The First Record of Omsk Hemorrhagic Fever Virus and Tick-Borne Encephalitis Virus of Baltic Lineage from the Kemerovo Region of Russia

Abstract

Objectives:

Tick-borne encephalitis virus Siberian subtype (TBEV-Sib) and Omsk hemorrhagic fever virus (OHFV) are causative agents of natural focal infections in Western Siberia, Russia. The distribution of TBEV phylogenetic lineages and OHFV in the Kemerovo Region of Western Siberia remains poorly investigated.

Methods:

The phylogenetic analyses of fragment genome sequences 26 flaviviruses identified in 2019 were performed, and the amino acid variation was determined to reveal to which clusteron they belong. The age of Baltic and Asian lineages of the TBEV-Sib was calculated for Kemerovo District and Region, respectively.

Results:

Twenty-five isolates were members of three TBEV-Sib phylogenetic lineages: Baltic (48%), Asian (36%), and East Siberian (16%). The Baltic lineage's eastern boundary is commonly thought to be in the Novosibirsk Region, but our data suggest that it may reach further east. Analysis of the Baltic lineage clusteron structure showed that the isolates found are unique (6) or belong to clusteron-founder 3D (1) and derived clusteron 3O (5). Based on the age of 3O clusteron, Baltic lineage could have appeared in the Kemerovo Region by the late 1970s. One of the isolated viruses turned out to be the OHFV of the first subtype and not to belong to any known clusteron. This finding is the first known detection of the virus outside the endemic area of Russia. Given the recent discovery of OHFV in Kazakhstan, it can be assumed that the area of this virus distribution is much wider than previously thought.

Conclusions:

This report provides insights into the population structure of TBEV and OHFV, which may be helpful for epidemiological investigation and surveillance of the viruses.

Introduction

The genus Orthoflavivirus of the family Flaviviridae is represented by two clinically significant groups of viruses: the first is associated with mosquitoes of the genera Aedes and Culex, and the second with ticks of the genus Ixodes. In Russia, the second group is represented by two phylogenetically close tick-borne flaviviruses: tick-borne encephalitis virus (TBEV) and Omsk hemorrhagic fever virus (OHFV). Despite phylogenetic and antigenic similarity, diseases caused by TBEV and OHFV may differ significantly in clinical manifestation.

The TBEV and OHFV genome is a positive single-stranded RNA molecule, ∼11,000 nucleotides, which encodes three structural (capsid, C; membrane, M, which is expressed as precursor prM; envelope, E) and seven nonstructural proteins (Chambers et al., 1990). The nucleotide sequence of the E gene is widely used in phylogenetic studies of TBEV since its length and variability are suitable for the calibration of the molecular clock and estimation of the evolutionary age of the virus (McGuire et al., 1998; Suzuki, 2007; Weidmann et al., 2011; Zanotto et al., 1996).

OHFV is found only in four regions of Western Siberia: Tyumen, Kurgan, Omsk, and Novosibirsk (Ruzek et al., 2010). The host of the virus is the muskrat (Ondatra zibethicus L. 1766). Ixodes ticks of the Dermacentor and Ixodes genus may be involved in the transmission of OHFV. Recently, the discovery of this virus in Northern Kazakhstan has been reported, but so far, this information has not been confirmed by sequencing of the viral genome or its fragment (Wagner et al., 2022). OHFV contains three subtypes (OHFV-1, OHFV-2, and OHFV-3) with a genetic distance of 9–11% between them (Kovalev et al., 2021). OHFV subtypes originated independent of each other because of TBEV adaptation to muskrat, which was introduced to Western Siberia in the first half of the 20th century (Kovalev and Mazurina, 2022).

