Plague is caused by the bacteria Yersinia pestis. Yersinia pestis is a gram-negative bacteria that can infect fleas. In fleas, the bacteria multiply in the digestive tract and form a biofilm in the foregut valve connecting the esophagus and the midgut.1,2 One to two weeks after infection, the biofilm impedes and might even entirely block the intake of blood during feeding.1,2 As a result, the fleas regurgitate the blood, now contaminated with Y. pestis bacteria back into the bite site.1,2 Small mammals become infected with these bacteria-ridden fleas and in rare instances, the fleas bite and infect mammals. In mice, which orally ingested Y. pestis, the bacteria initially colonized Peyer’s patches, which are groupings of lymphoid follicles in the lining of the small intestine.3 Y. pestis also colonizes mesenteric lymph nodes, the mesentery is a fold of the membrane that attaches the intestine to the abdominal wall.4 Next, Yersinia species cause abscesses to form in the medullary region.4 After the medullary region, the infection becomes systemic and spreads to the liver, spleen, and lungs where it forms additional abscesses.4 The bacteria spread systemically, causing severe fever, delusions, and ultimately sepsis.5 Without treatment, the plague has a 95% mortality rate.6
The Y. pestis bacteria have developed intricate machinery to avoid the immune response in humans. The Ysc-Yop injectisome attaches to host cells and secretes cytotoxic proteins into the plasma of the host cells. The secreted proteins disable macrophages and induce apoptosis. Normally, macrophages will engulf bacteria by phagocytosis as a measure of infection control. But, during Y. pestis infection macrophages are unable to carry out their native function.
Phagocytosis is defined as the process by which cells engulf matter later than 0.5μm.7 In humans, phagocytosis by phagocutes such as neutrophils and macrophages are key to the immune response.
Phagocytosis has seven stages. The first stage is particle recognition; during this stage, the receptors on the phagocyte bind to the receptors on the particle it will engulf (i.e. bacteria), this interaction may be transient. The surface of gram-negative bacteria displays lipopolysaccharides.7 Next, is particle binding. If the interaction between target ligands and phagocyte receptors are strong enough to overcome the natural motion of both particles, then the binding will hold.7 The third step is particle signaling. In this step, the phagocyte will generate signals that inform of the nature of the bound particle.7 The next step is phagocytic cup formation where the phagocytic cup forms and holds the particle firmly, increasing the number of interactions between the phagocyte and particle surface.7 The fifth step is pseudopodia extension during which the phagocytic cup and pseudopodia grow around the particle.7 Next, the phagocyte pseudopodia connect at the end of the particle opposite the phagocytic cup, fully capturing the particle.7 Finally, the last step is phagosome formation and withdrawal. In the last step, the outer membrane of the pseudopodia forms the cell membrane and the inner membrane of the pseudopodia forms the phagosome membrane. At this point, the particle is fully engulfed in the cell body and phagocytosis is complete. The KEGG pathway for phagocytosis is pictured in Figure 1.8 For reference, the KEGG pathway for Yersinia infection is depicted in Figure 2.9
(1) Bacot, A. W.; Martin, C. J. LXVII. Observations on the Mechanism of the Transmission of Plague by Fleas. J. Hyg. (Lond.) 1914, 13 (Suppl), 423–439.
(2) Bacot, A. W. LXXXI. Further Notes on the Mechanism of the Transmission of Plague by Fleas. J. Hyg. (Lond.) 1915, 14 (Suppl), 774-776.3.
(3) Smego, R. A.; Frean, J.; Koornhof, H. J. Yersiniosis I: Microbiological and Clinicoepidemiological Aspects of Plague and Non-Plague Yersinia Infections. Eur. J. Clin. Microbiol. Infect. Dis. 1999, 18 (1), 1–15. https://doi.org/10.1007/s100960050219.
(4) Demeure, C. E.; Dussurget, O.; Mas Fiol, G.; Le Guern, A.-S.; 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. https://doi.org/10.1038/s41435-019-0065-0.
(5) Sun, Y.-C.; Jarrett, C. O.; Bosio, C. F.; Hinnebusch, B. J. Retracing the Evolutionary Path That Led to Flea-Borne Transmission of Yersinia Pestis. Cell Host Microbe 2014, 15 (5), 578–586. https://doi.org/10.1016/j.chom.2014.04.003.
(6) Butler, T. Plague and Other Yersinia Infections; Springer US: Boston, MA, 1983.
(7) Molecular and Cellular Biology of Phagocytosis; Hallett, M. B., Ed.; Advances in experimental medicine and biology; Springer: Cham, Switzerland, 2020.
(8) KEGG PATHWAY: Yersinia infection – Homo sapiens (human) https://www.kegg.jp/kegg-bin/show_pathway?hsa05135 (accessed 2022 -04 -29). (9) KEGG PATHWAY: Phagosome + Reference pathway https://www.genome.jp/pathway/map04145 (accessed 2022 -05 -01).
