Crosstalk between Signaling Processes of Innate Immunity and Yersinia YopP Effector Functions
Final Report Abstract
The interaction of microbial pathogens with host cells critically determines the genesis of infectious diseases. Gram-negative, pathogenic bacteria from the genus Yersinia deliver a set of virulence proteins, the so-called Yops (Yersinia outer proteins), inside the eukaryotic cell where the Yops perturb key cellular functions of innate immunity. We used Y. enterocolitica as tool to explore the interaction between the bacterial pathogen and its host cell. Yersiniae counteract phagocytosis, suppress proinflammatory signalling and trigger apoptosis in macrophages. We were able to characterize different aspects of this crosstalk between Yersinia and host cells. Our results revealed that macrophage cell death in response to Yersinia infection results form the deregulation of conserved Toll-like receptors-dependent signalling pathways of innate immunity. Yersiniae suppress survivalpromoting signaling pathways by the injection of a specific Yop virulence factor (YopP) inside the host cell, and simultaneously activate cytotoxic events by the engagement of immune receptors that respond to conserved bacterial components (TLR4). A related cytotoxic signal relay can potentially be activated also by viral infection (TLR3). The host cell may desensitize these pathways to become refractory to microbe-induced cell death. A second mechanism of the infected host to resist Yop activities and to possibly counteract Yersinia infection is the degradation and inactivation of injected Yops through a conserved protein recycling pathway of the cell (proteasome). Yop inactivation by this pathway requires specific lysine residues found only in a subset of Y. enterocolitica serotypes. The exploration of the crosstalk between Yersinia and host cells revealed a number of unexpected insights into the regulation of host defence responses. This gives an example on how the study of bacterial virulence can shed light into the biology of the infected celt. In the long-term, this may help to develop drugs that specifically direct or channel cell reactions.
Publications
- (2002): Divergence of apoptosis-inducing and preventing signals in bacteria-faced macrophages through MyD88 and IRAK members. J. Immunol. 168:4601-4611
K. Ruckdeschel, O. Mannel, and P. Schröttner
- (2002): Immunomodulation of macrophages by pathogenic Yersinia species. Archivum Immunoloaiae et Therapiae Experimentalis 50: 131 137
K. Ruckdeschel
- (2002): LPS desensitization of macrophages provides protection against Yersinia enterocolitica-induced apoptosis. Infect. Immun. 70: 5259-5264
K. Ruckdeschel, and K. Richter
- (2003): A dominant role of Tolllike receptor 4 (TLR4) in the signaling of apoptosis in bacteria-faced macrophages. J. Immunol. 171: 4294-4303
R. Haase, C.J. Kirschning, A. Sing, P. Schröttner, K. Fukase, S. Kusumoto, H. Wagner, J. Heesemann, and K. Ruckdeschel
- (2004): Signaling of apoptosis through TLRs critically involves toll/IL-1 receptor domain-containing adapter inducing IFNß, but not MyD88, in bacteria-infected murine macrophages. J. Immunol. 173: 3320-3328
K. Ruckdeschel, G. Pfaffinger, R. Haase, A. Sing, H. Weighardt, G. Hacker, B. Holzmann, and J. Heesemann
- (2005): Yersinia outer protein P suppresses transforming growth factor-ß-activated kinase-1 activity to impair innate immune signaling in Yersinia enterocoliticainfected cells. J. Immunol. 175: 8209-8217
R. Haase, K. Richter, G. Pfaffinger, G. Courtois, and K. Ruckdeschel
- (2006): The proteasome pathway destabilizes Yersinia outer protein E and represses its anti-host cell activities. J. Immunol. 176: 6093-6102
K. Ruckdeschel, G. Pfaffinger, G. Zenner, K. Richter, K. Trülzsch, J. Heesemann, and M. Aepfelbacher
- (2007): Serogroup-Related Escape of Y. enterocolitica YopE from Degradation by the Ubiquitin-Proleasome Pathway. Infect. Immun. 75: 4423- 4431
M. Hentschke, K. Trülzsch, J. Heesemann, M. Aepfelbacher, and K. Ruckdeschel
- (2008): Crosstalk of signalling processes of innate immunity with Yersinia Yop effector functions. lmmunobiology 213: 261-269
K. Ruckdeschel, A. Deuretzbacher, and R. Haase
