William M. Mitchell, M.D., Ph.D.

Professor

bill.mitchell@vanderbilt.edu
Faculty Appointments
Professor of Pathology, Microbiology and Immunology
Education
Ph.D., Johns Hopkins University, Baltimore, MarylandM.D., Medicine , Vanderbilt University, Nashville, TennesseeB.A., Vanderbilt University, Nashville, Tennessee
Office Address
U-3302 MCN
2561
Research Description
Current active areas of investigation include the following:
1. Innate immunity initiated by Activation of Toll-Like Receptor 3 (TLR3). The TLRs are microbial pattern recognition proteins that initiate innate immune responses to microbial invasion. TLR3 is unique among the 10 human TLRs in its intracellular signaling pathways and reduced inflammatory responses. Agonists of TLR3 and response elements are being examined as viral inhibitors and next generation immune vaccine enhancers (super adjuvants) with reduced adverse advents in humans. We have investigated efficacy against highly pathogenic avian influenza viruses in humans (HPIVh) including H5N1 and oseltamivir resistant H7N9 as well as seasonal influenza vaccines with activity against HPIVh.
2. Next Generation Sequencing (NGS) applications. We have used a variety of NGS platforms to develop new diagnostic massively parallel sequencing methods for the real time evaluation of efficacy of cancer therapy using plasma/serum analysis of DNA from apoptotic neoplastic cells.
3. Pathogenesis of human intracellular pathogens. Our current focus is on the pathogenesis of latency of two microorganisms: a) Chlamydia pneumoniae is a recently recognized member of the genus Chlamydia. This obligate intracellular bacterium has been recently linked to a variety of human idopathic inflammatory diseases. C. pneumoniae is an obligate intracellular pathogen which lacks a mechanism for generating energy and relies on the host cell mitochondria as an energy source. We have developed improved methods for detection (culture, immunoassay, and PCR) of this microbe in human tissue and blood. The organism is difficult to eradicate since elements of the immune system (IFN) and/or antibiotics induce the acquisition of a stringent response in which the organism stops replication and enters an anaerobic phase which we refer to as a cryptic or latent phase. Reactivation of the cryptic phase yields a resumption of replication. b) Human immunodeficiency virus (HIV) is the etiological agent of the Acquired Immunodeficiency Syndrome (AIDS). Current studies are focused on HIV latency. Latent HIV provirus integrated into the human genome of memory B lymphocytes provide silent sites of reactivation not susceptible to current anti-retroviral therapy (ART). Strategies involve activation of provirus by TLR3 agonists and interferon with ART control of infection to eliminate proviral foci of latent infection.

Research Keywords
Innate immunity initiated by Activation of Toll-Like Receptor 3 (TLR3) Next Generation Sequencing (NGS) applications (Cancer diagnostics, intracellular pathogen discovery and analysis) Pathogenesis of intracellular microbes (Chlamydia / HIV )
Publications
Mitchell WM, Nicodemus CF, Carter WA, Horvath JC, Strayer DR. Discordant biological and toxicological species responses to TLR3 activation. Am. J. Pathol [print-electronic]. 2014 Apr; 184(4): 1062-72. PMID: 24486326, PII: S0002-9440(14)00011-X, DOI: 10.1016/j.ajpath.2013.12.006, ISSN: 1525-2191.

Beck J, Urnovitz HB, Saresella M, Caputo D, Clerici M, Mitchell WM, Sch├╝tz E. Serum DNA motifs predict disease and clinical status in multiple sclerosis. J Mol Diagn [print-electronic]. 2010 May; 12(3): 312-9. PMID: 20228264, PMCID: PMC2860467, PII: S1525-1578(10)60066-9, DOI: 10.2353/jmoldx.2010.090170, ISSN: 1943-7811.

Tang YW, Sriram S, Li H, Yao SY, Meng S, Mitchell WM, Stratton CW. Qualitative and quantitative detection of Chlamydophila pneumoniae DNA in cerebrospinal fluid from multiple sclerosis patients and controls. PLoS ONE [print-electronic]. 2009; 4(4): e5200. PMID: 19357786, PMCID: PMC2664471, DOI: 10.1371/journal.pone.0005200, ISSN: 1932-6203.

Mitchell WM. 18th International Conference on Antiviral Research. Expert Opin Pharmacother. 2005 Aug; 6(10): 1765-8. PMID: 16086663, DOI: 10.1517/14656566.6.10.1765, ISSN: 1744-7666.

Sams HH, Mitchell WM, Stratton CW, King LE. Culture and immunohistochemical evidence of Chlamydia pneumoniae infection in ulcerative pyoderma gangrenosum. J. Am. Acad. Dermatol. 2003 Jun; 48(6): 966-9. PMID: 12789196, PII: S019096220300402X, DOI: 10.1067/mjd.2003.305, ISSN: 0190-9622.

