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Related Research Units

Infectious Diseases Research
Goldfeld Laboratory Research
PCMM Research

Research Overview

A major focus of the Goldfeld laboratory is understanding the mechanisms of transcriptional activation of the tumor necrosis factor (TNF) gene. Through studies of TNF gene expression in a range of cell types, including T cells, B cells, macrophages, and fibroblasts, the laboratory developed the paradigm of cell type- and stimulus-specific inducible eukaryotic gene regulation through the formation of distinct enhanceosomes and higher-order chromatin structure.  A key feature of this process is the recruitment of different sets of transcription factors, including the nuclear factor of activated T cells (NFAT) proteins, and associated co-activators to overlapping binding motifs within a highly conserved ~200 nucleotide region of the TNF promoter.  Furthermore, through comparative sequence analysis of the TNF promoter in multiple species (which was the broadest interspecies comparison for an immune response gene regulatory region) and distinct human populations, the laboratory has discovered SNPs that mark primate ancestry and that are linked with neighboring HLA molecules in ethnic-specific patterns, providing insight into the evolution of TNF gene regulation.  The laboratory has also discovered that in T cells and cells of the monocyte/macrophage lineage, the native TNF locus displays distinct patterns of DNase hypersensitive sites (HSSs), which function as distal enhancers or as matrix attachment regions (MARs).  In T cells, activation-dependent intrachromosomal interactions between distal enhancers and the TNF promoter bring NFAT complexes into close proximity and, through circularizing the TNF gene (the first such observation in a mammalian gene), optimally position it for transcriptional re-initiation. Ongoing work in the laboratory is elucidating the role of chromatin organization in cell type- and stimulus-specific regulation of the TNF gene, in particular during tolerance and interferon-γ stimulation.  These studies have provided key insights into the basic mechanisms of inducible eukaryotic gene expression in a clinically and physiologically relevant model system.

The regulation of transcription and replication of HIV is another main research focus in the Goldfeld laboratory.  Although the majority of HIV research has examined the virus in isolation, tuberculosis represents the greatest threat to AIDS patients worldwide; thus, a critical feature of studies in the laboratory is the use of co-infection model systems using both HIV and M. tuberculosis (MTb).  Furthermore, by analyzing a range of viral isolates representing major HIV subtypes circulating in the world's population, the laboratory has characterized both conserved and subtype-specific sequences in the HIV long terminal repeat (LTR), identifying a role for NFAT5 as a host factor and elucidating the binding patterns of nuclear factor κB and Sp1 proteins.

A third area of focus of the Goldfeld laboratory is the study of host susceptibility and resistance genes and their variants that influence the pathogenesis of TB and AIDS, including the first identification and role of IL-10-producing T regulatory cells in an infectious disease and the first gene associated with susceptibility to TB progression.  Through collaborations with international partners, the laboratory has established clinical trials with patient cohorts in Cambodia and Ethiopia.  The impact of these clinical studies such as the determination of optimal timing of antiretroviral therapy in the CAMELIA (CAMbodian Early vs. Late Introduction of Antiretrovirals) trial has resulted in improved drug regimens for thousands of patients: and provides a model for HIV/TB care that will be transferred and adapted to resource-poor settings elsewhere in Asia and Africa.  By nesting scientific studies within this clinical trial, the laboratory is elucidating immunological mechanisms and genetic associations with different disease outcomes in TB, AIDS, and TB/HIV co-infection.

