Characterization of the Puumala orthohantavirus Strains in the Northwestern Region of the Republic of Tatarstan in Relation to the Clinical Manifestations in Hemorrhagic Fever With Renal Syndrome Patients
Abstract:Over 1,000 cases of hemorrhagic fever with renal syndrome (HFRS) were recorded in the Republic of Tatarstan (RT) in 2015. HFRS is a zoonotic disease caused by several different Old World hantaviruses. In RT, Puumala orthohantavirus (PUUV) is a prevalent etiological agent of HFRS. We looked for the genetic link between the PUUV strains isolated from the bank voles and from the infected humans. In addition, possible correlation between the genetic makeup of the PUUV strain involved and different clinical picture… Show more
“…We therefore identified PUUV as the causative infectious agent of NE from the RT and the RM. These data support previous observations that PUUV is the prevalent etiological agent of NE in the Volga Federal District [38,40,41], which includes the RT, the RM, the RB, and Udmurtia. Therefore, we suggest that differences in cytokine activation in NE from the RT and the RM could be explained by host immune response mechanisms to viral infection.…”
Nephropathia Epidemica (NE), endemic to several Volga regions of Russia, including the Republic of Tatarstan (RT) and the Republic of Mordovia (RM), is a mild form of hemorrhagic fever with renal syndrome caused by infection with rodent-borne orthohantaviruses. Although NE cases have been reported for decades, little is known about the hantavirus strains associated with human infection in these regions. There is also limited understanding of the pathogenesis of NE in the RT and the RM. To address these knowledge gaps, we conducted comparative analyses of patients with NE in the RT and the RM. Clinical symptoms were more severe in patients with NE from the RM with longer observed duration of fever symptoms and hospitalization. Analysis of patient sera showed changes in the levels of numerous cytokines, chemokines, and matrix metalloproteases (MMPs) in patients with NE from both the RT and the RM, suggesting leukocyte activation, extracellular matrix degradation, and leukocyte chemotaxis. Interestingly, levels of several cytokines were distinctly different between patients NE from the RT when compared with those from the RM. These differences were not related to the genetic variation of orthohantaviruses circulating in those regions, as sequence analysis showed that Puumala virus (PUUV) was the causative agent of NE in these regions. Additionally, only the “Russia” (RUS) genetic lineage of PUUV was detected in the serum samples of patients with NE from both the RT and the RM. We therefore conclude that differences in serum cytokine, chemokine, and MMP levels between the RT and the RM are related to environmental factors and lifestyle differences that influence individual immune responses to orthohantavirus infection.
“…We therefore identified PUUV as the causative infectious agent of NE from the RT and the RM. These data support previous observations that PUUV is the prevalent etiological agent of NE in the Volga Federal District [38,40,41], which includes the RT, the RM, the RB, and Udmurtia. Therefore, we suggest that differences in cytokine activation in NE from the RT and the RM could be explained by host immune response mechanisms to viral infection.…”
Nephropathia Epidemica (NE), endemic to several Volga regions of Russia, including the Republic of Tatarstan (RT) and the Republic of Mordovia (RM), is a mild form of hemorrhagic fever with renal syndrome caused by infection with rodent-borne orthohantaviruses. Although NE cases have been reported for decades, little is known about the hantavirus strains associated with human infection in these regions. There is also limited understanding of the pathogenesis of NE in the RT and the RM. To address these knowledge gaps, we conducted comparative analyses of patients with NE in the RT and the RM. Clinical symptoms were more severe in patients with NE from the RM with longer observed duration of fever symptoms and hospitalization. Analysis of patient sera showed changes in the levels of numerous cytokines, chemokines, and matrix metalloproteases (MMPs) in patients with NE from both the RT and the RM, suggesting leukocyte activation, extracellular matrix degradation, and leukocyte chemotaxis. Interestingly, levels of several cytokines were distinctly different between patients NE from the RT when compared with those from the RM. These differences were not related to the genetic variation of orthohantaviruses circulating in those regions, as sequence analysis showed that Puumala virus (PUUV) was the causative agent of NE in these regions. Additionally, only the “Russia” (RUS) genetic lineage of PUUV was detected in the serum samples of patients with NE from both the RT and the RM. We therefore conclude that differences in serum cytokine, chemokine, and MMP levels between the RT and the RM are related to environmental factors and lifestyle differences that influence individual immune responses to orthohantavirus infection.