Sams,H.H., Mitchell, W.M., Stratton,C.W., and King,L.E.. Culture and Immunochemical Evidence of Chlamydia pneumoniae Infection in Ulcerative Pyoderma Gangrenosum. J.Am. Acad. Dermatol. 2003; 48: 966-9.

Mitchell, W.M., Blick,G, Strayer,D, Carter,WA and AMP 720 Investigators.. A Phase IIB Prospective, Randomized, Controlled Study Evaluating AMPLIGEN During Structured Treatment Interruption (STI) of HAART in HIV Infection. Antiviral Res. 2003; 57: A41.

Sriram, S., Yao, S., Mitchell, W.M., Calibresi, P., Stratton, C.W., Ikejima, H., and Yamamoto, Y.. Comparative study of the presence of Chalamydia pneumoniae in cerebrospinal fluid from clinically definite and monosymptomatic multiple sclerosis patients. Clin. Diag. Lab. Immunol. 2002; 9: 1332-7.

King LE, Stratton CW, Mitchell WM. Chlamydia pneumoniae and chronic skin wounds: a focused review. J. Investig. Dermatol. Symp. Proc. 2001 Dec; 6(3): 233-7. PMID: 11924834, DOI: 10.1046/j.0022-202x.2001.00050.x, ISSN: 1087-0024.

Yao SY, Stratton CW, Mitchell WM, Sriram S. CSF oligoclonal bands in MS include antibodies against Chlamydophila antigens. Neurology. 2001 May 5/8/2001; 56(9): 1168-76. PMID: 11342681, ISSN: 0028-3878.

Yao SY, Ljunggren-Rose A, Stratton CW, Mitchell WM, Sriram S. Regulation by IFN-beta of inducible nitric oxide synthase and interleukin-12/p40 in murine macrophages cultured in the presence of Chlamydia pneumoniae antigens. J. Interferon Cytokine Res. 2001 Mar; 21(3): 137-46. PMID: 11331036, DOI: 10.1089/107999001750133131, ISSN: 1079-9907.

Yao, S.-Y., Stratton, C.W., Mitchell, W.M., Sriram, S.. CSF Oligoclonal Bands in Multiple Sclerosis Include Antibodies Against Chlamydophila pneumoniae. Neurology. 2001; 56: 1168-76.

Vannucci SA, Mitchell WM, Stratton CW, King LE. Pyoderma gangrenosum and Chlamydia pneumoniae infection in a diabetic man: pathogenic role or coincidence?. J. Am. Acad. Dermatol. 2000 Feb; 42(2 Pt 1): 295-7. PMID: 10642692, PII: S0190-9622(00)90145-2, DOI: 10.1016/S0190-9622(00)90145-2, ISSN: 0190-9622.

Sriram S, Stratton CW, Yao S, Tharp A, Ding L, Bannan JD, Mitchell WM. Chlamydia pneumoniae infection of the central nervous system in multiple sclerosis. Ann. Neurol. 1999 Jul; 46(1): 6-14. PMID: 10401775, ISSN: 0364-5134.

Mitchell WM, Ding L, Gabriel J. Inactivation of a common epitope responsible for the induction of antibody-dependent enhancement of HIV. AIDS. 1998 Jan 1/22/1998; 12(2): 147-56. PMID: 9468363, ISSN: 0269-9370.

Sriram, S., Mitchell, W.M., and Stratton, C.W. Multiple sclerosis associated with Chlamydia pneumoniae infection of the central nervous system. 1998.

Mitchell, W.M., Ding, L., and Gabriel, J. Inactivation of a common epitope responsible for the induction of antibody- dependent enhancement of the Human Immunodeficiency Virus. 1998.

1998; Available from: .

Robinson, Jr., W.E., Cordeiro, M., Abdel-Malek, S., Qi, J., Chow, S.A., Reinecke, M.G., and Mitchell, W.M. Dicaffeoylquinic acid inhibitors of human immunodeficiency virus (HIV) integrase: Inhibition of the core catalytic domain of HIV integrase. 1996.

Mitchell WM, Rosenbloom ST, Gabriel J. Induction of mucosal anti-HIV antibodies by facilitated transfection of airway epithelium with lipospermine/DNA complexes. Immunotechnology. 1995 Dec; 1(3-4): 211-9. PMID: 9373349, ISSN: 1380-2933.

Mitchell, W.M., Torres, J., Johnson, P.R., Hirsch, V., Yilma, T., Gardner, M.B., and Robinson, Jr., W.E. An animal model for antibody-dependent enhancement of HIV infection: Antibodies to the putative SIV infection-enhancing domain diminish beneficial effects of an SIV gp160 vaccine in Rhesus macaques. 1995.

