The role of the tumor suppressor CYLD in Yersinia enterocolitica infection

Recent studies have identified the tumor suppressor CYLD as a key
regulator of NF -κB, a transcription factor that promotes cell
survival and oncogenesis, as well as host defence to infection. In
th e pr esent study, we investigated the role of tumor suppressor
CYLD in regulation of innate immune responses of mice to Y.
enterocolitica infection and for comparison to Salmonella
Typhimurium infection . Yersinia is an extracellular multiplying
bacterium that ensures its extracellular growth by injecting
virulence proteins (Yops) into host cells by the injectisome
Ysc-T3SS , which interfere with several signaling pathways (such as
MAPK and NF-κB cascades), resulting in the inhibition of
phagocytosis, oxidative burst and cytokine production. In contrast,
Salmonella Typhimurium is endowed with 2 T3SS which inject effector
proteins to induce pathogen uptake and intracellular replication.
Surprisingly, we found that Cyld-/- mice were more resistant to Y.
enterocolitica than Cyld+/- mice in contrast to Salmonella
Typimurium infection which appeared to be CYLD- independent. These
results suggest that CYLD acts as a detrimental factor for host
survival during early Y. enterocolitica infection. Furthermore, we
showed that Yops-mediated inhibition of host defense mechanisms ,
such as phagocytosis, oxidative burst, NF-κB, cytokine production
and p38 activation is attenuated in Cyld-/--phagocytic cells in
respect of Cyld+/- cells. Taken together, this study provides for
the first time, an empirical demonstration of a pathogen-specific
contribution of a tumor suppressor gene and its encoded protein,
respectively, CYLD, to infection susceptibility in a manner that
seems to be independent of its tumor suppression mechanism. This is
another example of the extraordinary complexity of the
pathogen/host cell interactions.