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 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 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 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

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