TBEV is widespread in Eurasia and is associated with hard ticks of the genus Ixodes (Acari: Ixodidae), Ixodes persulcatus Schulze 1930 and Ixodes ricinus L. 1758, which are its hosts and vectors. Five subtypes are distinguished in the structure of TBEV, four of which, Far Eastern (TBEV-FE), Siberian (TBEV-Sib), Baikalian (TBEV-Bkl), and Himalayan, are mainly associated with I. persulcatus, and the European subtype (TBEV-Eu) is mainly associated with I. ricinus. Four phylogenetic lineages are distinguished in the structure of TBEV-Sib: Baltic (TBEV-Sib^Baltic), Asian (TBEV-Sib^Asia), South Siberian (TBEV-Sib^S.-Sib.), and East Siberian (TBEV-Sib^E.-Sib.) (Kovalev and Mukhacheva, 2017). Some researchers suggest the existence of at least two more lineages, Bosnian and Ob’ (Tkachev et al., 2020). Western Siberia is unique in that all major phylogenetic lineages of TBEV-Sib, as well as occasional representatives of TBEV-Eu and TBEV-FE, are found in its territory (Demina et al., 2017; Pogodina et al., 2007).

The study of the genetic diversity of TBEV provides an insight into the structure of the virus population and makes it possible to reconstruct its evolutionary history. It is generally accepted to use full genomic sequences, E gene, or an E gene fragment to achieve this goal. GenBank does not have enough of such sequences from Western Siberia. For example, the Novosibirsk Region is represented by 157 sequences, Tyumen Region (53), Omsk Region (42), Tomsk Region (33), Kemerovo Region (22), while other regions of Western Siberia are represented by significantly smaller numbers of sequences. The Kemerovo Region is of the greatest interest because, along with nearby regions, it is classified as a considerable risk for tick-borne encephalitis (Fig. 1). Based on the 2022 data, the incidence of TBE was 4.1 cases per 100,000 population in this area (Andaev et al., 2023).

FIG. 1.

The enlargement shows the Kemerovo Region (Russia, Western Siberia) and Denisovo village with the locations where the Ixodes ticks were collected. Neighboring regions (TR: Tomsk Region, KK: Krasnoyarsk Krai, RK: Republic of Khakassia, RA: Republic of Altai, AK: Altai Krai, NR: Novosibirsk region). The incidence of TBE per 100,000 population is given in parentheses. Asterisks indicate regions where OHFV was confirmed by sequencing of the viral genome or its fragment. Triangles indicate regions where OHFV was detected by qPCR or serological methods. OHFV, Omsk hemorrhagic fever virus; TBE, tick-borne encephalitis.

Furthermore, all known phylogenetic lineages of TBEV-Sib have now been identified in the Kemerovo Region, and in 2014, two isolates belonging to the Siberian subtype but distant from all studied strains by a genetic distance of double the divergence within this subtype were detected (Efimova et al., 2015). Later, a similar strain was isolated in the Novosibirsk Region. Analysis of the complete genome of this strain suggests the existence of a new phylogenetic lineage of TBEV-Sib tentatively named as the Ob’ lineage (Tkachev et al., 2017). Another peculiarity of Western Siberia and, in particular, the Kemerovo Region, is the phenomenon of expansion of the tick Ixodes pavlovskyi in recent decades (Efimova et al., 2017; Kovalevskiy et al., 2018). I. persulcatus dominated in the Kemerovo Region for a long time, its share among ixodid species was 96.71%. However, in 2015, the distribution of I. pavlovskyi was shown to account for 41.62% of ixodid species (Efimova et al., 2017). The increasing proportion of I. pavlovskyi in natural foci of tick-borne encephalitis may affect the genetic diversity of TBEV-Sib.

The collection of ticks to decide TBEV genetic diversity can be divided into two strategies. The first, or selective method, is the collection of several relatively small batches of ticks but covering large areas. The other, or localized method, is the collection of large numbers of ticks, but in one specific (limited) area. Both strategies have advantages and disadvantages. In the first case, it is possible to get an approximate idea of the virus population structure within the region, quickly (during one season of tick activity) and at low cost. In the second case, it is possible to get an objective idea of the virus genetic diversity, but this strategy will require several seasons on a regional scale.

Within this study, the second approach was employed for tick collection. It involved selecting an area near Denisovo, a village located 20 km north of Kemerovo City. In 2014, the strain of the Ob’ phylogenetic lineage TBEV-Sib was isolated at this location. Therefore, along with studying the population structure of TBEV at this site, we aimed to find strains of this lineage. We did not find the strains we were seeking, but we found representatives of the TBEV Baltic lineage and the OHFV.

