Pathomorphology of experimental infection caused by dormant Yersinia pseudotuberculosis strains

Cover Page

Cite item

Abstract

In the 2000s, with the development of scientific research on the uncultivated (dormant) state of pathogenic bacteria, the ideas about persistent, chronically recurrent infections, difficult to respond to antibiotic therapy have begun to shape. However, regarding human pseudotuberculosis (Far Eastern scarlet-like fever, FESLF), this question remains open. While analyzing the pathology of pseudotuberculosis, its clinical and epidemic manifestation as FESLF, we identified the etiopathogenetic prerequisites for the disease recurrence and development of persistent infection. In this study it was found that the strains of Yersinia pseudotuberculosis which were in a dormant state caused the development of a peculiar granulomatous inflammation in target organs with pronounced delayed-type hypersensitivity reactions in vivo. To reproduce the experimental infection, sexually mature white mice were inoculated with the strain 512 Y. pseudotuberculosis, serotype I stored for 10 years at the Museum of Somov Research Institute of Epidemiology and Microbiology and transformed into a dormant state. For comparative studies, a dormant form from vegetative bacteria of the strain 512 Y. pseudotuberculosis was obtained by exposure to a large dose of kanamycin (the minimum antibiotic dose was exceeded 25 times). The infecting dose of both forms of bacteria was 108 μ/mouse. Samples of target organs (lung, liver, spleen) were collected for histological examination on days 3, 7, 10, 14, 21 and 32 after infection. Histological sections with 3–5 μm thickness were stained with hematoxylin and eosin according to standard techniques. It was established that strains of Y. pseudotuberculosis in dormant state caused in vivo development of a peculiar granulomatous inflammation due to delayed-type hypersensitivity reactions (DHR), which characterizes the protective reaction in infected host and reflects formation of local, tissue immunity in target organs. The peculiarities of granulomatous inflammation were revealed, in comparison with that of found during infection with vegetative (“wild”) Y. pseudotuberculosis bacteria, namely: the granulomas were predominantly small in size, clearly delimited from the surrounding tissue, without destruction of central zone cells and formation of the so-called “granulomas with central karyorrhexis” (terminology proposed by A.P. Avtsyn); perivascular infiltrates and vasculitis consisted mainly of lymphocytes and often had a follicle-like appearance, resembling the follicles in lymphoid organs; in the lungs, a well-marked reaction of the bronchial-associated lymphoid tissue was observed, and in the spleen, a follicular hyperplasia, indicating a T-cell defense reaction, was observed. Thus, the causative agent of Y. pseudotuberculosis infection/FESLF, being in a dormant state, initiates the development of immunomorphological changes of protective nature such as productive granulomatous inflammation with reactions of local tissue immunity in target organs and can contribute to the formation of persistent infection.

About the authors

L. M. Somova

Somov Research Institute of Epidemiology and Microbiology

Author for correspondence.
Email: l_somova@mail.ru
ORCID iD: 0000-0003-2023-1503

Larisa M. Somova - PhD, MD (Medicine), Professor, Head Researcher, Laboratory of Molecular Microbiology, Somov Research Institute of Epidemiology and Microbiology.

690087, Vladivostok, Selskaya str., 1.

Phone/fax: +7 (423) 244-14-38.

Russian Federation

B. G. Andryukov

Somov Research Institute of Epidemiology and Microbiology

Email: andrukov_bg@mail.ru
ORCID iD: 0000-0003-4456-808X

PhD, MD (Medicine), Leading Researcher, Laboratory of Molecular Microbiology, Somov Research Institute of Epidemiology and Microbiology.

690087, Vladivostok, Selskaya str., 1.

Russian Federation

I. N. Lyapun

Somov Research Institute of Epidemiology and Microbiology

Email: irina-lyapun@list.ru
ORCID iD: 0000-0002-5290-3864

PhD (Biology), Senior Researcher, Laboratory of Molecular Microbiology, Somov Research Institute of Epidemiology and Microbiology.

690087, Vladivostok, Selskaya str., 1.

Russian Federation

E. I. Drobot

Somov Research Institute of Epidemiology and Microbiology

Email: eidrobot@mail.ru
ORCID iD: 0000-0001-7672-1582

PhD (Biology), Senior Researcher, Laboratory of Molecular Microbiology, Somov Research Institute of Epidemiology and Microbiology.

690087, Vladivostok, Selskaya str., 1.

Russian Federation

O. S. Ryazanova

Somov Research Institute of Epidemiology and Microbiology

Email: osriazanova@yandex.ru

Junior Researcher, Laboratory of Molecular Microbiology, Somov Research Institute of Epidemiology and Microbiology.