Publications

  1. Fc?R-mediated SARS-CoV-2 infection of monocytes activates inflammation. Nature. 2022 06; 606(7914):576-584. View Abstract
  2. The oral drug nitazoxanide restricts SARS-CoV-2 infection and attenuates disease pathogenesis in Syrian hamsters. bioRxiv. 2022 Feb 09. View Abstract
  3. SARS-CoV-2 infects blood monocytes to activate NLRP3 and AIM2 inflammasomes, pyroptosis and cytokine release. Res Sq. 2021 Aug 11. View Abstract
  4. SARS-CoV-2 infects blood monocytes to activate NLRP3 and AIM2 inflammasomes, pyroptosis and cytokine release. medRxiv. 2021 Mar 08. View Abstract
  5. Identification of a Distal Locus Enhancer Element That Controls Cell Type-Specific TNF and LTA Gene Expression in Human T Cells. J Immunol. 2020 11 01; 205(9):2479-2488. View Abstract
  6. Comment on: Effects of time of initiation of antiretroviral therapy in the treatment of patients with HIV/TB co-infection, by Chelkeba L. et al. Ann Med Surg (Lond). 2020 Sep; 57:22-23. View Abstract
  7. Cytoplasmic RNA Sensor Pathways and Nitazoxanide Broadly Inhibit Intracellular Mycobacterium tuberculosis Growth. iScience. 2019 Dec 20; 22:299-313. View Abstract
  8. The FDA-Approved Oral Drug Nitazoxanide Amplifies Host Antiviral Responses and Inhibits Ebola Virus. iScience. 2019 Sep 27; 19:1279-1290. View Abstract
  9. Treatment of drug-resistant tuberculosis among people living with HIV. Curr Opin HIV AIDS. 2018 11; 13(6):478-485. View Abstract
  10. Initiation, scale-up and outcomes of the Cambodian National MDR-TB programme 2006-2016: hospital and community-based treatment through an NGO-NTP partnership. BMJ Open Respir Res. 2018; 5(1):e000256. View Abstract
  11. Diagnostic Potential of Imaging Flow Cytometry. Trends Biotechnol. 2018 07; 36(7):649-652. View Abstract
  12. Imaging flow cytometry analysis of intracellular pathogens. Methods. 2017 01 01; 112:91-104. View Abstract
  13. Achieving high treatment success for multidrug-resistant TB in Africa: initiation and scale-up of MDR TB care in Ethiopia--an observational cohort study. Thorax. 2015 Dec; 70(12):1181-8. View Abstract
  14. A Role for IFITM Proteins in Restriction of Mycobacterium tuberculosis Infection. Cell Rep. 2015 Nov 03; 13(5):874-83. View Abstract
  15. T cells and adaptive immunity to Mycobacterium tuberculosis in humans. Immunol Rev. 2015 Mar; 264(1):74-87. View Abstract
  16. TB-IRIS, T-cell activation, and remodeling of the T-cell compartment in highly immunosuppressed HIV-infected patients with TB. AIDS. 2015 Jan 28; 29(3):263-73. View Abstract
  17. A distal locus element mediates IFN-? priming of lipopolysaccharide-stimulated TNF gene expression. Cell Rep. 2014 Dec 11; 9(5):1718-1728. View Abstract
  18. Causes and determinants of mortality in HIV-infected adults with tuberculosis: an analysis from the CAMELIA ANRS 1295-CIPRA KH001 randomized trial. Clin Infect Dis. 2014 Aug 01; 59(3):435-45. View Abstract
  19. Plasma concentrations, efficacy and safety of efavirenz in HIV-infected adults treated for tuberculosis in Cambodia (ANRS 1295-CIPRA KH001 CAMELIA trial). PLoS One. 2014; 9(3):e90350. View Abstract
  20. Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome after early initiation of antiretroviral therapy in a randomized clinical trial. AIDS. 2013 Oct 23; 27(16):2577-86. View Abstract
  21. Epigenetic control of cytokine gene expression: regulation of the TNF/LT locus and T helper cell differentiation. Adv Immunol. 2013; 118:37-128. View Abstract
  22. Plasma concentrations of efavirenz with a 600 mg standard dose in Cambodian HIV-infected adults treated for tuberculosis with a body weight above 50 kg. Antivir Ther. 2013; 18(3):419-23. View Abstract