Materials and Methods

In early June 2019, 1145 adult ixodid ticks were sampled from a pine forest (6.64 km²) neighboring Denisovo village (Kemerovo District), near the Tom River, about 20 km north of Kemerovo City during peak tick activity season. All ticks were collected from a 1.4 km long trail by flagging method (70 × 110 cm) and then stored at −20°C, until further analysis. The location of the tick collection is shown in Fig. 1.

RNA was extracted from individual tick suspensions using AmpliSens Riboprep kits, and reverse transcription of RNA to cDNA was performed with an AmpliSens Reverta-L Kit according to the manufacturer's instructions (Central Research Institute of Epidemiology, Moscow, Russia).

Determination of tick species by ITS2 marker was performed by qPCR, as described previously (Kovalev et al., 2015).

The fragment of gene E was amplified using nested PCR with internal and external forward and reverse primers, as described previously (Ternovoi et al., 2003), with modification (Kovalev et al., 2009). Nucleotide sequences of gene E fragment PCR products (506 bp) of TBEV were decided using BigDye Terminator v3.1. Cycle Sequencing Kit and ABI 3500 Genetic Analyzer according to the manufacturer's protocol (Applied Biosystems, Foster City, CA). The assembly of the sequences of PCR fragments was performed by SeqScape v.4.0 (Applied Biosystems). GenBank accession numbers (OQ908921–OQ908946) of the nucleotide sequences are given in Supplementary Table S1.

In the research, 26 nucleotide sequences were obtained in the present study and 21 Kemerovo Region sequences of TBEV from GenBank, all containing a 454-nucleotide gene E fragment (Supplementary Table S1). Multiple sequence alignment was performed using the MUSCLE software module, part of the MEGA software package, v.11.0.13. Distance tables were generated in MEGA to determine pairwise sequence identity.

The phylogenetic tree was constructed by the neighbor-joining method for TBEV or OHFV gene E fragment sequences using the p-distance model (Nei and Kumar, 2000) in the MEGA11 software (Tamura et al., 2021). The OHFV subtype I sequence (strain Kubrin_AY438626) was taken as an outgroup. Phylogenetic relationships between different TBEV isolates were confirmed by bootstrap analysis with values >50%.

Phylogenetic analysis was performed for TBEV or OHFV sequences that belong to the clusterons. It included the nucleotide sequences of the E gene fragment (from 309 to 762 nt according to the Zausaev strain GenBank: AF527415) and the deduced amino acid sequences (from 104 to 254 aa) of the corresponding protein. Phylogenetic networks were reconstructed for clusterons using Phylogenetic Network Software v. 10.2.0.0 (www.fluxus-engineering.com) with the Median-joining algorithm (Bandelt et al., 1999).

The clusterons to which the sequences belonged were determined by the on-line TBEV Analyzer v.3.0 software (https://tbev.viroinformatics.com) or OHFV Analyzer v. 1.0 (https://ohfv.viroinformatics.com) (Forghani et al., 2022, 2023).

Sequences of the TBEV and OHFV were grouped into clusterons, sharing the identical amino acid signature of the E protein fragment and being phylogenetically related, according to the approach proposed earlier (Kovalev and Mukhacheva, 2013).

The evolutionary ages of clusterons were calculated based on the previously determined nucleotide substitution rate, 1.56 ± 0.29 × 10⁻⁴ synonymous substitutions per site per year for the E gene fragment (Kovalev et al., 2009).

Results

A high tick abundance of 829 specimens per flag-kilometer was recorded during the collection, of which 601 ticks were selectively examined to decide the species by qPCR. It was found that the dominant species is I. persulcatus (95.72% [94.55–96.89]), the proportion of I. pavlovskyi is 1.75% (0.99–2.51), and their hybrids account for 2.53% (1.62–3.44). Flavivirus was detected in 26 ticks, and thus, the infection rate of the ticks was 2.27%. Phylogenetic analysis of nucleotide sequences of the E gene fragment revealed that 25 of them related to TBEV, and one related to the OHFV (Fig. 2A).

