Imke Steffen ZIB-Seminar 15. December 2008
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Transcript of Imke Steffen ZIB-Seminar 15. December 2008
Imke Steffen
ZIB-Seminar 15. December 2008
Microbial “Anti-Immunology“
Highly effective mechanisms of pathogens to overcome both innate and acquired immunity
Difficulties in controlling these pathogens and developing vaccines (examples: HIV (virus), Tuberculosis (bacterium), Malaria (parasite))
Bacteria and viruses have developed a surprising number of parallel strategies and shared mechanistic concepts to neutralize host immunity
→ key concepts
Bacteria and viruses use various mechanisms to overcome immunity
Finley, B. B. and McFadden, G., 2006
Overview
Surface Expression and Secretion of Immune Modulators (examples: HIV gp120, bacterial secretion systems)
Avoiding Immune Surveillance (examples: interference with antigen presentation, GPCR signaling, antigenic variation)
Subversion of Immune Response Pathways (examples: Yersinia TTSS, complement inhibition)
Surface Expression and Secretion of Immune Modulators
Finley, B. B. and McFadden, G., 2006
Surface Expression and Secretion of Immune Modulators
The external surface of pathogens is the central interface between host and pathogen recognition microbial clearance
Pathogens can: present mimics of host immune modulators to alter or prevent immune
responses
express adhesins or receptor ligands to anchor the pathogen to the host surfaces
present invasins or fusion proteins to mediate uptake into host cells
HIV virus can counterattack the CTL response through apoptosis
Petrovas, C. et al., 2005
(1) Resistance to CD95/Fas-mediated apoptosis in HIV-infected cells
(2) Upregulation of CD95L/FasL on the surface of infected cells (HIV nef)
(1) Chronic antigen-specific TCR activation
(2) Loss or lack of HIV-specific CD4+ T-cell help
(3) Aberrant or inappropriate chemokine receptor signaling
Acute infection and macrophage subversion by Mycobacterium tuberculosis require a specialized secretion system
Stanley, S. A. et al. 2003
The proteins Snm1, -2, and -4 are required for the secretion of ESAT-6 and CFP-10, small proteins previously identified as major T cell antigens
Snm4 mutants fail to limit both cytokine and effector responses early after infection of cultured macrophages and ultimately fail to replicate after phagocytosis
Stanley, S. A. et al. 2003
Acute infection and macrophage subversion by Mycobacterium tuberculosis require a specialized secretion system
Avoiding Immune Surveillance
Finley, B. B. and McFadden, G., 2006
Avoiding Immune Surveillance
Interference with Antigen Presentation
Hijacking of Chemokine Signaling
Bacterial and Viral Antigenic Variation
MHC class I antigen presentation pathway and the common targets of viral immunoevasins
Ambagala, A. P. et al. 2005
The MHC class I HC and β2mare co-translationally translocated into the ER lumen
ER-resident chaperones (CNX, ERp57, CRT) facilitate properfolding
The MHC class I HC + β2m + CRT + ERp57 complex is bridged to TAP by tapasin, making the PLC
Peptides generated by the proteasome are translocated into the lumen of the ER by TAP
Peptide-loaded, stable MHCclass I molecules leave the ER, transit through the Golgi network and reach the cell surface
The peptide-loading complex and viral proteins that exploit it
Lybarger, L. et al., 2005
Viral pathogen hijacking of intracellular signalling networks is regulated by GPCRs
Sodhi, A. et al., 2004
(a) GPCR signaling upon chemokine binding, (b) viral glycoproteins might function as agonists or antagonists and use GPCRs as entry co-receptor, (c) / (d) viruses encode their own GPCR receptors or chemokines, (e) virally encoded chemokine binding proteins sequester cellular chemokines
Blockade of chemokine activity by soluble vCKBPs from poxviruses and herpesviruses
Alcami, A., 2003
Strategy used by poxvirus vIFN-α/βBP to block the biological activity of IFNs
Alcami, A., 2003
By covering the cells with decoy receptors, vaccinia virus creates an environment in which IFNs cannot induce a protective anti-viral response and prevent virus replication
Role of KSHV-GPCR signalling pathways in Kaposi’s sarcomagenesis
Sodhi, A. et al., 2004
Possible functions of virus-encoded chemokines and chemokine receptors
Alcami, A., 2003
Lipid A modified by PagL and/or PagP in S. typhimurium show decreased ability to induce NF-B activation
Kawasaki, K et al., 2004
Molecular mechanisms of HIV-1 genetic variation
Letvin, N. L., 2006
(a) The viral reverse transcriptase is
highly error prone, resulting in
each new virion encoding
approximately one new mutation
(b)When two HIV-1 virions with
different genetic sequences
enter the same cell, they can
both integrate and produce
viral RNA. Homologous
recombination or packaging
of RNA from different parent
viruses leads to the creation
of entirely new HIV-1
genomes
Subversion of Immune Response Pathways
Finley, B. B. and McFadden, G., 2006
Subversion of Immune Response Pathways
Bacterial Subversion of Innate Pathways
Bacterial and Viral Subversion of Phagocytes
Complement Inhibition by Viruses
Cell Death Manipulation
The Yersinia effectors target multiple signaling pathways to inhibit host immune responses
Navarro, L. et al., 2005
Myxoma Virus vCD200 Is Responsible for Down-Regulation of Macrophage Activation In Vivo
Cameron, C. M. et al., 2005
Pathogens capturing C4BP are protected from complement-mediated lysis and phagocytosis
Blom, A.M., 2004
C4BP bound to the surface of a pathogen inhibits classical C3-convertase by accelerating its decay
C4BP serves as acofactor in cleavage of C4b both in solution and surface-bound, and C3b in solution
C4BP capture leadsto decrease in opsonization and less efficient phagocytosis
Viral interactions with the BTLA/HVEM/LIGHT cosignaling pathway
Watts, T. H. and Gommerman, J. L., 2005
HSV gD binds to themembrane-distal CRD1 domain ofHVEMopposite the LIGHT-binding site and overlapping the binding siteof HVEM for BTLA
hCMV UL144 acts as a mimic of HVEM and binds to BTLA to send an inhibitory signal to T cells
Concluding Remarks
Successful vertebrate pathogens must overcome or alter many effective host
defense mechanisms
Pathogens can serve as excellent tools to probe immune functions
Understanding the various Achilles heels of host defense helps to deconstruct
the fundamental properties of microbial pathogenesis
Studying the “anti-immune systems“ of pathogens is critical to contemplating
new therapies