  23. The transcription factor NFATp plays a key role in susceptibility to TB in mice. PLoS One. 2012; 7(7):e41427. View Abstract
  24. Regulation of Mycobacterium tuberculosis-dependent HIV-1 transcription reveals a new role for NFAT5 in the toll-like receptor pathway. PLoS Pathog. 2012; 8(4):e1002620. View Abstract
  25. Monocyte-specific accessibility of a matrix attachment region in the tumor necrosis factor locus. J Biol Chem. 2011 Dec 23; 286(51):44126-44133. View Abstract
  26. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J Med. 2011 Oct 20; 365(16):1471-81. View Abstract
  27. The use of HaloTag-based technology in flow and laser scanning cytometry analysis of live and fixed cells. BMC Res Notes. 2011 Sep 09; 4:340. View Abstract
  28. Arc of a vicious circle: pathways activated by Mycobacterium tuberculosis that target the HIV-1 long terminal repeat. Am J Respir Cell Mol Biol. 2011 Dec; 45(6):1116-24. View Abstract
  29. Transcriptional control of the TNF gene. Curr Dir Autoimmun. 2010; 11:27-60. View Abstract
  30. HIV-1 replication is differentially regulated by distinct clinical strains of Mycobacterium tuberculosis. PLoS One. 2009 Jul 01; 4(7):e6116. View Abstract
  31. A dimer-specific function of the transcription factor NFATp. Proc Natl Acad Sci U S A. 2008 Dec 16; 105(50):19637-42. View Abstract
  32. Activation-dependent intrachromosomal interactions formed by the TNF gene promoter and two distal enhancers. Proc Natl Acad Sci U S A. 2007 Oct 23; 104(43):16850-5. View Abstract
  33. Treatment strategies for HIV-infected patients with tuberculosis: ongoing and planned clinical trials. J Infect Dis. 2007 Aug 15; 196 Suppl 1:S46-51. View Abstract
  34. Primate TNF promoters reveal markers of phylogeny and evolution of innate immunity. PLoS One. 2007 Jul 18; 2(7):e621. View Abstract
  35. Pathogenesis and management of HIV/TB co-infection in Asia. Tuberculosis (Edinb). 2007 Aug; 87 Suppl 1:S26-30. View Abstract
  36. Post-induction, stimulus-specific regulation of tumor necrosis factor mRNA expression. J Biol Chem. 2007 Apr 20; 282(16):11629-38. View Abstract
  37. NFAT5 regulates HIV-1 in primary monocytes via a highly conserved long terminal repeat site. PLoS Pathog. 2006 Dec; 2(12):e130. View Abstract
  38. Transactivator of transcription from HIV type 1 subtype E selectively inhibits TNF gene expression via interference with chromatin remodeling of the TNF locus. J Immunol. 2006 Apr 01; 176(7):4182-90. View Abstract
  39. Geographical distribution and disease associations of the CD45 exon 6 138G variant. Immunogenetics. 2006 Apr; 58(2-3):235-9. View Abstract
  40. Aspartic acid homozygosity at codon 57 of HLA-DQ beta is associated with susceptibility to pulmonary tuberculosis in Cambodia. J Immunol. 2006 Jan 15; 176(2):1090-7. View Abstract
  41. Identification of a macrophage-specific chromatin signature in the IL-10 locus. J Immunol. 2005 Jul 15; 175(2):1041-6. View Abstract
  42. NFAT5 binds to the TNF promoter distinctly from NFATp, c, 3 and 4, and activates TNF transcription during hypertonic stress alone. Nucleic Acids Res. 2005; 33(12):3845-54. View Abstract
  43. Lentiviral delivery of short hairpin RNAs protects CD4 T cells from multiple clades and primary isolates of HIV. Blood. 2005 Aug 01; 106(3):818-26. View Abstract
  44. IL-10-producing and naturally occurring CD4+ Tregs: limiting collateral damage. J Clin Invest. 2004 Nov; 114(10):1372-8. View Abstract