FIG. 2.

Identification of species and subtype of isolates. (A) Phylogenetic analysis of the E gene fragment (454 bp). Strains isolated in the Kemerovo Region before 2019. ● Strains from the present study. (B) Clusteron structure of TBEV-Sib. Clusterons to which the isolated strains belong are colored dark gray. Dotted lines connect homoplastic clusterons (light gray circles) characterized by the same amino acid sequences but belonging to different phylogenetic lineages. TBEV-Sib, tick-borne encephalitis virus Siberian subtype.

Phylogenetic analysis revealed that all TBEV isolates are members of TBEV-Sib. Within this subtype, the sequences corresponded to three phylogenetic lineages: Baltic (12), Asian (9), and East Siberian (4) (Fig. 2A; Supplementary Table S1). To identify the place of the isolates in the population structure of TBEV phylogenetic lineages, a clusteron approach was applied. Of the 25 isolates, 13 were included in the clusterons, while the remaining isolates were classified as unique (Fig. 2B; Supplementary Table S1).

Since the Baltic lineage of TBEV-Sib was detected in almost half of the sequences (48%), its clusteron structure was investigated in more detail (Fig. 3). Six sequences from the present study and 164 Baltic lineage sequences from GenBank included in clusterons were taken for analysis. Based on the results, one isolate was identified as clusteron-founder 3D, whereas the remaining five isolates were assigned to the derived clusteron 3O (Fig. 3). Earlier studies have revealed that TBEV-Sib^Baltic can be divided into three genetic groups: Balt^I , Balt^II , and Balt^III (Fig. 3A), each characterized by a distinct set of clusterons (Kovalev and Mukhacheva, 2016). All TBEV-Sib^Baltic isolates found in Denisovo village belong to the Balt^II genetic group (Fig. 3B). The mean age calculation of clusteron 3O was 42 (35–52) years.

FIG. 3.

(A) Genetic groups of the Baltic lineage: Balt^I , Balt^II , and Balt^III. (B) Phylogenetic tree based on strains of the Baltic lineage of TBEV-Sib, including strains found in Denisovo village, Kemerovo Region. Each clusteron is marked with a figure of its own color.

Of the nine TBEV-Sib^Asia isolates, four belonged to the clusteron-founder 3A, one derived clusteron 3M, and the rest were unique (Fig. 2B; Supplementary Table S1). The mean age of 3A was estimated to be 155 (130–190) years. The calculation of the mean age of clusteron 3A based on all sequences isolated in the Kemerovo Region turned out to be slightly higher at 183 (154–225) years. The age of TBEV-Sib^E.-Sib could not be decided because the two sequences of the clusteron-founder 3J had an identical sequence of the E gene fragment.

In addition to TBEV, we found one isolate of OHFV, Kmrv753-2019 (OQ908946). Phylogenetic analysis showed that the virus belongs to the most common OHFV-1 subtype (Fig. 4A). Clusteron analysis of the E protein fragment showed that this isolate is unique, that is, it does not belong to any known clusterons in the OHFV-1 clusteron structure. Considering the limited number of known OHFV strains, we have assigned a new 3G clusteron (Fig. 4B).

FIG. 4.

Subtype identification of OHFV strain Kmrv753-2019 (OQ908946). (A) Phylogenetic analysis of the E gene fragment (454 bp). Strain Sofjin_KSY (TBEV-FE) was taken as the outgroup. ■ This strain was obtained in the present study. (B) Position of the new strain in the OHFV clusteron structure. The new 3G clusteron is highlighted in dark gray. Hypothetical clusterons (OHFV sequences not previously reported but presumed to exist) 2A and 3D are circled in dashed outline. Dotted lines connect homoplastic clusterons characterized by the same amino acid sequences but belonging to different phylogenetic lineages. TBEV-FE, TBEV Far Eastern.

