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Medicine

Pathology

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Faculty

Clifford Harding, MD, PhD

Clifford Harding, MD, PhD

Kahn Professor, Chair ITP Director, MSTP Director

clifford.harding@case.edu (216) 368-3611 (o) (216) 368-1539 (f)

Dr. Harding graduated magna cum laude and with Highest Honors in Biology from Harvard College in 1979. He completed his M.D. and Ph.D. in Cell Biology at Washington University of St. Louis in 1985. He served as Resident in Pathology, Chief Resident in Pathology, Instructor in Pathology and Assistant Professor of Pathology at Washington University. Since 1993 he has been a faculty member at CWRU/University Hospitals Case Medical Center. He is currently the Joseph R. Kahn Professor and Chair of Pathology, Director of the Medical Scientist Training Program, and Interim Chair of Anatomy.

Dr. Harding has a long-standing NIH-funded research program on the cell biology of antigen presenting cells (APCs) and their regulation by Toll-like receptors (TLRs) or infection with Mycobacterium tuberculosis (Mtb) or HIV.  He has over 190 publications on topics in immunology, cell biology and infectious diseases (>10,500 citations, h-index = 55).  His early work included the discovery of exosomes and their genesis by exocytosis of multivesicular exosomes in 1983, and participation in the first study demonstrating that exosomes from APCs contain MHC molecules (1996).  In recent years he has published on exosomes released from macrophages, including exosomes from Mtb-infected macrophages that bear bacterial molecules.  His work from the 1980’s and 1990’s included fundamental discoveries concerning cell biological and biochemical mechanisms of antigen processing and antigen presentation by MHC-I and MHC-II molecules.  His recent research has studied the regulation of APCs, particularly in the context of infection and signaling by innate immune receptors.  He has studied the regulation of APCs by TLR2 agonists expressed by Mtb (lipoproteins and glycolipids) and the signaling pathways by which Mtb regulates the balance of inflammatory mechanisms in macrophages and the magnitude and differentiation of T cell responses.  These mechanisms may contribute to immune evasion and the persistence of Mtb infection. Other projects have focused on regulation of immune responses by TLR9 and type I interferon. 

Please see the links below for more information pertaining to Dr. Harding's research, publications, and training.

To learn more about Dr. Harding's education, research, publications, and contributions to science, please refer to his NIH Biosketch (PDF)

Much of our effort is now directed to understanding regulation of antigen presenting cell (APC) function in the context of infectious diseases, e.g. tuberculosis and HIV infection. APCs sense pathogens by innate immune receptors, including Toll-like receptors (TLRs), and are regulated by cytokines and interferons that are produced during infection. For example, we are studying regulation of APCs by Mycobacterium tuberculosis through TLR2 and the resulting signaling and cytokine responses that contribute to the balance of host defense and immune evasion mechanisms. The following model has been developed from our studies.

 

 

 