Mitchell WM, Torres J, Johnson PR, Hirsch V, Yilma T, Gardner MB, Robinson WE. Antibodies to the putative SIV infection-enhancing domain diminish beneficial effects of an SIV gp160 vaccine in rhesus macaques. AIDS. 1995 Jan; 9(1): 27-34. PMID: 7893438, ISSN: 0269-9370.

Crouse JA, Mitchell WM. Interferon-gamma receptor: mRNA half-life, receptor mass, and abundance on A431 human epidermoid carcinoma cells. J. Interferon Res. 1992 Feb; 12(1): 23-5. PMID: 1374108, ISSN: 0197-8357.

Robinson WE, Gorny MK, Xu JY, Mitchell WM, Zolla-Pazner S. Two immunodominant domains of gp41 bind antibodies which enhance human immunodeficiency virus type 1 infection in vitro. J. Virol. 1991 Aug; 65(8): 4169-76. PMID: 2072448, PMCID: PMC248851, ISSN: 0022-538X.

Robinson WE, Kawamura T, Lake D, Masuho Y, Mitchell WM, Hersh EM. Antibodies to the primary immunodominant domain of human immunodeficiency virus type 1 (HIV-1) glycoprotein gp41 enhance HIV-1 infection in vitro. J. Virol. 1990 Nov; 64(11): 5301-5. PMID: 1698995, PMCID: PMC248578, ISSN: 0022-538X.

Montefiori DC, Robinson WE, Modliszewski A, Mitchell WM. Effective inactivation of human immunodeficiency virus with chlorhexidine antiseptics containing detergents and alcohol. J. Hosp. Infect. 1990 Apr; 15(3): 279-82. PMID: 1971635, ISSN: 0195-6701.

Robinson WE, Montefiori DC, Mitchell WM. Complement-mediated antibody-dependent enhancement of HIV-1 infection requires CD4 and complement receptors. Virology. 1990 Apr; 175(2): 600-4. PMID: 2327077, ISSN: 0042-6822.

Robinson WE, Kawamura T, Gorny MK, Lake D, Xu JY, Matsumoto Y, Sugano T, Masuho Y, Mitchell WM, Hersh E. Human monoclonal antibodies to the human immunodeficiency virus type 1 (HIV-1) transmembrane glycoprotein gp41 enhance HIV-1 infection in vitro. Proc. Natl. Acad. Sci. U.S.A. 1990 Apr; 87(8): 3185-9. PMID: 2326277, PMCID: PMC53860, ISSN: 0027-8424.

Montefiori DC, Robinson WE, Modliszewski A, Rowland JM, Schuffman SS, Mitchell WM. Differential inhibition of HIV-1 cell binding and HIV-1-induced syncytium formation by low molecular weight sulphated polysaccharides. J. Antimicrob. Chemother. 1990 Mar; 25(3): 313-8. PMID: 1692572, ISSN: 0305-7453.

Montefiori DC, Robinson WE, Hirsch VM, Modliszewski A, Mitchell WM, Johnson PR. Antibody-dependent enhancement of SIV infection: further characterization and cross reactivity between macaque and sooty mangabey isolates. J. Med. Primatol. 1990; 19(3-4): 269-78. PMID: 2231684, ISSN: 0047-2565.

Montefiori DC, Robinson WE, Hirsch VM, Modliszewski A, Mitchell WM, Johnson PR. Antibody-dependent enhancement of simian immunodeficiency virus (SIV) infection in vitro by plasma from SIV-infected rhesus macaques. J. Virol. 1990 Jan; 64(1): 113-9. PMID: 2152808, PMCID: PMC249059, ISSN: 0022-538X.

Robinson WE, Mitchell WM. Neutralization and enhancement of in vitro and in vivo HIV and simian immunodeficiency virus infections. AIDS. 1990; 4 Suppl 1: S151-62. PMID: 2152561, ISSN: 0269-9370.

Montefiori DC, Sobol RW, Li SW, Reichenbach NL, Suhadolnik RJ, Charubala R, Pfleiderer W, Modliszewski A, Robinson WE, Mitchell WM. Phosphorothioate and cordycepin analogues of 2',5'-oligoadenylate: inhibition of human immunodeficiency virus type 1 reverse transcriptase and infection in vitro. Proc. Natl. Acad. Sci. U.S.A. 1989 Sep; 86(18): 7191-4. PMID: 2476814, PMCID: PMC298022, ISSN: 0027-8424.

