Research Summary

The research in the Kaplan lab focuses on defining the host immune response to M. tuberculosis (MTB) infection and identifying immunologic correlates of protection against tuberculosis disease. Scientist in the Kaplan lab has been testing the hypothesis that some clinical isolates of MTB are more virulent than others - that they cause more severe disease in the infected host. This hypervirulence is hypothesized to be driven by activation of a suboptimal immune response. To test this hypothesis, members of the lab are combining studies of human white blood cells infected with MTB in vitro with observations made on mice and rabbits infected with MTB in vivo, as well as with studies in tuberculosis (TB) patients.

Two clinical isolates of MTB, CDC1551 and HN878, are used as model strains for experimental infections. Human monocytes or dendritic cells (DC) are infected with the bacilli followed by an analysis of the activity of selected genes known to regulate the immune response in those cells. When compared with HN878, CDC1551 induces more rapid and higher levels of activity of key genes regulating the Th1 protective host immune response. This differential response is being further investigated.

Using rabbit models of central nervous system (CNS) and pulmonary infection, the Kaplan lab are comparing the in vivo host response to these clinical isolates. They find that HN878 is more virulent compared to CDC1551. Virulence is associated with higher bacillary loads in the cerebrospinal fluid and in the brain with a propensity to breach the blood brain barrier (BBB) and disseminate to other organs. HN878 also has the ability to cause more prolonged inflammation. Rabbits infected with HN878 develop severe progressive meningitis with loss of coordination and paralysis of the limbs. Animals infected with CDC1551 do not show any neurologic signs. In the model of aerosol infection, HN878 causes more extensive bacillary growth and worse tissue damage in the lungs, resulting in progressive granulomatous pulmonary disease. CDC1551 infection is controlled in the lungs, leading to latency. Taken together these results suggest that the ability of the bacilli to induce protective immunity determines the extent of disease (virulence) and clinical outcome in the infected host. This model is being used to dissect the host and pathogen response during progressive chronic and during latent infection.

In a recent collaborative study the investigators described the identification and functional relevance of a highly biologically active lipid species-a polyketide synthase-derived phenolic glycolipid (PGL) produced by a subset of MTB isolates belonging to the W-Beijing family (including HN878) that show 'hyperlethality' in murine disease models. Disruption of PGL synthesis results in loss of this hypervirulent phenotype without significantly affecting bacterial load during disease. Loss of PGL was found to correlate with an increase in the release of the pro-inflammatory cytokines tumour-necrosis factor-alpha and interleukins 6 and 12 in vitro. Furthermore, the overproduction of PGL by MTB or the addition of purified PGL to monocyte-derived macrophages was found to inhibit the release of these pro-inflammatory mediators in a dose-dependent manner. These results suggest that the PGL of MTB confers a hypervirulent phenotype on the bacilli which is manifest as an interference of this MTB lipid with optimal induction of host protective immunity.

In addition to Dr. Kaplan's studies at the Public Health Research Institute, she has a number of off shore collaborative studies being conducted at the University of Cape Town, Cape Town, South Africa. The pathogenic process that occurs in the lung of TB patients is being analyzed and the effect of antiretroviral treatment of HIV infected individuals on TB disease and MTB transmission are being studied in collaboration with Dr. Linda-Gail Bekker Wood. In addition, immunologic correlates of BCG vaccination-induced protective immunity against TB disease in infants are being defined in collaboration with Dr (s) Willem Hanekom and Greg Hussey.




Recent Articles

Murray, R.A., N. Mansoor, R. Harbacheuski, J. Soler, H. Maecker, A. Hawkridge, G.D. Hussey, V. Davids, G. Kaplan and W.A. Hanekom. (2006).
BCG vaccination of human newborns induces a specific functional CD8+ T cell response.
J. Immunol., In Press, 2006.

Timm J., N. Kurepina, B.N. Kreiswirth, F.A. Post, G.B. Walther, H.C. Wainwright, L-G. Bekker, G. Kaplan and J.D. McKinney. (2006).
A multidrug-resistant, alpha-crystallin-deficient clinical isolate of mycobacterium tuberculosis is unimpaired for replication in macrophages.
J. Infect. Dis., 193:1703-1710, 2006.

Tsenova L., R. Harbacheuski, A.L Moreira, E. Ellison, W. Dalemans, M.R. Alderson, S. G. Reed, Y.A.W. Skeiky and G. Kaplan. (2006).
Evaluation of the Mtb72F polyprotein vaccine in a rabbit model of tuberculous meningitis.
Infec. Immun., 74: 2392-2401, 2006.