  1. Harding CV, Heuser J & Stahl P. 1983. Receptor‑mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes. J. Cell Biol. 97:329‑339. (*first report of exosomes)
  2. Harding, CB & Unanue ER. 1990. Quantitation of peptide‑class II MHC complexes generated in antigen presenting cells and necessary for T cell stimulation. Nature 346:574‑576.
  3. Harding, CB, Collins, DS, Slot, JW, Geuze, HJ & Unanue ER. 1991. Liposome-encapsulated antigens are processed in lysosomes, recycled and presented to T cells. Cell 64:393‑401.
  4. Harding CV, & Geuze HJ. 1992. Class II MHC molecules are present in macrophage lysosomes and phagolysosomes that function in the phagocytic processing of Listeria monocytogenes for presentation to T cells. J. Cell Biol. 119:531‑542.
  5. Pfeifer JD, Wick MJ, Roberts RL, Findlay KF, Normark SJ & Harding CV. 1993. Phagocytic processing of bacterial antigens for class I MHC presentation to T cells. Nature 361:359‑362.
  6. Harding CV & Geuze HJ. 1993. Immunogenic peptides bind to class II MHC molecules in an early lysosomal compartment. J. Immunol. 151:3988-3998.
  7. Griffin J, Chu R & Harding CV. 1997. Early endosomes and a late endocytic compartment generate distinct species of peptide:MHC-II complexes via different mechanisms. J. Immunol. 158: 1523-1532.
  8. Ramachandra L, Song R & Harding CV. 1999. Phagosomes are fully competent antigen processing organelles that mediate the formation of peptide:class II MHC complexes.  J. Immunol. 162:3263-3272.
  9. Noss EH, Pai RK, Sellati TJ, Radolf JD, Belisle J, Golenbock DT, Boom WH & Harding CV.  2001. Toll-like receptor 2-dependent inhibition of macrophage class II MHC expression and antigen processing by 19 kD lipoprotein of Mycobacterium tuberculosis. J. Immunol., 167: 910-918.
  10. Sieg, S.F., Harding, C.V. and Lederman, M.M. 2001. HIV-1 infection impairs cell cycle progression of CD4(+) T cells without affecting early activation responses. J. Clin. Invest. 108: 757-764.
  11. Ramachandra L, Noss EH, Boom WH & Harding CV.  2001.  Processing of Mycobacterium tuberculosis antigen 85B involves intra-phagosomal formation of peptide:MHC-II complexes and is inhibited by live bacilli that decrease phagosome maturation. J. Exp. Med., 194:1421-1432.
  12. Pai RK, Askew D, Boom WH & Harding CV.  2002. Regulation of class II MHC expression in APCs: Roles of types I, III and IV class II transactivator.  J. Immunol. 169: 1326-1333.
  13. Pai RK, Convery M, Hamilton TA, Boom WH & Harding CV. 2003. Inhibition of IFN-g-induced class II transactivator expression by a 19-kDa lipoprotein from Mycobacterium tuberculosis: A potential mechanism for immune evasion.  J Immunol 171: 175-184.
  14. Pai RK, Pennini ME, Tobian AAR, Canaday DH, Boom WH & Harding CV. 2004. Prolonged Toll-like receptor signaling by Mycobacterium tuberculosis and its 19-kDa lipoprotein inhibits interferon-gamma-induced gene regulation in macrophages.  Infect Immun 72:6603-6614.
  15. Jiang, W, Lederman, MM, Salkowitz, JR, Harding, CB & Sieg, SS. 2005. CpG ODN induces monocyte maturation in cells from healthy individuals and HIV-infected patients. J. Virol. 79: 4109-4119.
  16. Pennini, ME, Pai, RK, Schultz, DC, Boom, WH & Harding, CB. 2006. Mycobacterium tuberculosis 19-kDa lipoprotein inhibits IFN-g-induced chromatin remodeling of MHC2TA by TLR2 and MAPK signaling.  J. Immunol. 176: 4323-4330.
  17. Pecora, ND, Gehring, AJ, Canaday, DH, Boom, WH & Harding, CB. 2006. M. tuberculosis LprA is a lipoprotein agonist of TLR2 that regulates innate immunity and APC function. J. Immunol. 177:422-429.
  18. Pennini, ME, Yang, J, Croniger, CM, Boom, WH and Harding, CB.  2007. C/EBP-beta binds to CIITA promoters and inhibits CIITA expression in response to M. tuberculosis 19-kDa lipoprotein.  J. Immunol. 179: 6910–6918.  PMC2631233.
  19. Funderberg, N., Lederman, M.M., Feng, Z., Drage, M.G., Jadlowsky, J., Harding, C.V., Weinberg, A. and Sieg, S.F.  2008.  Human beta-defensin-3 activates professional antigen-presenting cells via Toll-like receptors 1 and 2.  Proc. Natl. Acad. Sci. USA 104: 18631-18635. PMCID:PMC2141828
