Circulation of Yersinia pestis in the Volga-Ural Sandy Focus: Spatiotemporal Analysis

Aim. The present paper provides a comparative analysis of the phylogenetic relationship between Yersinia pestis strains isolated in the Volga-Ural sandy natural focus during the periods of 1912-1945 and 1963-2003, which were characterised by different levels of epidemic activity, in order to identify the spatiotemporal patterns in the circulation of the plague pathogen in the North Caspian region. Materials and methods. We studied the properties and performed whole-genome sequencing of 18 Y. pestis strains from the Volga-Ural sandy focus, along with 12 strains from other foci in the North Caspian and North Aral regions, isolated from 1912 to 2003. The phylogenetic analysis was performed drawing on the whole-genome SNP analysis, which was conducted on the basis of 2188 SNPs identified in the core genome using the Wombac 2.0 program. Maximum Likelihood Dendrogram (GTR model) was used for the analysis of phylogenetic relationships between strains. Results and discussion. All studied strains from the foci of the North Caspian region belong to the main subspecies (biovar medievalis) of the plague pathogen. These are highly virulent and epidemiologically dangerous strains. The whole-genome sequencing and phylogenetic analysis of 30 strains from the Volga-Ural sandy focus, as well as adjacent plague foci, reveal that the strains (biovar medievalis) of two phylogenetic branches - 2.MED4 and 2.MED1 - were spread across the focus under study in the early 20th century. It is confirmed that 2.MED1 strains were the etiological agents of plague outbreaks in the Volga-Ural sandy focus during this period. The study revealed the presence of parallel evolutionary lines in 2.MED1 associated with plague outbreaks in the first half of the last century. In the second half of the 20th and early 21st centuries, the modern evolutionary line of 2.MED1 became widespread in the Volga-Ural sandy focus. The strains of this line are closely grouped, which indicates their close genetic relationship. Only sporadic cases of plague were recorded during this period. Modern strains from the Volga-Ural sandy focus (1963-2003), as well as the strains previously isolated there (1912-1945), do not originate from each other. These strains represent closely related, independent evolutionary branches, extending from the common trunk of 2.MED1. Modern strains originating from those of the North Aral desert focus (1945) form a separate cluster in the dendrogram. This suggests that, following a break in the 1950s, the Volga-Ural sandy focus was recolonised by closely related strains from the North Aral region.

1. Onishchenko G.G., Kutyrev VV, editors. Natural plague foci of the Caucasus, Caspian area, Central Asia and Siberia. Moscow: Medicine; 2004. 192 p.

2. Wang S.B., Sun Y.Z. The geographical distribution and main ecological characteristics of plague natural foci in the Middle Asia, Russian Siberia and Mongolia. Endem. Dis. Bull. 1999; 14:83-8.

3. Burdelova L.A., editor. Atlas of highly dangerous infections in the Republic of Kazakhstan. Almaty; 2012. 232 p.

4. Kalabukhov N.I. Long breaks in the epizootic activity of natural plague foci and their probable causes. Zoological Journal. 1969; 48(2):165-75.

5. Shevchenko V.L., Kaimashnikov VI., Andreeva T.A. The mechanism involved in maintaining natural plague focality in the Volga-Ural sands. Zoological Journal. 1969; 48(2):270-81.

6. Bidashko F.G., Pak M.V., Belonozhkina L.B., Parfenov A.V. Cyclicity of plague activity in the foci located in the north-west of Kazakhstan. Quarantine and zoonotic infections in Kazakhstan. Almaty. 2018; 1-2:14-25.

7. Davis S, Begon M, De Bruyn L, Ageyev VS, Klassovskiy NL, Pole SB, Viljugrein H, Stenseth NC, Leirs H. Predictive thresh-olds for plague in Kazakhstan. Science. 2004; 304(5671):736-8. DOI: 10.1126/science.1095854.

8. Samia NI, Kausrud KL, Heesterbeek H, Ageyev V, Begon M, Chan KS, Stenseth NC. Dynamics of the plague-wildlife-human system in Central Asia are controlled by two epidemiological thresh-olds. Proc. Natl. Acad. Sci. USA. 2011; 108(35):14527-32. DOI: 10.1073/pnas.1015946108.

9. Khamzin E.Kh., Saraev F.A., Kozulina I.G., Nasikhanova K.N., Bashmakova A.A., Melyatova I.B., Bashmakov A.A. Epizootic activity in the Volga-Ural sandy plague focus on the territory of the Atyrau region in the last decade and the number of main carriers. Quarantine and zoonotic infections in Kazakhstan. Almaty. 2017;. 1-2:34-6.

