Heightened Virulence of Yersinia Is Associated with Decreased Function of the YopJ Protein

• Published in: Infection and immunity 2021-11, Vol.89 (12), p.e0043021
• Main Authors: Mares, Chris A, Lugo, Fernando P, Albataineh, Mohammad, Goins, Beth A, Newton, Irene G, Isberg, Ralph R, Bergman, Molly A
• Format: Article
• Language: English
• Subjects: Animals; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Disease Susceptibility; Gene Expression Regulation, Bacterial; Host-Microbial Interactions; Host-Pathogen Interactions; Humans; Molecular Pathogenesis; Mutation; Virulence - genetics; Virulence Factors; Yersinia - pathogenicity; Yersinia - physiology; Yersinia Infections - microbiology
• ISSN: 0019-9567; 1098-5522
• DOI: 10.1128/IAI.00430-21

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