Tsenova L, Harbacheuski R, Ellison E, Manca C and Kaplan G. (2006).
Aerosol exposure system for rabbits: application to M. tuberculosis infection.
Applied Biosafety, 11:7-14, 2006.

Freeman S, Post FA., Bekker L-G, Harbacheuski R, Steyn LM, Ryffel B, Connell ND, Kreiswirth BN and Kaplan G. (2006).
Mycobacterim tuberculosis H37Ra and H37Rv differential growth and cytokine/chemokine induction in murine macrophages in vitro.
J. Interferon Cytokine Res., 26: 27-33, 2006.

Davids, V, Hanekom WA, Mansoor N, Gamieldien H, Gelderbloem SJ, Hawkridge A, Hussey GD, Huges EJ, Soler J, Murray RA, Ress SR, and Kaplan G. (2006).
The effect of BCG vaccine strain and route of administration on induced immune responses in vaccinated infants.
J. Infect. Dis., 196: 531-536, 2006.

Manca, C, Tsenova L, Freeman S, Barczak AK, Tovey M, Murray PJ, Barry CE 3rd, and Kaplan G. (2005).
Hypervirulent M. tuberculosis W/Beijing strains upregulate type I IFNs and increase expression of negative regulators of the Jak/Stat pathway.
J. Interferon Cytokine Res., 694-701, 2005.

Haslett PAJ, Roche P, Butlin R, Macdonald M, Shrestha N, Manandhar R, LeMaster J, Hawkhurst R, Shah M, Lubinsky AS, Albert M, Worley J and Kaplan G. (2005).
Effective treatment of erythema nodosum leprosum with thalidomide is associated with immune stimulation.
J. Infect. Dis., 192:2045-2053, 2005.

Shrestha N., J.A. Ida, A.S. Lubinski, M Pallin, G. Kaplan, and P.A.J. Haslett. (2005).
Regulation of Acquired Immunity by T-cell dendritic cells Interactions.
Ann. N.Y. Acad. Sci. 1062:1-16, 2005.

Kaplan G. (2005).
Rational vaccine development--a new trend in tuberculosis control.
N Engl J. Med. 2005 Oct 13;353(15):1624-5.

Tsenova L, Ellison E, Harbacheuski R, Moreira A.L, Kurepina N, Reed MB, Mathema B, Barry C E 3rd and Kaplan G. (2005).
Virulence of selected Mycobacterium tuberculosis clinical isolates in the rabbit model of meningitis is dependent on phenolic glycolipid produced by the bacilli.
J Infect Dis. 2005 Jul 1;192(1):98-106.

Barczak A, Domenech P, Boshoff HIM, Reed M.B, Kaplan G, and Barry CE 3rd. (2005).
In vivo phenotypic dominance in mouse mixed infections with Mycobacterium tuberculosis clinical isolates.
J Infect Dis. 2005 Aug 15;192(4):600-6.

Davidow, A, Kanaujia GV, Shi L, Kaviar J, Guo X, Sung N, Kaplan G, Menzies D, and Gennaro ML. (2005).
Antibody profiles characteristic of Mycobacterium tuberculosis infection state.
Infect Immun. 2005 Oct;73(10):6846-51.

Hanekom WA, Hughes J, Mavinkurve M, Mendillo M, Watkins M, Gamieldien H, Gelderbloem SJ, Sidibana M, Mansoor N, Davids V, Murray RA, Hawkridge A, Haslett PA, Ress S, Hussey GD, Kaplan G. (2004).
Novel application of a whole blood intracellular cytokine detection assay to quantitate specific T-cell frequency in field studies.
J Immunol Methods. 2004 Aug;291(1-2):185-95
PMID: 15345316
Abstract

Reed MB, Domenech P, Manca C, Su H, Barczak AK, Kreiswirth BN, Kaplan G, Barry CE 3rd. (2004).
A glycolipid of hypervirulent tuberculosis strains that inhibits the innate immune response.
Nature. 2004 Sep 2;431(7004):84-7
PMID: 15343336
Abstract  |  Full Article

Manca C, Reed MB, Freeman S, Mathema B, Kreiswirth B, Barry CE 3rd, Kaplan G. (2004).
Differential monocyte activation underlies strain-specific Mycobacterium tuberculosis pathogenesis.
Infect Immun. 2004 Sep;72(9):5511-4
PMID: 15322056
Abstract  |  Full Article

