Heightened virulence of Yersinia is associated with decreased function of the YopJ protein

This is the authors' abstract. We don't add key points for this paper.

Despite the maintenance of YopP/J alleles throughout the human-pathogenic Yersinia lineage, the benefit of YopP/J-induced phagocyte death for Yersinia pathogenesis in animals is not obvious. To determine how sequence divergence of YopP/J has impacted Yersinia virulence, we examined protein polymorphisms in this Type III secreted effector protein across 17 Yersinia species, and tested the consequences of polymorphism in a murine model of sub-acute systemic yersiniosis. Our evolutionary analysis revealed that codon 177 has been subjected to positive selection - the Y. enterocolitica residue had been altered from a leucine to a phenylalanine in nearly all Y. pseudotuberculosis and Y. pestis strains examined. Despite being a minor change, as both leucine and phenylalanine have hydrophobic side chains, reversion of YopJ F177 to the ancestral YopJ L177 variant yielded a Y. pseudotuberculosis strain with enhanced cytotoxicity towards macrophages, consistent with previous findings. Surprisingly, expression of YopJ F177L in the mildly attenuated ksgA - background rendered the strain completely avirulent in mice. Consistent with this hypothesis that YopJ activity indirectly relates to Yersinia pathogenesis in vivo , ksgA - strains lacking functional YopJ failed to kill macrophages but actually regained virulence in animals. Also, treatment with the anti-apoptosis drug suramin prevented YopJ-mediated macrophage cytotoxicity and enhanced Y. pseudotuberculosis virulence in vivo . Our results demonstrate that Yersinia -induced cell death is detrimental for bacterial pathogenesis in this animal model of illness, and indicate that positive selection has driven YopJ/P and Yersinia evolution towards diminished cytotoxicity and increased virulence, respectively.