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Imke Steffen ZIB-Seminar 15. December 2008. Microbial “Anti-Immunology“. Highly effective mechanisms of pathogens to overcome both innate and acquired immunity

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Imke steffen zib seminar 15 december 2008

Imke Steffen

ZIB-Seminar 15. December 2008


Microbial anti immunology
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
Bacteria and viruses use various mechanisms to overcome immunity

Finley, B. B. and McFadden, G., 2006


Overview
Overview immunity

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
Surface Expression and Secretion of Immune Modulators immunity

Finley, B. B. and McFadden, G., 2006


Surface expression and secretion of immune modulators1
Surface Expression and Secretion of Immune Modulators immunity

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
HIV virus can counterattack the CTL response through apoptosis

  • Resistance to CD95/Fas-mediated apoptosis in HIV-infected cells

  • Upregulation of CD95L/FasL on the surface of infected cells (HIV nef)

  • Chronic antigen-specific TCR activation

  • Loss or lack of HIV-specific CD4+ T-cell help

  • Aberrant or inappropriate chemokine receptor signaling

Petrovas, C. et al., 2005


Imke steffen zib seminar 15 december 2008
Acute infection and macrophage subversion by apoptosisMycobacterium 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


Imke steffen zib seminar 15 december 2008
Acute infection and macrophage subversion by apoptosisMycobacterium tuberculosis require a specialized secretion system

Stanley, S. A. et al. 2003


Avoiding immune surveillance
Avoiding Immune Surveillance apoptosis

Finley, B. B. and McFadden, G., 2006


Avoiding immune surveillance1
Avoiding Immune Surveillance apoptosis

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
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



Viral pathogen hijacking of intracellular signalling networks is regulated by gpcrs
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
Blockade of chemokine activity by soluble vCKBPs from poxviruses and herpesviruses

Alcami, A., 2003


Strategy used by poxvirus vifn bp to block the biological activity of ifns
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
Role of KSHV-GPCR signalling pathways in Kaposi’s sarcomagenesis

Sodhi, A. et al., 2004



Imke steffen zib seminar 15 december 2008
Lipid A modified by PagL and/or PagP in receptorsS. typhimurium show decreased ability to induce NF-B activation

Kawasaki, K et al., 2004


Molecular mechanisms of hiv 1 genetic variation
Molecular mechanisms of HIV-1 genetic variation receptors

  • The viral reverse transcriptase is highly error prone, resulting in each new virion encoding approximately one new mutation

  • 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
Subversion of Immune Response Pathways receptors

Finley, B. B. and McFadden, G., 2006


Subversion of immune response pathways1
Subversion of Immune Response Pathways receptors

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
The receptorsYersinia 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
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
Pathogens capturing C4BP are protected from complement-mediated lysis and phagocytosis

C4BP bound to the surface of a pathogen inhibits classical C3-convertase 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
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
Concluding Remarks pathway

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