  45. A community-based tuberculosis program in Cambodia. JAMA. 2004 Aug 04; 292(5):566-8. View Abstract
  46. Diagnostic and clinical implications of response to tuberculin in two ethnically distinct populations from Peru and Cambodia. Int J Tuberc Lung Dis. 2004 Aug; 8(8):982-7. View Abstract
  47. Mycobacterium tuberculosis recall antigens suppress HIV-1 replication in anergic donor cells via CD8+ T cell expansion and increased IL-10 levels. J Immunol. 2004 Feb 01; 172(3):1953-9. View Abstract
  48. Genetic susceptibility to pulmonary tuberculosis in Cambodia. Tuberculosis (Edinb). 2004; 84(1-2):76-81. View Abstract
  49. T cell-specific expression of the human TNF-alpha gene involves a functional and highly conserved chromatin signature in intron 3. J Immunol. 2003 Oct 01; 171(7):3612-9. View Abstract
  50. The -1030/-862-linked TNF promoter single-nucleotide polymorphisms are associated with the inability to control HIV-1 viremia. Immunogenetics. 2003 Oct; 55(7):497-501. View Abstract
  51. Regulation of tumor necrosis factor alpha gene expression by mycobacteria involves the assembly of a unique enhanceosome dependent on the coactivator proteins CBP/p300. Mol Cell Biol. 2003 Jan; 23(2):526-33. View Abstract
  52. TNF-alpha promoter single nucleotide polymorphisms are markers of human ancestry. Genes Immun. 2002 Dec; 3(8):482-7. View Abstract
  53. Ethnic-specific genetic associations with pulmonary tuberculosis. J Infect Dis. 2002 Nov 15; 186(10):1463-8. View Abstract
  54. Antigen-specific and persistent tuberculin anergy in a cohort of pulmonary tuberculosis patients from rural Cambodia. Proc Natl Acad Sci U S A. 2002 May 28; 99(11):7576-81. View Abstract
  55. Inducer-specific enhanceosome formation controls tumor necrosis factor alpha gene expression in T lymphocytes. Mol Cell Biol. 2002 Apr; 22(8):2620-31. View Abstract
  56. Control of HIV-1 viremia and protection from AIDS are associated with HLA-Bw4 homozygosity. Proc Natl Acad Sci U S A. 2001 Apr 24; 98(9):5140-5. View Abstract
  57. Post-genomics and the neutral theory: variation and conservation in the tumor necrosis factor-alpha promoter. Gene. 2000 Dec 30; 261(1):19-25. View Abstract
  58. Nuclear factor of activated T cells transcription factor NFATp controls superantigen-induced lethal shock. J Exp Med. 2000 Aug 21; 192(4):581-6. View Abstract
  59. A lipopolysaccharide-specific enhancer complex involving Ets, Elk-1, Sp1, and CREB binding protein and p300 is recruited to the tumor necrosis factor alpha promoter in vivo. Mol Cell Biol. 2000 Aug; 20(16):6084-94. View Abstract
  60. Identification of phylogenetic footprints in primate tumor necrosis factor-alpha promoters. Proc Natl Acad Sci U S A. 2000 Jun 06; 97(12):6614-8. View Abstract
  61. IL-10-producing T cells suppress immune responses in anergic tuberculosis patients. J Clin Invest. 2000 May; 105(9):1317-25. View Abstract
  62. A stimulus-specific role for CREB-binding protein (CBP) in T cell receptor-activated tumor necrosis factor alpha gene expression. Proc Natl Acad Sci U S A. 2000 Apr 11; 97(8):3925-9. View Abstract
  63. Stimulus-specific assembly of enhancer complexes on the tumor necrosis factor alpha gene promoter. Mol Cell Biol. 2000 Mar; 20(6):2239-47. View Abstract
  64. Engagement of tumor necrosis factor (TNF) receptor 1 leads to ATF-2- and p38 mitogen-activated protein kinase-dependent TNF-alpha gene expression. J Biol Chem. 1999 Oct 22; 274(43):30882-6. View Abstract
  65. Signaling through the lymphotoxin-beta receptor stimulates HIV-1 replication alone and in cooperation with soluble or membrane-bound TNF-alpha. J Immunol. 1999 May 15; 162(10):6016-23. View Abstract