Post FA, Willcox PA, Mathema B, Steyn LM, Shean K, Ramaswamy SV, Graviss EA, Shashkina E, Kreiswirth BN, Kaplan G. (2004).
Genetic polymorphism in Mycobacterium tuberculosis isolates from patients with chronic multidrug-resistant tuberculosis.
J Infect Dis. 2004 Jul 1;190(1):99-106. Epub 2004 May 28
PMID: 15195248
Abstract  |  Full Article

Schoeman JF, Springer P, van Rensburg AJ, Swanevelder S, Hanekom WA, Haslett PA, Kaplan G. (2004).
Adjunctive thalidomide therapy for childhood tuberculous meningitis: results of a randomized study.
J Child Neurol. 2004 Apr;19(4):250-7
PMID: 15163089
Abstract

Domenech P, Reed MB, Dowd CS, Manca C, Kaplan G, and Barry CE. (2004).
The role of MmpL8 in sulfatide biogenesis and virulence of Mycobacterium tuberculosis.
J Biol Chem. 2004 May 14;279(20):21257-65. Epub 2004 Mar 04.
PMID: 15001577
Abstract  |  Full Article

Kaplan G, Post FA, Moreira AL, Wainwright H, Kreiswirth BN, Tanverdi M, Mathema B, Ramaswamy SV, Walther G, Steyn LM, Barry CE 3rd, Bekker LG. (2003).
Mycobacterium tuberculosis growth at the cavity surface: a microenvironment with failed immunity.
Infect Immun. 2003 Dec;71(12):7099-108
PMID: 14638800
Abstract  |  Full Article

Dawes SS, Warner DF, Tsenova L, Timm J, McKinney JD, Kaplan G, Rubin H, Mizrahi V. (2003).
Ribonucleotide reduction in Mycobacterium tuberculosis: function and expression of genes encoding class Ib and class II ribonucleotide reductases.
Infect Immun. 2003 Nov;71(11):6124-31
PMID: 14573627
Abstract  |  Full Article

Timm J, Post FA, Bekker LG, Walther GB, Wainwright HC, Manganelli R, Chan WT, Tsenova L, Gold B, Smith I, Kaplan G, McKinney JD. (2003).
Differential expression of iron-, carbon-, and oxygen-responsive mycobacterial genes in the lungs of chronically infected mice and tuberculosis patients.
Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14321-6. Epub 2003 Nov 17
PMID: 14623960
Abstract  |  Full Article

Dahl JL, Kraus CN, Boshoff HI, Doan B, Foley K, Avarbock D, Kaplan G, Mizrahi V, Rubin H, Barry CE 3rd. (2003).
The role of RelMtb-mediated adaptation to stationary phase in long-term persistence of Mycobacterium tuberculosis in mice.
Proc Natl Acad Sci U S A. 2003 Aug 19;100(17):10026-31. Epub 2003 Aug 01
PMID: 12897239
Abstract  |  Full Article

Hanekom WA, Mendillo M, Manca C, Haslett PA, Siddiqui MR, Barry C 3rd, Kaplan G. (2003).
Mycobacterium tuberculosis inhibits maturation of human monocyte-derived dendritic cells in vitro.
J Infect Dis. 2003 Jul 15;188(2):257-66. Epub 2003 Jul 09
PMID: 12854081
Abstract  |  Full Article

Tsenova, L., B. Mangaliso, A.L. Moreira and G. Kaplan. (2003).
Virulent clinical isolates of M. tuberculosis cross the blood-brain barrier and cause severe pulmonary and central nervous system disease.
Submitted, 2003

Haslett PA, Hanekom WA, Muller G, Kaplan G. (2003).
Thalidomide and a Thalidomide Analogue Drug Costimulate Virus-Specific CD8+ T Cells In Vitro.
J Infect Dis 2003 Mar 15;187(6):946-55
PMID: 12660941
Abstract  |  Full Article

Post, F.A., L-G., Bekker, P. Bifani, L.M. Steyn, B. Ryffel, N.D. Connell, B.N. Kreiswirth and G. Kaplan. (2002).
TNF-a dependent growth restriction of M. tuberculosis H37Ra in murine macrophages in vitro.
Submitted, 2002

