Pathogenicity and virulence of Rodent-Borne Orthohantaviruses

Abstract

The Orthohantavirus genus in the family Hantaviridae includes viruses that cause zoonotic diseases in humans known as hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Exposure of humans to these viruses occurs through inhalation of aerosols of urine, feces, and saliva of rodents, who are the reservoirs for pathogenic orthohantaviruses. The clinical courses of HFRS and HPS are characterized by initial high fever and body pain with severe HFRS or HPS leading to renal failure, pulmonary failure, or both. The underlying pathogenic mechanism of both diseases includes vascular dysregulation leading to vessel leakage and shock.

Keywords: Hemorrhagic fever with renal syndrome; hantavirus pulmonary syndrome; immune evasion; orthohantavirus; vascular leakage; virulence.

Figure 1.

Replication cycle of orthohantaviruses.

Figure 2.

Molecular mechanisms of immune evasion by orthohantavirus proteins. Orthohantavirus GP and N can inhibit multiple arms of the innate immune response, but mechanisms differ among viruses tested. Gn and N proteins of HPS-causing viruses target IFN by binding TRAF3, preventing TBK1 complex formation, and inhibiting IRF-3. Gn can also HFRS-causing N blocks NF-κB by interacting with importin-α and preventing translocation to the nucleus. HPS-causing N or Gn block JAK/STAT signaling to inhibit induction of IFN-β.

Figure 3.

Cellular mechanisms of orthohantavirus pathogenesis. Orthohantaviruses primarily infect endothelial cells without significant pathology suggesting pathogenesis is the result of indirect dysregulation of cellular pathways. There are currently several hypotheses that focus on vascular permeability and coagulopathy to explain pathogenesis. Excessive activation and secretion of cytokines and VEGF-A are seen during infection with increased paracellular permeability. PKa and FXIIa activity is increased upon orthohantavirus-infected cell exposures allowing for liberation of BK and increased permeability. Increased TF, thrombin, and fibrin are thought to contribute to thrombocytopenia and DIC. Fibrinolysis is increased during infection, however, the inhibitor PAI-1 is only elevated in HPS and may contribute to differences in hemorrhaging manifestations.