  20. Drage, M.G., Pecora, N.D., Hise, A.G., Febbraio, M., Silverstein, R.L., Golenbock, D.T., Boom, W.H. and Harding, C.V.  2009.  TLR2 and its co-receptors determine responses of macrophages and dendritic cells to lipoproteins of Mycobacterium tuberculosis.  Cell. Immunol. 258: 29-37. PMCID:PMC2730726.
  21. Pecora, N.D., Fulton, S.A., Reba, S.M., Drage, M.G., Simmons, D.P., Urankar-Nagy, N.J., Boom, W.H. and Harding, C.V.  2009.  Mycobacterium bovis BCG decreases MHC-II expression in vivo on murine lung macrophages and dendritic cells during aerosol infection.  Cell. Immunol. 254: 94-104. PMCID:PMC2653222
  22. Hardy, G.A., Sieg, S.F., Rodriguez, B., Jiang, W., Asaad, R., Lederman, M.M. and Harding, C.V. 2009. Desensitization to type I interferon in HIV-1 infection correlates with markers of immune activation and disease progression.  Blood, 113: 5497-5505. PMCID:PMC2689050.
  23. Qu, Y., Ramachandra, L., Mohr, S., Franchi, L., Harding, C.V., Nunez, G. and Dubyak, G.R.  2009.  P2X7 receptor-stimulated secretion of MHC-II-containing exosomes requires the ASC/NLRP3 inflammasome but is independent of caspase-1.  2008.  J. Immunol. 182: 5052-5062. PMC2768485.
  24. Mahon, R.N., Rojas, R.E., Fulton, S.A., Franko, J., Harding, C.V.# and Boom, W.H.#  2009. Mycobacterium tuberculosis cell wall glycolipids directly inhibit CD4+ T cell activation by interfering with proximal TCR signaling. Infect. Immun. 77: 4574-4583.  #Joint senior authors. PMCID:PMC2747961.
  25. Liu, Y, Gray, RC, Hardy, GAD, Kuchtey, J, Abbott, DW, Emancipator, SN and Harding, CB. 2010. CpG-B oligodeoxynucleotides inhibit Toll-like receptor-dependent and independent induction of type I IFN in dendritic cells. J. Immunol. 184:3367-3376. PMCID: PMC2892962.
  26. Simmons, D.P., Canaday, D.H., Liu, Y., Li, Q., Huang, A., Boom, W.H. and Harding, C.V.  2010.  Mycobacterium tuberculosis and TLR2 agonists inhibit induction of type I IFN and MHC-I antigen cross processing by TLR9. J. Immunol. 185: 2405-2415. PMCID: PMC2990778.
  27. Reuter, M.A., Pecora, N.D., Harding, C.V., Canaday, D.H., McDonald, D.  2010.  Mycobacterium tuberculosis promotes HIV trans-infection and suppresses major histocompatibility complex class II antigen processing by dendritic cells.  J. Virol. 84: 8549-8560. PMCID: PMC2919047.
  28. Harding, C.V. and Boom, W.H. 2010.  Regulation of antigen processing by Mycobacterium tuberculosis: a role for Toll-like receptors.  Nature Rev Microbiol.  8: 296-307. PMCID: PMC3037727.
  29. Drage, M.G., Tsai, H.-C., Pecora, N.D., Cheng, T.-Y., Arida, A.R., Shukla, S., Rojas, R.E., Moody, D.B., Boom, W.H., Sacchettini, J.C., and Harding, C.V.   2010. Mycobacterium tuberculosis lipoprotein LprG (Rv1411c) binds triacylated glycolipid agonists of Toll-like receptor 2.  Nature Struct Mol Biol. 17: 1088-1095. PMCID: PMC2933325.
  30. Ramachandra, L., Qu, Y., Wang, Y., Cobb, B., Takatsu, K., Boom, W.H., Dubyak, G.R. and Harding, C.V. 2010. Mycobacterium tuberculosis synergizes with ATP to induce release of microvesicles and exosomes containing MHC-II molecules capable of antigen presentation. Infect Immun. 78:5116-5125. PMC2981298.
  31. Lancioni CL, Li Q, Thomas JJ, Ding X, Thiel, D, Drage MG, Pecora ND, Ziady AG, Shank SL, Harding CV, Boom WH and Rojas RE.  2011.  Mycobacterium tuberculosis lipoproteins directly regulate human memory CD4+ T cell activation via TLR2/1. Infect Immun, 79:663-73, 2011. PMC3028837.
  32. Liu, Y.C., Simmons, D.P., Li, X., Abbott, D., Boom, W.H., Harding, C.V.  2012. TLR2 signaling depletes IRAK1 and inhibits induction of type I IFN by TLR7/9.  J. Immunol. 188: 1019-1026. PMCID: PMC3262948.
  33. Simmons, D.P., Wearsch, P.A., Canaday, D.H., Meyerson, H.J., Liu, Y.C., Wang, Y., Boom, W.H. and Harding, C.V.  2012.  Type I interferon drives a distinctive dendritic cell maturation phenotype that allows continued class II MHC synthesis and antigen processing. J. Immunol., 188:3116-3126. PMCID: PMC3311734.