Murray HW, Lu CM, Mauze S, Freeman S, Moreira AL, Kaplan G, Coffman RL. (2002).
Interleukin-10 (IL-10) in experimental visceral leishmaniasis and IL-10 receptor blockade as immunotherapy.
Infect Immun. 2002 Nov;70(11):6284-93
PMID: 12379707
Abstract  |  Full Article

Jaslow R, Kaplan G, Lyons L, Michaeli J, Coleman M. (2002). Thalidomide in multiple myeloma--from the clinic to the laboratory.
Cancer Invest 2002;20(7-8):1051-8
PMID: 12449738

Siddiqui MR, Moreira AL, Negesse Y, Taye GA, Hanekom WA, Haslett PA, Britton S, Kaplan G. (2002).
Local nerve damage in leprosy does not lead to an impaired cellular immune response or decreased wound healing in the skin.
J Infect Dis 2002 Jul 15;186(2):260-5
PMID: 12134264
Abstract  |  Full Article

Tsenova L, Mangaliso B, Muller G, Chen Y, Freedman VH, Stirling D, Kaplan G. (2002).
Use of IMiD3, a Thalidomide Analog, as an Adjunct to Therapy for ExperimentalTuberculous Meningitis.
Antimicrob Agents Chemother 2002 Jun;46(6):1887-95
PMID: 12019105
Erratum in: Antimicrob Agents Chemother 2002 Jul;46(7):2313
Abstract  |  Full Article

Wohl DA, Aweeka FT, Schmitz J, Pomerantz R, Cherng DW, Spritzler J, Fox L, Simpson D, Bell D, Holohan MK, Thomas S, Robinson W, Kaplan G, Teppler H;
National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group267. (2002).
Safety, tolerability, and pharmacokinetic effects of thalidomide in patients infected with human immunodeficiency virus: AIDS Clinical Trials Group 267.
J Infect Dis 2002 May 1;185(9):1359-63
PMID: 12001058
Abstract  |  Full Article

Moreira AL, Tsenova L, Aman MH, Bekker LG, Freeman S, Mangaliso B, Schroder U, Jagirdar J, Rom WN, Tovey MG, Freedman VH, Kaplan G. (2002).
Mycobacterial antigens exacerbate disease manifestations in Mycobacterium tuberculosis-infected mice.
Infect Immun 2002 Apr;70(4):2100-7
PMID: 11895976
Abstract  |  Full Article

Oliver SJ, Kikuchi T, Krueger JG, Kaplan G. (2002).
Thalidomide induces granuloma differentiation in sarcoid skin lesions associated with disease improvement.
Clin Immunol 2002 Mar;102(3):225-36
PMID: 11890709
Abstract  |  Full Article

Strauch B, Rodriguez DM, Diaz J, Yu HL, Kaplan G, Weinstein DE. (2001).
Autologous Schwann cells drive regeneration through a 6-cm autogenous venous nerve conduit.
J Reconstr Microsurg 2001 Nov;17(8):589-95; discussion 596-7
PMID: 11740653
Abstract

Hanekom WA, Hughes J, Haslett PA, Apolles P, Ganiso V, Allin R, Goddard E, Hussey GD, Kaplan G (2001).
The immunomodulatory effects of thalidomide on human immunodeficiency virus-infected children.
J Infect Dis 2001 Nov 1;184(9):1192-6
PMID: 11598844
Abstract  |  Full Article

Bekker LG, Freeman S, Murray PJ, Ryffel B, Kaplan G. (2001).
TNF-alpha controls intracellular mycobacterial growth by both inducible nitric oxide synthase-dependent and inducible nitric oxide synthase-independent pathways.
J Immunol 2001 Jun 1;166(11):6728-34
PMID: 11359829
Abstract |  Full Article

Manca C, Tsenova L, Bergtold A, Freeman S, Tovey M, Musser JM, Barry CE 3rd, Freedman VH, Kaplan G. (2001).
Virulence of a Mycobacterium tuberculosis clinical isolate in mice is determined by failure to induce Th1 type immunity and is associated with induction ofIFN-alpha /beta.
Proc Natl Acad Sci USA 2001 May 8;98(10):5752-7
PMID: 11320211
Abstract  |  Full Article

Post FA, Manca C, Neyrolles O, Ryffel B, Young DB, Kaplan G. (2001).
Mycobacterium tuberculosis 19-kilodalton lipoprotein inhibits Mycobacterium smegmatis-induced cytokine production by human macrophages in vitro.
Infect Immun 2001 Mar;69(3):1433-9
PMID: 11179309
Abstract  |  Full Article

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