Robinson WE, Montefiori DC, Mitchell WM, Prince AM, Alter HJ, Dreesman GR, Eichberg JW. Antibody-dependent enhancement of human immunodeficiency virus type 1 (HIV-1) infection in vitro by serum from HIV-1-infected and passively immunized chimpanzees. Proc. Natl. Acad. Sci. U.S.A. 1989 Jun; 86(12): 4710-4. PMID: 2471977, PMCID: PMC287341, ISSN: 0027-8424.

Montefiori DC, Robinson WE, Mitchell WM. Antibody-independent, complement-mediated enhancement of HIV-1 infection by mannosidase I and II inhibitors. Antiviral Res. 1989 Apr; 11(3): 137-46. PMID: 2472115, PII: 0166-3542(89)90025-9, ISSN: 0166-3542.

Montefiori DC, Robinson WE, Mitchell WM. In vitro evaluation of mismatched double-stranded RNA (ampligen) for combination therapy in the treatment of acquired immunodeficiency syndrome. AIDS Res. Hum. Retroviruses. 1989 Apr; 5(2): 193-203. PMID: 2469450, ISSN: 0889-2229.

Montefiori DC, Pellegrino MG, Robinson WE, Engle K, Field M, Mitchell WM, Gillespie DH. Inhibition of HIV-1 proviral DNA synthesis and RNA accumulation by mismatched dsRNA. Biochem. Biophys. Res. Commun. 1989 Feb 2/15/1989; 158(3): 943-50. PMID: 2784055, PII: 0006-291X(89)92813-1, ISSN: 0006-291X.

Robinson WE, Montefiori DC, Gillespie DH, Mitchell WM. Complement-mediated, antibody-dependent enhancement of HIV-1 infection in vitro is characterized by increased protein and RNA syntheses and infectious virus release. J. Acquir. Immune Defic. Syndr. 1989; 2(1): 33-42. PMID: 2465404, ISSN: 0894-9255.

Montefiori DC, Robinson WE, Mitchell WM. Role of protein N-glycosylation in pathogenesis of human immunodeficiency virus type 1. Proc. Natl. Acad. Sci. U.S.A. 1988 Dec; 85(23): 9248-52. PMID: 3264072, PMCID: PMC282716, ISSN: 0027-8424.

Robinson WE, Mitchell WM, Chambers WH, Schuffman SS, Montefiori DC, Oeltmann TN. Natural killer cell infection and inactivation in vitro by the human immunodeficiency virus. Hum. Pathol. 1988 May; 19(5): 535-40. PMID: 3286479, ISSN: 0046-8177.

Robinson WE, Montefiori DC, Mitchell WM. Antibody-dependent enhancement of human immunodeficiency virus type 1 infection. Lancet. 1988 Apr 4/9/1988; 1(8589): 790-4. PMID: 2895317, ISSN: 0140-6736.

Montefiori DC, Robinson WE, Schuffman SS, Mitchell WM. Evaluation of antiviral drugs and neutralizing antibodies to human immunodeficiency virus by a rapid and sensitive microtiter infection assay. J. Clin. Microbiol. 1988 Feb; 26(2): 231-5. PMID: 3422647, PMCID: PMC266258, ISSN: 0095-1137.

Montefiori DC, Robinson WE, Mitchell WM. Mismatched dsRNA (ampligen) induces protection against genomic variants of the human immunodeficiency virus type 1 (HIV-1) in a multiplicity of target cells. Antiviral Res. 1988 Jan; 9(1-2): 47-55. PMID: 2968777, ISSN: 0166-3542.

Robinson WE, Montefiori DC, Mitchell WM. A human immunodeficiency virus type 1 (HIV-1) infection-enhancing factor in seropositive sera. Biochem. Biophys. Res. Commun. 1987 Dec 12/16/1987; 149(2): 693-9. PMID: 3426595, PII: 0006-291X(87)90423-2, ISSN: 0006-291X.

Montefiori DC, Mitchell WM. Persistent coinfection of T lymphocytes with HTLV-II and HIV and the role of syncytium formation in HIV-induced cytopathic effect. Virology. 1987 Oct; 160(2): 372-8. PMID: 2821680, ISSN: 0042-6822.

Robinson WE, Montefiori DC, Mitchell WM. Evidence that mannosyl residues are involved in human immunodeficiency virus type 1 (HIV-1) pathogenesis. AIDS Res. Hum. Retroviruses. 1987; 3(3): 265-82. PMID: 2829950, ISSN: 0889-2229.

Breau AP, Field L, Mitchell WM. Thiono compounds. 4. In vitro mutagenic and antineoplastic activity of TEPA and thio-TEPA. Cell Biol. Toxicol. 1984 Oct; 1(1): 21-30. PMID: 6086064, ISSN: 0742-2091.