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Review
. 2023 Feb 18;15(2):561.
doi: 10.3390/v15020561.

Hemorrhagic Fever with Renal Syndrome in Asia: History, Pathogenesis, Diagnosis, Treatment, and Prevention

Ayushi Sehgal  1 , Sanya Mehta  1 , Kritika Sahay  1 , Ekaterina Martynova  2 , Albert Rizvanov  2 , Manoj Baranwal  1 , Sara Chandy  3 , Svetlana Khaiboullina  2 , Emmanuel Kabwe  2   4 , Yuriy Davidyuk  2
Affiliations
Review

Hemorrhagic Fever with Renal Syndrome in Asia: History, Pathogenesis, Diagnosis, Treatment, and Prevention

Ayushi Sehgal et al. Viruses. .

Abstract

Hemorrhagic Fever with Renal Syndrome (HFRS) is the most frequently diagnosed zoonosis in Asia. This zoonotic infection is the result of exposure to the virus-contaminated aerosols. Orthohantavirus infection may cause Hemorrhagic Fever with Renal Syndrome (HRFS), a disease that is characterized by acute kidney injury and increased vascular permeability. Several species of orthohantaviruses were identified as causing infection, where Hantaan, Puumala, and Seoul viruses are most common. Orthohantaviruses are endemic to several Asian countries, such as China, South Korea, and Japan. Along with those countries, HFRS tops the list of zoonotic infections in the Far Eastern Federal District of Russia. Recently, orthohantavirus circulation was demonstrated in small mammals in Thailand and India, where orthohantavirus was not believed to be endemic. In this review, we summarized the current data on orthohantaviruses in Asia. We gave the synopsis of the history and diversity of orthohantaviruses in Asia. We also described the clinical presentation and current understanding of the pathogenesis of orthohantavirus infection. Additionally, conventional and novel approaches for preventing and treating orthohantavirus infection are discussed.

Keywords: emerging viruses; immunology; orthohantaviruses; therapeutics; vaccines.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of an orthohantavirus virion. (A) The structure is spherical, having a diameter of 8–120 nm, enveloped with a lipid bilayer containing spikes of glycoproteins (Gn and Gc). Inside the virion are three segments of single-stranded RNA: small (S), medium (M) and large (L). (B) The S, M, and L genomic segments encode for the nucleocapsid protein (433 aa), glycoprotein precursor (1138 aa) and the RNA-dependent RNA polymerase (2155 aa), respectively.
Figure 2
Figure 2
Orthohantavirus infection portal of entry and initial replication sites. Orthohantaviruses use the respiratory tract as one of the portals of entry (A). The initial replication site is believed to be in alveolar pneumocytes. From there, the virus crosses the respiratory membrane infecting nearby endothelial cells of the alveolar capillaries (B). These steps occur before the patient presents with HFRS symptoms. Once orthohantavirus infects endothelial cells, it becomes released into the blood leading to viremia (C). The immune system’s reaction to viremia could cause tissue damage, while increased endothelial permeability and blood coagulation could result from infected endothelial cell activation.
Figure 3
Figure 3
Orthohantavirus effect on endothelium barrier integrity. In uninfected endothelial cells, VE-cadherin is expressed in junctions between adjacent cells (A). In orthohantavirus-infected cells, a profound reorganization of VE-cadherin was described (B). It was shown that VE-cadherin becomes internalized in orthohantavirus-infected endothelial cells. This change in molecule expression appears to be a response to the binding of infected cells to VEGF. As a result, the integrity of adherence junctions becomes compromised, leading to increased endothelium permeability. Expression of claudin, a TJ molecule, decreased in orthohantavirus-infected cells. This would also contribute to the disintegration of cell adhesion and vascular leakage.
Figure 4
Figure 4
Schematics of orthohantavirus effect on blood coagulation. (1) Orthohantavirus-infected endothelial cell express TF. (2) TF interacts with active FVII (FVIIa) and calcium to convert FIX and FX to active IXa and Xa, respectively. FXa binds to factor II to form the thrombin (FIIa). (3) Thrombin interacts with FV, FVIII, and FXI. (4) Thrombin activates FV, FVIII, and FXI, forming FVa, FVIIIa, and FXIa. (5,6) FVIIIa forms a complex with FVa and FXa, which acts as a prothrombinase and accelerates the formation of thrombin (FIIa).
Figure 5
Figure 5
Schematics of “cytokine storm” activation upon orthohantavirus infection. Orthohantavirus infection activates endothelial cells and leukocytes to produce various cytokines. These cytokines could activate leukocytes and attract them to the site of infection. Massive infiltration of leukocytes producing proinflammatory cytokines and chemoattractants could induce severe local inflammation inflicting tissue destruction.
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Grants and funding

This work was funded by RSF-DST 22-44-02007 grant. Also, the Kazan Federal University Strategic Academic Leadership Program (PRIORITY-2030) supported this research.

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