690087, Vladivostok, Selskaya str., 1.

Russian Federation

E. V. Matosova

Somov Research Institute of Epidemiology and Microbiology

Email: e_matosova@mail.ru
ORCID iD: 0000-0001-9968-3347

Junior Researcher, Laboratory of Molecular Microbiology, Somov Research Institute of Epidemiology and Microbiology.

690087, Vladivostok, Selskaya str., 1.

Russian Federation

M. P. Bynina

Somov Research Institute of Epidemiology and Microbiology

Email: marina.bynina@mail.ru
ORCID iD: 0000-0001-8255-328X

Junior Researcher, Laboratory of Molecular Microbiology, Somov Research Institute of Epidemiology and Microbiology.

690087, Vladivostok, Selskaya str., 1.

Russian Federation

N. F. Timchenko

Somov Research Institute of Epidemiology and Microbiology

Email: ntimch@mail.ru

PhD, MD (Medicine), Professor, Leading Researcher, Laboratory of Molecular Microbiology, Somov Research Institute of Epidemiology and Microbiology.

690087, Vladivostok, Selskaya str., 1.

Russian Federation

References

  1. Персиянова Е.В., Адгамов Р.Р., Сурин А.К., Псарева Е.К., Ермолаева С.А. Цитотоксический некротизирующий фактор Yersinia pseudotuberculosis, возбудителя дальневосточной скарлатиноподобной лихорадки // Бюллетень СО РАМН. 2013. Т. 33, № 2. С. 16–20.
  2. Сомова Л.М., Андрюков Б.Г., Дробот Е.И., Ляпун И.Н. Гранулематозное воспаление как фактор, способствующий персистенции патогена при инфекции, вызванной Yersinia pseudotuberculosis // Клиническая и экспериментальная морфология. 2020. Т. 1, № 9. С. 5–10. doi: 10.31088/CEM2020.9.1.5-10
  3. Сомова Л.М., Андрюков Б.Г., Тимченко Н.Ф., Псарева Е.К. Псевдотуберкулез как персистентная инфекция: этиопатогенетические предпосылки // Журнал микробиологии, эпидемиологии и иммунобиологии. 2019. № 2. С. 110–119. doi: 10.36233/0372-9311-2019-2-110-119
  4. Сомова Л.М., Антоненко Ф.Ф. Псевдотуберкулез (клинико-морфологические аспекты). М.: Наука, 2019. 328 с.
  5. Сомова Л.М., Тимченко Н.Ф., Ляпун И.Н., Матосова Е.В., Бынина М.П. Ультраструктурные изменения бактерий статической культуры Yersinia pseudotuberculosis при длительном хранении в условиях низкой температуры // Бюллетень экспериментальной биологии и медицины. 2020. Т. 170, № 8. С. 192–195.
  6. Ayrapetyan M., Williams T.C., Baxter R., Oliver J.D. Viable but nonculturable and persister cells coexist stochastically and are induced by human serum. Infect. Immunol., 2015, vol. 83, no. 11, pp. 4194–4203. doi: 10.1128/IAI.00404-15
  7. Grant S.S., Hung D.T. Persistent bacterial infections, antibiotic tolerance and the oxidative stress response. Virulence, 2013, vol. 4, no. 4, pp. 273–283. doi: 10.4161/viru.23987
  8. Heine W., Beckstette M., Heroven K., Thiemann S., Heise U., Niss A.M., Pisano F., Strowig T., Dersch P. Loss of CNFy toxin-induced inflammation drives Yersinia pseudotuberculosis into persistence. PLoS Pathog., 2018, vol. 14, no. 2: e1006858. doi: 10.1371/journal.ppat.1006858
  9. Jayaraman R. Bacterial persistence: some new insights into an old phenomenon. J. Biosci., 2008, vol. 33, no. 5, pp. 795–805. doi: 10.1007/s12038-008-0099-3
  10. Kim J.-S., Chowdhury N., Wood T.K. Viable but non-culturable cells are persister cells. Environ. Microbiol., 2018, vol. 20, no. 6, pp. 2038–2048. doi: 10.1111/1462-2920.14075
  11. Lewis K. Persister cells: molecular mechanisms related to antibiotic tolerance. Handb. Exp. Pharmacol., 2012, vol. 211, pp. 121– 133. doi: 10.1007/978-3-642-28951-4-8

Supplementary files

There are no supplementary files to display.


Copyright (c) 2021 Somova L.M., Andryukov B.G., Lyapun I.N., Drobot E.I., Ryazanova O.S., Matosova E.V., Bynina M.P., Timchenko N.F.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies