Transcript Folie 1 - MH

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
(1) Resistance to
CD95/Fas-mediated
apoptosis in HIVinfected cells
(2) Upregulation of
CD95L/FasL on the
surface of infected
cells (HIV nef)
(1) Chronic antigenspecific TCR
activation
(2) Loss or lack of HIVspecific CD4+ T-cell
help
(3) Aberrant or
inappropriate
chemokine receptor
signaling
Petrovas, C. et al., 2005
Acute infection and macrophage subversion by Mycobacterium
tuberculosis require a specialized secretion system
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
Stanley, S. A. et al. 2003
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
The MHC class I HC and β2m
are co-translationally translocated
into the ER lumen
ER-resident chaperones (CNX,
ERp57, CRT) facilitate proper
folding
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 MHC
class I molecules leave the ER,
transit through the Golgi network
and reach the cell surface
Ambagala, A. P. et al. 2005
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
(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
Sodhi, A. et al., 2004
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
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
Alcami, A., 2003
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
(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
Letvin, N. L., 2006
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 complementmediated lysis and phagocytosis
C4BP bound to the
surface of a pathogen
inhibits classical C3convertase by
accelerating its decay
C4BP serves as a
cofactor in cleavage of
C4b both in solution
and surface-bound,
and C3b in solution
C4BP capture leads
to decrease in
opsonization and less
efficient phagocytosis
Blom, A.M., 2004
Viral interactions with the BTLA/HVEM/LIGHT cosignaling pathway
HSV gD binds to the
membrane-distal CRD1
domain ofHVEMopposite the
LIGHT-binding site and
overlapping the binding site
of HVEM for BTLA
hCMV UL144 acts as a
mimic of HVEM and binds to
BTLA to send an inhibitory
signal to T cells
Watts, T. H. and Gommerman, J. L., 2005
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