Micah Luftig

Overview:

The Luftig laboratory studies viruses that cause cancer with an overarching goal of defining the basic molecular mechanisms underlying pathogenesis and leveraging these findings for diagnostic value and therapeutic intervention. Our work primarily focuses on the common herpesvirus, Epstein-Barr virus (EBV). This virus latently infects virtually all adults worldwide being acquired early in life. In the immune suppressed, EBV promotes lymphomas in the B cells that it naturally infects. However, EBV can also infect epithelial cells and other lymphocytes contributing to human cancers as wide-ranging as nasopharyngeal and gastric carcinoma to aggressive NK/T-cell, Burkitt, and Hodgkin lymphomas. Overall, EBV contributes to approximately 2% of all human cancers worldwide leading to nearly 200,000 deaths annually.

We use cutting-edge, cross-disciplinary and highly collaborative approaches to characterize the temporal dynamics and single cell heterogeneity of EBV infection. With these strategies, we aim to discover fundamental molecular circuits underlying transcriptional control, viral manipulation of host signaling pathways, and metabolic regulation that collectively influence infected cell fate decisions. By understanding the nature of viral control of infected host cells, we are also well positioned to discover vulnerabilities in EBV-associated diseases and characterize new therapeutic interventions in cell-based and pre-clinical animal models.

Positions:

Associate Professor of Molecular Genetics and Microbiology

Molecular Genetics and Microbiology
School of Medicine

Vice-Chair in the Department of Molecular Genetics and Microbiology

Molecular Genetics and Microbiology
School of Medicine

Associate Professor of Medicine

Medicine, Hematologic Malignancies and Cellular Therapy
School of Medicine

Associate Professor of Immunology

Immunology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2003

Harvard University

Grants:

NIAID Virology Quality Assurance - Base to Opt 6

Administered By
Duke Human Vaccine Institute
Awarded By
National Institutes of Health
Role
Co Investigator
Start Date
End Date

Novel regulatory controls of Hepatitis C Virus envelopment and secretion by the viral NS4A protein

Administered By
Molecular Genetics and Microbiology
Awarded By
National Institutes of Health
Role
Co-Sponsor
Start Date
End Date

Host pathways regulating Epstein-Barr virus-mediated B cell growth transformation

Administered By
Molecular Genetics and Microbiology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Targeting Apoptosis and Immune Control of Epstein-Barr Virus Infected Tonsillar B Cells

Administered By
Molecular Genetics and Microbiology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

The role of EBNA3A in the survival of Epstein-Barr Virus-infected tonsillar B cells

Administered By
Molecular Genetics and Microbiology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Publications:

Infection and inflammation: New perspectives on Alzheimer's disease

Neuroinflammation has been recognized as a component of Alzheimer's Disease (AD) pathology since the original descriptions by Alois Alzheimer and a role for infections in AD pathogenesis has long been hypothesized. More recently, this hypothesis has gained strength as human genetics and experimental data suggest key roles for inflammatory cells in AD pathogenesis. To review this topic, Duke/University of North Carolina (Duke/UNC) Alzheimer's Disease Research Center hosted a virtual symposium: “Infection and Inflammation: New Perspectives on Alzheimer's Disease (AD).” Participants considered current evidence for and against the hypothesis that AD could be caused or exacerbated by infection or commensal microbes. Discussion focused on connecting microglial transcriptional states to functional states, mouse models that better mimic human immunity, the potential involvement of inflammasome signaling, metabolic alterations, self-reactive T cells, gut microbes and fungal infections, and lessons learned from Covid-19 patients with neurologic symptoms. The content presented in the symposium, and major topics raised in discussions are reviewed in this summary of the proceedings.
Authors
Whitson, HE; Colton, C; El Khoury, J; Gate, D; Goate, A; Heneka, MT; Kaddurah-Daouk, R; Klein, RS; Shinohara, ML; Sisodia, S; Spudich, SS; Stevens, B; Tanzi, R; Ting, JP; Garden, G; Aiello, A; Chiba-Falek, O; Heitman, J; Johnson, KG; Luftig, M; Moseman, A; Rawls, J; Swanstrom, R; Terrando, N
MLA Citation
Whitson, H. E., et al. “Infection and inflammation: New perspectives on Alzheimer's disease.” Brain, Behavior, and Immunity  Health, vol. 22, July 2022. Scopus, doi:10.1016/j.bbih.2022.100462.
URI
https://scholars.duke.edu/individual/pub1517953
Source
scopus
Published In
Brain, Behavior, & Immunity Health
Volume
22
Published Date
DOI
10.1016/j.bbih.2022.100462

Correction: Single-cell RNA-seq reveals transcriptomic heterogeneity mediated by host-pathogen dynamics in lymphoblastoid cell lines.

