Transcript Innate imunity, malaria and Burikitt’s lymphoma

Innate immunity, malaria and
Burikitt’s lymphoma
Michele Bernasconi, PhD
University Children’s Hospital
Experimental Infectious Diseases and Cancer Research
August Forel Strasse 1
CH-8008 Zurich
BIO430 2008
Innate immunity ↔ Adaptive immunity
Innate immunity ↔ Adaptive immunity
 Innate ( Nonspecific ) Immunity - The term, innate immunity,
refers to the basic resistance to disease that a species
possesses - the first line of defense against infection.
The characteristics of the innate immune response include the
following:
 Responses are Broad-Spectrum (non-specific)
 There is no memory or lasting protective immunity
 There is a limited repertoire of recognition molecules
 The responses are phylogenetically ancient
 Potential pathogens are encountered routinely, but only rarely
cause disease. The vast majority of microorganisms are
destroyed within minutes or hours by innate defenses. The
acquired specific immune response comes into play only if
these innate defenses are breached.
Receptors involved
Receptors involved (adaptive imm.)
Toll-like receptors
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Two distinct pathways control the inducible synthesis of antimicrobial peptides in
Drosophila adult flies.
The Toll receptor is activated by the cysteine-knot growth factor Spaetzle (Spz). The
activated Toll receptor triggers phosphorylation of the inhibitory protein Cactus though the
intermediates Tube and Pelle. Phosphorylated Cactus is degraded by the proteasome,
thus allowing nuclear translocation of the transcription factor DIF, which induces synthesis
of the antifungal peptide drosomycin. The antibacterial peptide diptericin is induced by a
distinct pathway in which a putative membrane receptor activates a signaling complex
comprising the Drosophila homologs of IKKβ and IKKγ (encoded by the genes ird5 and
kenny, respectively). This complex induces phosphorylation and cleavage of Relish. Upon
nuclear translocation, the Rel domain from Relish activates synthesis of diptericin. The
caspase Dredd is also required for the induction of the antibacterial peptide genes. Note
that it is not yet known whether Spaetzle directly interacts with Toll. Abbreviations: DD,
death domain; KD, kinase domain; IL, interleukin; TIR, Toll/IL-1 receptor homology domain.
Toll-like receptors
Chiron, D., I. Bekeredjian-Ding, et al. (2008). "Toll-like receptors: lessons to learn from normal and malignant human B cells." Blood.
Toll-like receptors - signaling
Malaria
 Plasodium vivax or falciparum
Malaria
 Plasodium vivax or falciparum
Burkitt lymphoma
 B cell lymphoma
 Reciprocal translocation Ig-enhancers and chr 8
 c-myc: similar to myelocytomatosis viral oncogene (v-myc)
Taub R, Morton C, Lenoir G, et al. Translocation of the c-myc gene into the immunoglobulin
heavy chain locus in human Burkitt lymphoma and murine plasmacytoma cells. Proc Natl
Acad Sci USA 1982;79:7837-7841
Burkitt lymphoma
 1956 Denis Burkitt
 1964 Epstein and Barr identify virus
Endemic Burkitt's lymphoma: a polymicrobial disease?
Rosemary Rochford, Martin J. Cannon & Ann M. Moormann
Nature Reviews Microbiology 3, 182-187 (February 2005)
Burkitt lymphoma
 Endemic BL & endemic malaria
Malaria activate innate immune system
 Malaria pigment hemozoin activates TLR9
 J Exp Med (2005) 201: 19-25.
Toll-like receptor 9 mediates innate immune activation by the malaria
pigment hemozoin.
C Coban, KJ Ishii, T Kawai, H Hemmi, S Sato, S Uematsu, M
Yamamoto, O Takeuchi, S Itagaki, N Kumar, T Horii, S Akira
Malaria activate innate immune system
Malaria activate innate immune system
Malaria activate innate immune system
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CIDR1a: cystein-rich inter-domain region 1a of the P. falciparum erythrocyte membraneprotein 1 (PfEMP1)
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RBCs or CIDR1a bind to EBV positive Burkitt lymphoma cells (memory B cell) and activate proliferation
Malaria activate innate immune system
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CIDR1a: cystein-rich inter-domain region 1a of the P. falciparum erythrocyte membraneprotein 1 (PfEMP1)
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RBCs or CIDR1a bind to EBV positive Burkitt lymphoma cells (memory B cell) and activate proliferation
TLR expression and function during
normal B cell differentiation and in B
cell malignancies.
Chiron, D., I. Bekeredjian-Ding, et al. (2008). "Toll-like receptors: lessons to learn from normal and malignant human B cells." Blood.
Further reading
Reviews
 Chiron, D., I. Bekeredjian-Ding, et al. (2008). "Toll-like receptors: lessons to
learn from normal and malignant human B cells." Blood.
 Coban, C., K. J. Ishii, et al. (2007). "Manipulation of host innate immune
responses by the malaria parasite." Trends in microbiology 15(6): 271-8.
 Krieg, A. M. (2007). "Development of TLR9 agonists for cancer therapy." The
Journal of clinical investigation 117(5): 1184-94.
Original articles
 Ewald, S. E., B. L. Lee, et al. (2008). "The ectodomain of Toll-like receptor 9 is
cleaved to generate a functional receptor." Nature 456(7222): 658-62.
 Chaturvedi, A., D. Dorward, et al. (2008). "The B cell receptor governs the
subcellular location of Toll-like receptor 9 leading to hyperresponses to DNAcontaining antigens." Immunity 28(6): 799-809.
 Chene, A., D. Donati, et al. (2007). "A molecular link between malaria and
Epstein-Barr virus reactivation." PLoS pathogens 3(6): e80.
 Coban, C., K. J. Ishii, et al. (2005). "Toll-like receptor 9 mediates innate immune
activation by the malaria pigment hemozoin." J Exp Med 201(1): 19-25.
Akata cells
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Sporadic Burkitt's lymphoma cell line
c-myc translocation
EBV positive
EBV can be reactivated by IgG cross-linking
 Model system to study EBV reactivation to lytic
infection
 Model system to study innate immunity and EBV?
qPCR / Real time quantitative PCR
 Quantitative analysis of gene expression
qPCR / Real time quantitative PCR
 Quantitative analysis of gene expression
Quantitative analysis of TLR9
expression in Akata cells
 mRNA from Akata cells stimulated with different
cytokines
 Retro-transcription mRNA → cDNA
 PCR with TaqMan probes
 TLR9
 GAPDH (reference)
 Data analysis