, (D) mtDNA replication and stability, or (E) the respiratory chain. Genes listed were compiled from MitoMap.]

This protocol is the first organized effort to examine immune function in patients with mitochondrial disease. These investigations are complemented by concurrent studies of immune function using animal models. By expanding the immune phenotype of patients with mitochondrial disease, these studies will have an impact on the clinical care of patients as well as serving as the foundation for understanding the role of mitochondria in immune function.

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Publications

Offit, K., Gilewski, T., McGuire, P., Schluger, A., Hampel, H., Brown, K., Swenson, J., Neuhausen, S., Skolnick, M., Norton, L., and Goldgar, D. Germline BRCA1 185delAG mutations in Jewish women affected by breast cancer. Lancet, 347, 1643-1644. 1996. [PubMed]

Neuhausen, S., Gilewski, T., Norton, L., Tran, T., McGuire, P., Swensen, J., Hampel, H., Borgen, P., Brown, K., Skolnick, M., et al. Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer. Nature Genetics, 13, 126-128. 1996. [PubMed]

Gurrieri, C., McGuire, P., Zan, H., Yan, X. J., Cerutti, A., Albesiano, E., Allen, S., Vinciguerra, V., Rai, K. R., Ferrarini, M., et al. Chronic lymphocytic leukemia B cells can undergo somatic hypermutation and intraclonal Ig VHDJH gene diversification. J Exp Med, 196, 629-639. 2002. [PubMed]

McGuire, P., Lim-Melia, E., Diaz, G.A., Raymond, K., Larkin, A., Shneider, B.L.,Wasserstein, M.P., Sansaricq, C. Combined liver-kidney transplant for the management of methylmalonic aciduria: a case report and review of the literature. Mol Genet Metab, 93: 22-29. 2008. [PubMed]

McGuire, P., Parikh, A., Diaz, G.A. Profiling of oxidative stress in patients with inborn errors of metabolism. Mol Genet Metab, 98:173-180. 2009. [PubMed]

Weisfeld-Adams, J.D., Morrissey, M.A., Kirmse, B.M., Salveson, B.R. Wasserstein, M.P., McGuire, P.J., Sunny, S., Cohen-Pfeffer, J.L., Yu, C., Caggana, M. Newborn screening and early biochemical follow-up in combined methylmalonic aciduria and homocystinuria, cblC type, and utility of methionine as a secondary screening analyte. Mol Genet Metab, 99:116-123. 2010. [PubMed]

McGuire, P.J., Cunningham-Rundles, C., Ochs, H., Diaz, G.A. Oligoclonality, impaired class switch and B cell memory responses in WHIM syndrome. Clin Immunol, 135:412-421. 2010. [PubMed]

McGuire, P.J., Lee, H.S., members of the Urea Cycle Disorders Consortium, Summar, M. Infectious precipitants of acute hyperammonemia are associated with indicators of increased morbidity in patients with urea cycle disorders. J Pediatr, 163:1705-1710. 2013. [PubMed]

Chandler, R. J., Tarasenko, T.N., Cusmano-Ozog, K., Sun, Q., Reid Sutton, V., Venditti, C.P., McGuire, P.J. Liver-directed adeno-associated virus serotype 8 gene transfer rescues a lethal murine model of citrullinemia type 1. Gene Ther, 20:1188-1191. 2013. [PubMed]

McGuire, P.J., Tarasenko, T.N., Wang, T., Levy, E., Zerfas, P.M., Moran, T.M., Lee, H.S., Bequette, B.J., Diaz, G.A. Acute metabolic decompensation due to influenza in a mouse model of ornithine transcarbamylase deficiency. Dis Model Mech, 7:205-213. 2014. [PubMed]

Tan M., Peng C., Anderson K.A., Chhoy P., Xie Z., Dai L., Park J.S., Chen Y., Huang H., Zhang Y., Ro J., Wagner G.R., Green M.F., Madsen A.S., Schmiesing J., Peterson B.S., Xu G., Ilkayeva O.R., Muehlbauer M.J., Braulke T., Mühlhausen C., Backos D.S., Olsen C.A., McGuire P.J., Pletcher S.D., Lombard D.B., Hirschey M.D., Zhao Y. Lysine Glutarylation Is a Novel Protein Modification Regulated by SIRT5. Cell Metab, 19:605-617. 2014. [PubMed]

Batshaw, M.L., Tuchman, M., Summar, M., Seminara, J.; Members of the Urea Cycle Disorders Consortium (McGuire, P.J.). A longitudinal study of urea cycle disorders. Mol Genet Metab, 113:127-130. 2014. [PubMed]

Tarasenko, T.N., Rosas, O.R., Singh, L.N., Kristaponis, K., Vernon, H.J, McGuire, P.J. A new mouse model of ornithine transcarbamylase deficiency (spf-j) displays cerebral amino acid perturbations at baseline and upon systemic immune activation. PLOS One, 10:e0116594. 2015. [PubMed]

Tarasenko, T.N., Gomez-Rodriguez, J., McGuire, P.J. Impaired T-cell function in argininosuccinate synthetase deficiency. J Leuk Biol, 97:273-278. 2015. [PubMed]

Gartner, V. McGuire, P.J., Lee, P.R. Child neurology: Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency. Neurology, 85:e37-e40. 2015. [PubMed]

Tarasenko, T.N., Singh, L.N., Chatterji-Len, M., Zerfas, P.M., Cusmano-Ozog, K., McGuire, P.J. Kupffer cells modulate hepatic fatty acid oxidation during infection with PR8 influenza. Biochim Biophys Acta 1852:2391-2401. 2015. [PubMed]

Macleod, E., Hall, K.D., McGuire, P.J. Computational modeling to predict nitrogen balance during acute metabolic decompensation in patients with urea cycle disorders. J Inherit Metab Dis, 39:17-24. 2016. [PubMed]

Harrington, E.A., Sloan, J.L., Manoli, I., Chandler, R.J., Schneider, M., McGuire, P.J., Calcedo, R., Wilson, J.M., Venditti, C.P. Neutralizing antibodies against adeno-associated viral capsids in patients with mut methylmalonic acidemia. Hum Gene Ther, 27:345-353. 2016. [PubMed]

Larsen, S.E., Bilenkin, A., Tarasenko, T.N., Arjunaraja, S., Stinson, J.R., McGuire, P.J., Snow, A.L. Sensitivity to restimulation-induced cell death is linked to glycolytic metabolism in human T cells. J Immunol, 198:147-155. 2017. PMCID: PMC5310646. [PubMed]

Tarasenko, T.N., Pacheco, S.E., Koenig, M.K., Gomez-Rodriguez, J., Kapnick, S.M., Diaz, F., Zerfas, P.M., Barca, E., Sudderth, J., DeBerardinis, R.J., Covian-Garcia, R., Balaban, R.S., DiMauro, S., McGuire, P.J. Cytochrome c oxidase (COX) activity is a metabolic checkpoint that regulates cell fate decisions during T-cell activation and differentiation. Cell Metab 25, 1254 - 1268. 2017. [PubMed]

Tarasenko, T.N., McGuire, P.J. The liver is a metabolic and immunologic organ: a reconsideration of metabolic decompensation due to infection in inborn errors of metabolism. Mol Genet Metab, 121: 283-88. PMCID: PMC5553615. 2017. [PubMed]

Kapnick, S.M., Pacheco, S.E., McGuire, P.J. The emerging role of immune dysfunction in mitochondrial diseases as a paradigm for understanding immunometabolism. Metabolism, [epub ahead of print]. 2017. [PubMed]