  66. Identification of three new single nucleotide polymorphisms in the human tumor necrosis factor-alpha gene promoter. Tissue Antigens. 1998 Oct; 52(4):359-67. View Abstract
  67. Involvement of Bruton's tyrosine kinase in FcepsilonRI-dependent mast cell degranulation and cytokine production. J Exp Med. 1998 Apr 20; 187(8):1235-47. View Abstract
  68. Association of an HLA-DQ allele with clinical tuberculosis. JAMA. 1998 Jan 21; 279(3):226-8. View Abstract
  69. TNF-alpha and genetic susceptibility to parasitic disease. Exp Parasitol. 1996 Nov; 84(2):300-3. View Abstract
  70. Cell-type-specific regulation of the human tumor necrosis factor alpha gene in B cells and T cells by NFATp and ATF-2/JUN. Mol Cell Biol. 1996 Oct; 16(10):5232-44. View Abstract
  71. Tumor necrosis factor alpha gene regulation in activated T cells involves ATF-2/Jun and NFATp. Mol Cell Biol. 1996 Feb; 16(2):459-67. View Abstract
  72. Transcriptional activation of the human TNF-alpha promoter by superantigen in human monocytic cells: role of NF-kappa B. J Immunol. 1995 Jul 15; 155(2):902-8. View Abstract
  73. Cyclosporin A and FK506 block induction of the Epstein-Barr virus lytic cycle by anti-immunoglobulin. Virology. 1995 May 10; 209(1):225-9. View Abstract
  74. The role of NFATp in cyclosporin A-sensitive tumor necrosis factor-alpha gene transcription. J Biol Chem. 1994 Dec 02; 269(48):30445-50. View Abstract
  75. Calcineurin mediates human tumor necrosis factor alpha gene induction in stimulated T and B cells. J Exp Med. 1994 Aug 01; 180(2):763-8. View Abstract
  76. Tumor necrosis factor alpha is an autocrine growth factor for normal human B cells. Proc Natl Acad Sci U S A. 1994 Jul 19; 91(15):7007-11. View Abstract
  77. Identification of a novel cyclosporin-sensitive element in the human tumor necrosis factor alpha gene promoter. J Exp Med. 1993 Oct 01; 178(4):1365-79. View Abstract
  78. Transcription of the tumor necrosis factor alpha gene is rapidly induced by anti-immunoglobulin and blocked by cyclosporin A and FK506 in human B cells. Proc Natl Acad Sci U S A. 1992 Dec 15; 89(24):12198-201. View Abstract
  79. Efficient transcription of the Epstein-Barr virus immediate-early BZLF1 and BRLF1 genes requires protein synthesis. J Virol. 1991 Dec; 65(12):7073-7. View Abstract
  80. Human tumor necrosis factor alpha gene regulation in phorbol ester stimulated T and B cell lines. J Exp Med. 1991 Jul 01; 174(1):73-81. View Abstract
  81. HIV-1 infection does not induce tumor necrosis factor-alpha or interferon-beta gene transcription. J Acquir Immune Defic Syndr (1988). 1991; 4(1):41-7. View Abstract
  82. Human tumor necrosis factor alpha gene regulation by virus and lipopolysaccharide. Proc Natl Acad Sci U S A. 1990 Dec; 87(24):9769-73. View Abstract
  83. Coordinate viral induction of tumor necrosis factor alpha and interferon beta in human B cells and monocytes. Proc Natl Acad Sci U S A. 1989 Mar; 86(5):1490-4. View Abstract
  84. The physical and psychological sequelae of torture. Symptomatology and diagnosis. JAMA. 1988 May 13; 259(18):2725-9. View Abstract
  85. Murder in Guatemala. N Engl J Med. 1984 May 03; 310(18):1186. View Abstract
  86. Recessive lethal deletion on mouse chromosome 7 affects glucocorticoid receptor binding activities. Proc Natl Acad Sci U S A. 1983 Mar; 80(5):1431-4. View Abstract
  87. Genetic control of insulin receptors. Proc Natl Acad Sci U S A. 1981 Oct; 78(10):6359-61. View Abstract

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