  34. Hardy, G.A.D., Sieg, S., Rodriguez, B., Anthony, D., Asaad, R., Jiang, W., Mudd, J., Schacker, T., Funderburg, N., Pilch, H., Rabin, R.L., Lederman, M.M. and Harding, C.V. 2013.  Interferon-α is the primary plasma type-I IFN in HIV-1 infection and correlates with immune activation and disease markers. PLOS One, 8, e56527. PMCID: PMC3577907.
  35. Mudd, J.C., Murphy, P., Manion, M., Debernardo, R., Hardacre, J., Ammori, J., Hardy, G.A., Harding, C.V., Mahabaleshwar, G.H., Jain, M.K., Jacobson, J.M., Brooks, A.D., Lewis, S., Shacker, T.W., Anderson, J., Haddad, E.K., Cubas, R.A., Rodriguez, B., Sieg, S.F., Lederman, M.M. 2013. Impaired T-cell responses to sphingosine-1-phosphate in HIV-1 infected lymph nodes.  Blood, 121: 2914-2922. PMCID: PMC3624937. 
  36. Reba, S.M., Li, Q., Onwuzulike, S., Ding, X., Karim, A.F., Hernandez, Y., Fulton, S.A., Harding, C.V., Lancioni, C.L., Nagy, N., Rodriguez, M.E., Wearsch, P.A., Rojas, R.E. 2014. TLR2 engagement on CD4+ T cells enhances effector functions and protective responses to Mycobacterium tuberculosis. Eur. J. Immunol. 40: 1410-1421. PMCID: PMC4112943.
  37. Yu, M., Zhou, H., Zhao, J., Xiao, N., Pisano, S., Roychowdhury, S., Schmitt, D., Nagy, N., Pai, R., Yerian, L., Harding, C.V., Hise, A., Hazan, S.L., DeFranco, A.L., Fox, P.L., Morton, R.E., DiCorleto, P.E., Febbraio, M., Croniger, C.M., Nagy, L.E., Smith, J.D., Wang, J., and Li, X. 2014. MyD88-dependent interplay between myeloid and endothelial cells in the initiation and progression of obesity-associated inflammatory diseases.  J. Exp. Med., 211: 887-907. PMCID: PMC4010914.
  38. Shukla, S*., Richardson, E.T*., Athman, J.J., Shi, L., Wearsch, P.A., McDonald, D., Banaei, N., Boom, W.H., Jackson, M. and Harding, C.V.  2014. Mycobacterium tuberculosis lipoprotein LprG binds lipoarabinomannan and determines its cell envelope localization to control phagolysosomal fusion. PLOS Pathogens, 10(10): e1004471. doi:10.1371/journal.ppat.1004471. PMCID: PMC4214796.
  39. Athman, J.J., Wang, Y., McDonald, D.J., Harding, C.V. and Wearsch, P.A. 2015. Bacterial membrane vesicles mediate the release of Mycobacterium tuberculosis lipoglycans and lipoproteins from infected macrophages. J. Immunol., 195: 1044-1053. PMCID: PMC4506856
  40. Richardson, E.T., Shukla, S., Wearsch, P.A., Tsichlis, P.N., Boom, W.H. and Harding, C.V. 2015. TLR2-dependent ERK signaling in Mycobacterium tuberculosis-infected macrophages drives anti-inflammatory responses and inhibits Th1 polarization of responding T cells. Infect. Immun. 83: 2242-2254. PMCID: PMC4432743. *Chosen for Spotlight recognition.
  41. Nguyen, T., Bazdar, D.A., Mudd, J.C., Lederman, M.M., Harding, C.V., Hardy, G., Sieg, S.F. 2015.  Interferon-alpha inhibits CD4 T cell responses to interleukin-7 and interleukin-2 and selectively interferes with Akt signaling.  J. Leukoc. Biol. 97: 1139-1146.
  42. Richardson, E.T., Supriya, S., Nagy, N., Boom, W.H., Beck, R.C., Zhou, L., Landreth, G.E. and Harding, C.V. 2015. ERK signaling is essential for macrophage development. PLOS ONE, in press.
  43. Sande, O.J., Karim, A.F., Ding, X., Li, Q., Harding, C.V., Rojas, R.E. and Boom, W.H. 2015.  Mannose-Capped Lipoarabinomannan (LAM) from Mycobacterium tuberculosis induces CD4+ T cell anergy.  J. Immunol., in press.

Dr. Harding has been active in developing research training for PhD students, MD-PhD students and physician-scientists, including both basic and translational research training programs. He has designed and launched new training programs in Immunology and Cancer Biology (e.g. as founding Director of the Immunology Training Program at CWRU) and a new Clinical and Translational Scientist Training Program (CTSTP; CTSA TL1 supported). He has contributed to the national/international Immunology research community with service on NIH study sections and through the American Association of Immunologists (e.g. as Chair of the AAI Committee on Public Affairs).