Matthew Landry

Background: Plague is one of the most historically and culturally important diseases ever to impact humankind. Yersinia pestis, the causative agent of plague, has led to no less than three pandemics within the last 1500 years, and continues to be medically relevant causing over 26,000 cases of illness since the year 2000.^1,2 Transmitted by a flea vector from one mammalian host to another, Y. pestis makes use of several indispensable virulence factors to subvert host immune defenses and cause septicemia and death within days. ^1,2,3,4

Objective: This narrative review investigates the most significant virulence mechanisms of Y. pestis in its establishment of severe and deadly infections.

Search Methods: A PubMed search was conducted within the timeframe of 2018 to 2023 using key words “Yersinia pestis”, “plague”, and “virulence”.

Results: Following transmission into the host bloodstream by flea vector, Y. pestis immediately begins to subvert the immune system by disguising its lipopolysaccharide layer. Due to the evolutionary loss of the pagP gene, fewer acylations are present in the lipid A portion of wildtype Y. pestis allowing it to avoid activation of Toll Like Receptor 4 on host immune cells.⁵ Compared to the pagP+ strain, the wild type strain contained fewer acylations as detected by GC-MS while leading to lower levels of inflammatory markers detected by EIA following incubation with neutrophils in vitro.⁵ The Type 3 Secretion System was also shown to dampen host response by direct interaction with immune cell functions.^6,7 Neutrophil degranulation was measured by flow cytometric assay following in vitro incubation with wild type and T3SS- strains.⁶ Neutrophils incubated with the wildtype had far fewer of the relevant CD markers present compared to those incubated with T3SS- strains.⁶ This suggests the wildtype strain was able to interfere with specific and azurophilic granule fusion with the neutrophil cell membrane to prevent degranulation.⁶ The T3SS effectuates subversion of immune cells by transferring Yersinia outer proteins from its own cytoplasm into the host cell. A gain of function assay determined Yops act in a cooperative fashion to sabotage host immune cells.⁷ Mice infected with strains of Y. pestis expressing three or fewer Yops showed 0% lethality, whereas strains expressing four to seven Yops showed increasing levels of lethality up to 100%.⁷ Metal acquisition from the host enables bacterial organisms to fulfill their metabolic needs while depriving the host of a vital resource. Iron acquisition in Y. pestis relies on an interaction between the siderophore Yersiniabactin with surface receptors encoded by the fyuA gene.⁸ Following incubation of wildtype and fyuA– strains with HeLa cells, decreased survivability was observed in cells incubated with the wildtype as indicated by a decreased normalized cell index.⁸

Conclusions: The most current research indicates that Y. pestis is able to evade and sabotage innate immune response by LPS modification, transfer of Yops by the T3SS, and metal acquisition from the host. These discoveries are of clinical importance in developing potential treatments and effective immunizations.

Works Cited

1.  Barbieri R, Signoli M, Chevé D, et al. Yersinia pestis: the Natural History of Plague. Clin Microbiol Rev. 2020;34(1):e00044-19. Published 2020 Dec 9. doi:10.1128/CMR.00044-19
2. Demeure CE, Dussurget O, Mas Fiol G, Le Guern AS, Savin C, Pizarro-Cerdá J. Yersinia pestis and plague: an updated view on evolution, virulence determinants, immune subversion, vaccination, and diagnostics. Genes Immun. 2019;20(5):357-370. doi:10.1038/s41435-019-0065-0
3. Dewitte A, Bouvenot T, Pierre F, et al. A refined model of how Yersinia pestis produces a transmissible infection in its flea vector. PLoS Pathog. 2020;16(4):e1008440. Published 2020 Apr 15. doi:10.1371/journal.ppat.1008440
4. Sebbane F, Lemaître N. Antibiotic Therapy of Plague: A Review. Biomolecules. 2021;11(5):724. Published 2021 May 12. doi:10.3390/biom11050724
5. Chandler CE, Harberts EM, Pelletier MR, et al. Early evolutionary loss of the lipid A modifying enzyme PagP resulting in innate immune evasion in Yersinia pestis [published correction appears in Proc Natl Acad Sci U S A. 2020 Dec 22;117(51):32817]. Proc Natl Acad Sci U S A. 2020;117(37):22984-22991. doi:10.1073/pnas.1917504117
6. Pulsifer AR, Vashishta A, Reeves SA, et al. Redundant and Cooperative Roles for Yersinia pestis Yop Effectors in the Inhibition of Human Neutrophil Exocytic Responses Revealed by Gain-of-Function Approach. Infect Immun. 2020;88(3):e00909-19. Published 2020 Feb 20. doi:10.1128/IAI.00909-19
7. Palace SG, Proulx MK, Szabady RL, Goguen JD. Gain-of-Function Analysis Reveals Important Virulence Roles for the Yersinia pestis Type III Secretion System Effectors YopJ, YopT, and YpkA. Infect Immun. 2018;86(9):e00318-18. Published 2018 Aug 22. doi:10.1128/IAI.00318-18
8. Chen Y, Song K, Chen X, et al. Attenuation of Yersinia pestis fyuA Mutants Caused by Iron Uptake Inhibition and Decreased Survivability in Macrophages. Front Cell Infect Microbiol. 2022;12:874773. Published 2022 May 4. doi:10.3389/fcimb.2022.874773
9. Russo R, Kolesnikova I, Kim T, et al. Susceptibility of Virulent Yersinia pestis Bacteria to Predator Bacteria in the Lungs of Mice. Microorganisms. 2018;7(1):2. Published 2018 Dec 21. doi:10.3390/microorganisms7010002