Discussion

The uneven distribution of TBE morbidity, tick attack frequency, tick abundance, and viral morbidity allowed us to divide the Kemerovo Region into high-, moderate-, and low-risk zones according to the degree of epidemic risk (Efimova et al., 2015). According to our data, the tick infestation with TBEV was 2.18%, and the studied area belongs to the moderate-risk zone, where the tick infestation is between 2.0% and 2.5%. However, the extremely high number of ticks found (829 individuals per flag-kilometer) is almost 20 times higher than the average of 43 individuals per flag-kilometer for the high-risk zone (Efimova et al., 2015). In the Kemerovo District, an earlier sampling study showed that the tick I. pavlovskyi accounted for 39.8–62.6% of the total (Efimova et al., 2017). However, our studies show that the proportion of this tick lies within the range of 0.99–2.51%, that is, no significant increase in the occurrence of I. pavlovskyi has occurred in recent decades. As we can observe, local data can differ considerably from regional averages calculated using the selective approach. The same conclusion can be reached when studying the genetic diversity of TBEV.

The detection of TBEV-Sib^Asia and TBEV-Sib^E.-Sib was quite predictable since earlier studies showed their ubiquitous distribution in the Kemerovo Region (Dobler et al., 2008; Efimova et al., 2015). We did not detect isolates belonging to TBEV-Sib^S.-Sib, which also have a wide distribution in the Kemerovo Region, but this is because of the peculiarity of the local area study.

We also did not detect the Ob’ phylogenetic lineage of TBEV-Sib, although one of the three known isolates 294 (KR633017) was detected in 2014 near the Denisovo village (Efimova et al., 2015). Besides the Kemerovo Region, this lineage (strain TBEV-2871 [MG598818]) was isolated in the Novosibirsk Region in 2012. It is possible that this lineage is extremely rare, as it has not been found since 2012 despite attempts to locate it (Tkachev et al., 2022). This line is of considerable interest because some researchers believe that Ob’-like viruses belong to a group of relict viruses substituted later by other TBEV strains. This hypothesis is confirmed by the analysis of dendrograms and chronograms showing separation of the Ob’ lineage within TBEV-Sib even earlier than the Baltic lineage (Tkachev et al., 2017).

Almost half of the isolates belonged to TBEV-Sib^Baltic, which is unexpected (Fig. 2A) since the eastern boundary of this lineage was commonly believed to be the Novosibirsk Region and the Altai (Kovalev and Mukhacheva, 2016; Tkachev et al., 2020). Such a substantial proportion of Baltic isolates may suggest that this lineage is well adapted to the conditions of Western Siberia and the Kemerovo Region has become the easternmost border of the lineage's area of distribution. The ability to adapt to the Urals and Western Siberia was established by us earlier through the finding of a homoplasy phenomenon for this lineage (Kovalev and Mukhacheva, 2016).

Two isolates of this lineage (Ekb4-2009_JX315986 and Tmn3519-2008_JX315986) found in the Sverdlovsk and Tyumen Regions (clusteron 3C3) were identical in the amino acid sequence of the E protein fragment to isolates of clusterons 3C and 3C2 of the Asian and South Siberian lineages, respectively (Fig. 2Β). Five of the six isolates of the Baltic lineage belonged to clusteron 3O. Based on the age of this clusteron, they could have appeared in the Kemerovo Region by the late 70s of the last century. Interestingly, isolates of the clusteron 3O were previously found in the Sverdlovsk Region (Kamyshlov District) (Kovalev and Mukhacheva, 2014). They were phylogenetically close to the isolates from Kemerovo (Fig. 3) and had approximately the same age. How such closely related isolates could end up at such a considerable distance from each other (over 1400 km) will be the subject of future research.

Of the nine isolates of TBEV-Sib^Asia, four belonged to clusteron-founder 3A. This made it possible to estimate the age of this lineage and determine the time of its appearance in the studied area. It turned out that TBEV-Sib^Asia appeared in the second half of the 19th century. Considering all strains of clusteron 3A ever isolated in the Kemerovo Region, the time of its appearance appeared a little earlier in the first half of the 19th century. The timing of the appearance of TBEV-Sib^Asia in the Kemerovo Region corresponds well with the period of active economic development of Western Siberia and suggests a decisive influence of the anthropogenic factor on the distribution of TBEV in the past.