10. Atshabar B. B., Burdelov L. A., Izbanova U.A., Lukhnova L.Yu., Meka-Mechenko T.V, Meka-Mechenko V.G., Kunitsa T.N., Sadovskaya V.P., Saptaev S.K., Sarmantaeva A.B., Sansyzbaev E.B., Nurmakhanov T.I., Abdel Z.Zh., Kozhakhmetova M.K., Aymakhanov B.K., Kuznetsov A.N., Sagiev Z.A., Kulbaeva M.M., Alybaev S.D., Bekshin Zh.M., Esmagametova A.S., Zhumadilova Z.B Kazakov S.V., Kuatbaeva A.M. Passport of highly dangerous infections in Kazakh regions. Quarantine and zoonotic infections in Kazakhstan. Almaty. 2015; 1(31):5-177.

11. Kutyrev VV., Popova A.Yu editors. Cadastre of the epidemic and epizootic manifestations of plague on the territory of the Russian Federation and neighbouring countries (from 1876 to 2015). Saratov: “Amirit”; 2016. 248 p.

12. Serzhan O.S., AykimbaevA.M., Lukhnova L.Yu. Ecological forecast of the epidemic activity in the natural plague foci in the early 21st century. Quarantine and zoonotic infections in Kazakhstan. Almaty. 2000; 2:194-6.

13. Popov N.V, Toporkov V.P., Bezsmertny VE Popov V.P., Kuznetsov A.A., Matrosov A.N., Sludsky A.A., Udovikov A.I., Karavaeva T.B., Merkulova T.K., Kutyrev V.V. Long-term prognosis of the epizootic activity in the natural plague foci of the Russian Federation as the basis for increasing the effectiveness of preventive measures. Life without danger. Health. Prevention Longevity. 2012; 7(3):14-7.

14. Popova A.Yu., Kutyrev V.V., editors. Assurance of epidemiological welfare in the natural plague foci on the territory of the CIS countries and Mongolia in the modern context. Izhevsk: “Print”; 2018. 336p.

15. Suleymenov B.M. The mechanism of enzootic plague. Almaty; 2004. 234 p.

16. Jones S.D., Atshabar B., Schmid B.V, Zuk M., Amramina A., Stenseth N.C. Living with plague: Lessons from the Soviet Union's antiplague system. Proc. Natl. Acad. Sci. USA., 2019; 116(19): 9155-63. DOI: 10.1073/pnas.1817339116.

17. Kutyrev VV, Eroshenko G.A., Motin VL., Nosov N.Y., Krasnov J.M., Kukleva L.M., Nikiforov K.A., Al’hova J.V., Oglodin E.G., Guseva N.P. Phylogeny and classification of Yersinia pestis through the lens of strains from the plague foci of Commonwealth of Independent States. Front. Microbiol. 2018; 9:1106. DOI: 10.3389/fmicb.2018.01106.

18. Achtman M., Zurth K., Morelli G., Torrea G., Guiyoule A., Carniel E. Yersinia pestis, the cause of plague, is a recently emerged clone of Yersinia pseudotuberculosis. Proc. Natl. Acad. Sci. USA. 1999; 96:14043-8. DOI: 10.1073/pnas.96.24.14043.

19. Cui Y, Yu C., Yan Y, Li D., Li Y., JombartT., Weinert L.A., Wang Z., Guo Z., Xu L., Zhang Y., Zheng H., Qin N., Xiao X., Wu M., Wang X., Zhou D., Qi Z., Du Z., Wu H., Yang X., Cao H., Wang H., Wang J., Yao S., Rakin A., Li Y, Falush D., Balloux F., Achtman M., Song Y, Wang J., Yang R. Historical variations in mutation rate in an epidemic pathogen, Yersinia pestis. Proc. Natl. Acad. Sci. USA. 2013; 110(2):577-82. DOI: 10.1073/pnas.1205750110 PMID: 23271803. 5.

20. Eroshenko G.A., Popov N.V, Alkhova Zh.V, Balykova A.N., Kukleva L.M., Kutyrev V.V. Phylogenetic analysis of Yersinia pestis strains of biovar medievalis, isolated in the North-West Caspian steppe plague focus in the 20th century. Problemy Osobo Opasnykh Infektsii [Problems of Particularly Dangerous Infections]. 2019; 2:55-61. DOI: 10.21055/0370-1069-2019-2-55-61.

21. Onishchenko G.G., Kutyrev V.V., editors. Laboratory di-agnosis of highly dangerous infectious diseases. Practical Guide. Moscow: “Shiko”; 2013. 560 p.

22. Spyrou M. A., Tukhbatova, R. I., Feldman, M., Drath, J., Kacki, S., Beltran de Heredia J., Arnold S., Sitdikov A.G., Castex D., Wahl J., Gazimzyanov I.R., Nurgaliev D.K., Herbig A., Bos K.I., Krause J. Historical Y. pestis genomes reveal the European Black Death as the source of ancient and modern plague pandemics. Cell Host Microbe. 2016; 19:874-81. DOI: 10.1016/j:chom.2016.05.012.