Authors
SoRelle, ED; Dai, J; Bonglack, EN; Heckenberg, EM; Zhou, JY; Giamberardino, SN; Bailey, JA; Gregory, SG; Chan, C; Luftig, MA
MLA Citation
SoRelle, Elliott D., et al. “Correction: Single-cell RNA-seq reveals transcriptomic heterogeneity mediated by host-pathogen dynamics in lymphoblastoid cell lines.Elife, vol. 10, Nov. 2021. Pubmed, doi:10.7554/eLife.75422.
URI
https://scholars.duke.edu/individual/pub1501343
PMID
34762045
Source
pubmed
Published In
Elife
Volume
10
Published Date
DOI
10.7554/eLife.75422

Author Correction: Highly recurrent CBS epimutations in gastric cancer CpG island methylator phenotypes and inflammation.

Authors
Padmanabhan, N; Kyon, HK; Boot, A; Lim, K; Srivastava, S; Chen, S; Wu, Z; Lee, H-O; Mukundan, VT; Chan, C; Chan, YK; Xuewen, O; Pitt, JJ; Isa, ZFA; Xing, M; Lee, MH; Tan, ALK; Ting, SHW; Luftig, MA; Kappei, D; Kruger, WD; Bian, J; Ho, YS; Teh, M; Rozen, SG; Tan, P
MLA Citation
Padmanabhan, Nisha, et al. “Author Correction: Highly recurrent CBS epimutations in gastric cancer CpG island methylator phenotypes and inflammation.Genome Biol, vol. 22, no. 1, June 2021, p. 181. Pubmed, doi:10.1186/s13059-021-02405-z.
URI
https://scholars.duke.edu/individual/pub1485594
PMID
34140045
Source
pubmed
Published In
Genome Biology
Volume
22
Published Date
Start Page
181
DOI
10.1186/s13059-021-02405-z

Highly recurrent CBS epimutations in gastric cancer CpG island methylator phenotypes and inflammation.

<h4>Background</h4>CIMP (CpG island methylator phenotype) is an epigenetic molecular subtype, observed in multiple malignancies and associated with the epigenetic silencing of tumor suppressors. Currently, for most cancers including gastric cancer (GC), mechanisms underlying CIMP remain poorly understood. We sought to discover molecular contributors to CIMP in GC, by performing global DNA methylation, gene expression, and proteomics profiling across 14 gastric cell lines, followed by similar integrative analysis in 50 GC cell lines and 467 primary GCs.<h4>Results</h4>We identify the cystathionine beta-synthase enzyme (CBS) as a highly recurrent target of epigenetic silencing in CIMP GC. Likewise, we show that CBS epimutations are significantly associated with CIMP in various other cancers, occurring even in premalignant gastroesophageal conditions and longitudinally linked to clinical persistence. Of note, CRISPR deletion of CBS in normal gastric epithelial cells induces widespread DNA methylation changes that overlap with primary GC CIMP patterns. Reflecting its metabolic role as a gatekeeper interlinking the methionine and homocysteine cycles, CBS loss in vitro also causes reductions in the anti-inflammatory gasotransmitter hydrogen sulfide (H<sub>2</sub>S), with concomitant increase in NF-κB activity. In a murine genetic model of CBS deficiency, preliminary data indicate upregulated immune-mediated transcriptional signatures in the stomach.<h4>Conclusions</h4>Our results implicate CBS as a bi-faceted modifier of aberrant DNA methylation and inflammation in GC and highlights H<sub>2</sub>S donors as a potential new therapy for CBS-silenced lesions.
Authors
Padmanabhan, N; Kyon, HK; Boot, A; Lim, K; Srivastava, S; Chen, S; Wu, Z; Lee, H-O; Mukundan, VT; Chan, C; Chan, YK; Xuewen, O; Pitt, JJ; Isa, ZFA; Xing, M; Lee, MH; Tan, ALK; Ting, SHW; Luftig, MA; Kappei, D; Kruger, WD; Bian, J; Ho, YS; Teh, M; Rozen, SG; Tan, P
MLA Citation
Padmanabhan, Nisha, et al. “Highly recurrent CBS epimutations in gastric cancer CpG island methylator phenotypes and inflammation.Genome Biology, vol. 22, no. 1, June 2021, p. 167. Epmc, doi:10.1186/s13059-021-02375-2.
URI
https://scholars.duke.edu/individual/pub1484238
PMID
34074348
Source
epmc
Published In
Genome Biology
Volume
22
Published Date
Start Page
167
DOI
10.1186/s13059-021-02375-2

Monocarboxylate transporter antagonism reveals metabolic vulnerabilities of viral-driven lymphomas.