“…PUUV strains from cluster A and the subclades' Northwest of RT', including strains circulating in the bank vole populations west and north of Kazan [17], appear genetically distant, although the geographical distance between these areas is in the range of 20-70 km. This suggests that a group of strains in the North-West of RT was also formed as a result of a separate migration wave of bank voles.…”
Section: Clustermentioning
confidence: 96%
“…In the previous investigations, we have performed a comparative analysis of partial S and M segment sequences of the PUUV strains circulating in the Pre-Kama and Trans-Kama area and have demonstrated a significant variation of PUUV strains' genome in the RT [15,16]. It has been shown that the PUUV strains in the bank voles from Zelenodolsky and Vysokogorsky districts diverged significantly from the virus strains found in Laishevsky and Pestrechinsky districts [17]. The current study aims to analyze the genetic variability of PUUV in the Pre-Kama region.…”
Puumala orthohantavirus (PUUV) causes nephropathia epidemica (NE), a mild form of hemorrhagic fever with renal syndrome (HFRS) commonly diagnosed in Europe. The majority of HFRS cases in the European part of Russia are diagnosed in the Volga Federal District, which includes the Republic of Tatarstan (RT). The current study aims to analyze the genetic variability of PUUV in Pre-Kama region of the RT bounded by the Volga, Kama, and Vyatka rivers. In 2017, bank voles were caught in seven isolated forest traps in the Pre-Kama region and for the 26 PUUV-positive samples, the partial small (S), medium (M), and large (L) genome segment sequences were obtained and analyzed. It was determined that all identified PUUV strains belong to the Russian (RUS) genetic lineage; however, the genetic distance between strains is not directly correlated with the geographical distance between bank vole populations. One of the identified strains has S and L segments produced from one parental strain, while the M segment was supplied by another, suggesting that this strain could be the reassortant. We suggest that the revealed pattern of the PUUV strains distribution could be the result of a series of successive multidirectional migratory flows of the bank voles to the Pre-Kama region in the postglacial period.
“…NE is endemic in the republic of Tatarstan, Russia [16]. We have previously demonstrated that Puumala orthohantavirus (PUUV) is the primary cause of NE in Tatarstan [17]. It is believed that endothelial cells are the primary targets of PUUV, where the virus can replicate without a cytopathic effect [18].…”
Nephropathia epidemica (NE) is a zoonotic disease caused by hantaviruses transmitted from rodents, endemic in the Republic of Tatarstan, Russia. The disease presents clinically with mild, moderate, and severe forms, and time-dependent febrile, oliguric, and polyuric stages of the disease are also recognized. The patient’s cytokine responses have been suggested to play a central role in disease pathogenesis; however, little is known about the different patterns of cytokine expression in NE in cohorts of different ages and sexes. Serum samples and clinical records were collected from 139 patients and 57 controls (healthy donors) and were used to analyze 48 analytes with the Bio-Plex multiplex magnetic bead-based antibody detection kits. Principal component analysis of 137 patient and 55 controls (for which there was full data) identified two components that individually accounted for >15% of the total variance in results and together for 38% of the total variance. PC1 represented a proinflammatory TH17/TH2 cell antiviral cytokine profile and PC2 a more antiviral cytokine profile with patients tending to display one or the other of these. Severity of disease and stage of illness did not show any correlation with PC1 profiles; however, significant differences were seen in patients with high PC1 profiles vs. lower for a number of individual clinical parameters: High PC1 patients showed a reduced number of febrile days, but higher maximum urine output, higher creatinine levels, and lower platelet levels. Overall, the results of this study point towards a stronger proinflammatory profile occurring in younger NE patients, this being associated with markers of acute kidney injury and low levels of high-density cholesterol. This is consistent with previous work indicating that the pathology of NE is immune driven, with an inflammatory immune response being associated with disease and that this immune response is more extreme in younger patients.
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