The Omsk hemorrhagic fever (OHF) natural foci are confined to steppe and forest-steppe areas of the West-Siberian Lowland, where they occupy lake and marsh areas inhabited by muskrats. The area of OHF distribution includes the Omsk, Novosibirsk, Tyumen, and Kurgan Regions. OHFV detection in the Kemerovo Region marks the first case outside its endemic area of the Russian Federation. The Kemerovo Region borders the Novosibirsk Region from the east and is represented by four landscape zones: steppe, forest-steppe, transitional taiga, and mountain-taiga zones (Efimova et al., 2017). The place where the virus was found corresponds more to the transitional taiga zone and differs significantly from its natural area. Woody vegetation is mainly represented by pine, birch, and aspen. Forest litter is rich, formed by fallen needles, leaves, and dead grasses. Dermacentor ticks are absent among ixodid ticks.

The proximity of the Tom River, with its backwaters and the abundance of small rivers flowing into it, creates favorable conditions for the habitat of near-water mammals. The main host for OHFV is the muskrat, which is a near-water rodent (Kovalev and Mazurina, 2022). Virus-carrying muskrats excrete the virus into the environment with urine, feces and other secretions (Kharitonova and Leonov, 1985). The tick species I. persulcatus is an incidental host for the virus. Ticks get the virus by feeding on birds and mammals that have been in contact with water bodies inhabited by muskrats. This transmission pathway highlights the potential for the OHFV to spread among different species in the ecosystem.

The muskrat is an invasive species easily adapting to different landscape zones. Its dispersal after introduction in the mid-1930s covered almost the entire territory of the Russian Federation, as well as the countries of the former Soviet Union (Neronov et al., 2008). Dispersal of muskrats inevitably led to the spread of OHFV. Besides the four regions of Western Siberia, OHF foci have also been observed in the Orenburg Region of Russia and in the North Kazakhstan Region of the Republic of Kazakhstan (Chumakov, 1957) (Fig. 1). In addition, potential natural foci were detected in the East Kazakhstan Region (Temirbekov et al., 1969; Akberdin et al., 1969) (Fig. 1). However, the data on the identification of OHF foci outside the four regions of Western Siberia were preliminary reports that were not confirmed conclusively. Therefore, until now, there were not sufficient grounds to believe that the area of OHF extends beyond Western Siberia (Busygin, 2014). A recent report of OHFV detection in Kazakhstan confirms the existence of potential foci of OHF in this area, which was described over 50 years ago (Wagner et al., 2022) (Fig. 1).

The absence of nucleotide sequences of the virus from Kazakhstan makes it impossible to identify the virus subtype and its place in the clusteron structure. However, considering that the new isolate from the Kemerovo Region Kmrv753-2019 (OQ908946) belongs to the first subtype of OHFV, we can assume with high probability that the viruses from Kazakhstan will also belong to OHFV-1. OHFV-2 and OHFV-3 subtypes make a nonsignificant contribution to the population structure of the virus. OHFV-2 has not been seen since 1947, and OHFV-3 is sparse and appeared significantly later than the OHF foci in Kazakhstan (Kovalev and Mazurina, 2022). All known OHFV-1 strains are included in clusterons, but the new isolate is unique. As a result, we have made an exception and formed a new 3G clusteron with one isolate (Fig. 4). The discovery of OHFV outside the endemic area of Western Siberia suggests that the virus is more widespread than previously thought.

Conclusions

The Ob phylogenetic lineage of TBEV was not found. However, OHFV and the Baltic phylogenetic lineage of TBEV were detected for the first time in the Kemerovo Region. The data on the genetic diversity of TBEV obtained in this study allow us to expand our understanding of the population structure of the virus in Western Siberia. In addition, the results obtained may be useful for epidemiological investigations and viral surveillance.

Footnotes

Acknowledgments

The authors are indebted to Dr. Keith Chamberlain (United Kingdom) and Dr. Irina Belyaeva (United Kingdom) for their linguistic help in preparing the article.

Author Disclosure Statement

No conflicting financial interests exist.

Funding Information

No funding was received for this article.

Supplementary Material

Supplementary Table S1

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