Epstein-Barr virus (EBV) is a ubiquitous herpesvirus that typically causes asymptomatic infection but can promote B lymphoid tumors in the immune suppressed. In vitro, EBV infection of primary B cells stimulates glycolysis during immortalization into lymphoblastoid cell lines (LCLs). Lactate export during glycolysis is crucial for continued proliferation of many cancer cells-part of a phenomenon known as the "Warburg effect"- and is mediated by monocarboxylate transporters (MCTs). However, the role of MCTs has yet to be studied in EBV-associated malignancies, which display Warburg-like metabolism in vitro. Here, we show that EBV infection of B lymphocytes directly promotes temporal induction of MCT1 and MCT4 through the viral proteins EBNA2 and LMP1, respectively. Functionally, MCT1 was required for early B cell proliferation, and MCT4 up-regulation promoted acquired resistance to MCT1 antagonism in LCLs. However, dual MCT1/4 inhibition led to LCL growth arrest and lactate buildup. Metabolic profiling in LCLs revealed significantly reduced oxygen consumption rates (OCRs) and NAD+/NADH ratios, contrary to previous observations of increased OCR and unaltered NAD+/NADH ratios in MCT1/4-inhibited cancer cells. Furthermore, U-13C6-glucose labeling of MCT1/4-inhibited LCLs revealed depleted glutathione pools that correlated with elevated reactive oxygen species. Finally, we found that dual MCT1/4 inhibition also sensitized LCLs to killing by the electron transport chain complex I inhibitors phenformin and metformin. These findings were extended to viral lymphomas associated with EBV and the related gammaherpesvirus KSHV, pointing at a therapeutic approach for targeting both viral lymphomas.
Authors
Bonglack, EN; Messinger, JE; Cable, JM; Ch'ng, J; Parnell, KM; Reinoso-Vizcaíno, NM; Barry, AP; Russell, VS; Dave, SS; Christofk, HR; Luftig, MA
MLA Citation
Bonglack, Emmanuela N., et al. “Monocarboxylate transporter antagonism reveals metabolic vulnerabilities of viral-driven lymphomas.Proceedings of the National Academy of Sciences of the United States of America, vol. 118, no. 25, June 2021, p. e2022495118. Epmc, doi:10.1073/pnas.2022495118.
URI
https://scholars.duke.edu/individual/pub1485641
PMID
34161263
Source
epmc
Published In
Proceedings of the National Academy of Sciences of the United States of America
Volume
118
Published Date
Start Page
e2022495118
DOI
10.1073/pnas.2022495118

Research Areas:

3' Untranslated Regions
Actin Cytoskeleton
Adult
Algorithms
Animals
Antibodies, Monoclonal
Apoptosis
Automation
B-Lymphocytes
Base Sequence
Biological Markers
Cell Adhesion Molecules
Cell Cycle Proteins
Cell Growth Processes
Cell Line
Cell Line, Transformed
Cell Line, Tumor
Cell Nucleus
Cell Proliferation
Cell Survival
Cell Transformation, Neoplastic
Cell Transformation, Viral
Cells, Cultured
Chromatin Immunoprecipitation
Clone Cells
Coculture Techniques
Crystallography, X-Ray
DNA Damage
DNA Mutational Analysis
DNA, Neoplasm
DNA-Binding Proteins
Epithelial Cells
Epstein-Barr Virus Infections
Epstein-Barr Virus Nuclear Antigens
Epstein-barr Virus
Exome
Feeder Cells
Gene Expression
Gene Expression Profiling
Gene Expression Regulation
Gene Library
Gene Order
Genes, Reporter
Genes, cdc
Genetic Heterogeneity
Genetic Variation
Genetic Vectors
HIV Envelope Protein gp41
HIV-1
Herpesvirus 1, Human
Herpesvirus 4, Human
High-Throughput Nucleotide Sequencing
Host-Pathogen Interactions
Humans
Hydrophobic and Hydrophilic Interactions
Interleukin-1 Receptor-Associated Kinases
Leucine
Leukemia, Lymphocytic, Chronic, B-Cell
Luciferases
Lymphocyte Activation
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Lymphoproliferative Disorders
Macrophages
Mass Spectrometry
Mice
MicroRNAs
Microscopy, Electron
Models, Biological
Models, Molecular
Molecular Sequence Data
Molecular Targeted Therapy
Molecular Weight
Mutation
NF-kappa B
Neutralization Tests
Oligonucleotide Array Sequence Analysis
Oncogenes
Oncogenic Viruses
Peptide Fragments
Phosphatidylinositol 3-Kinases
Phosphorylation
Piperazines
Protein Binding
Protein Conformation
Protein Kinases
Protein Structure, Quaternary
Protein Structure, Secondary
Protein Structure, Tertiary
Protein Transport
Protein-Serine-Threonine Kinases
Proteins
Proto-Oncogene Proteins c-kit
RNA
RNA, Messenger
RNA, Viral
Real-Time Polymerase Chain Reaction
Receptor, Platelet-Derived Growth Factor alpha
Receptors, Virus
Recombinant Fusion Proteins
Recombinant Proteins
Retroviridae
Reverse Transcriptase Polymerase Chain Reaction
Sequence Analysis, RNA
Sequence Homology, Nucleic Acid
Signal Transduction
Structure-Activity Relationship
TNF Receptor-Associated Factor 6
Transcription Factors
Transduction, Genetic
Transfection
Tryptophan
Tumor Cells, Cultured
Tumor Suppressor Protein p53
Tumor Suppressor Proteins
Tumor Virus Infections
Up-Regulation
Vero Cells
Viral Envelope Proteins
Viral Matrix Proteins
Viral Proteins
Virus Internalization
Virus Latency
Virus Replication
epstein-barr virus