Hantavirus Induced Kidney Disease

Abstract

Hantavirus induced hemorrhagic fever with renal syndrome (HFRS) is an emerging viral zoonosis affecting up to 200,000 humans annually worldwide. This review article is focused on recent advances in the mechanism, epidemiology, diagnosis, and treatment of hantavirus induced HFRS. The importance of interactions between viral and host factors in the design of therapeutic strategies is discussed. Hantavirus induced HFRS is characterized by thrombocytopenia and proteinuria of varying severities. The mechanism of kidney injury appears immunopathological with characteristic deterioration of endothelial cell function and compromised barrier functions of the vasculature. Although multidisciplinary research efforts have provided insights about the loss of cellular contact in the endothelium leading to increased permeability, the details of the molecular mechanisms remain poorly understood. The epidemiology of hantavirus induced renal failure is associated with viral species and the geographical location of the natural host of the virus. The development of vaccine and antiviral therapeutics is necessary to avoid potentially severe outbreaks of this zoonotic illness in the future. The recent groundbreaking approach to the SARS-CoV-2 mRNA vaccine has revolutionized the general field of vaccinology and has provided new directions for the use of this promising platform for widespread vaccine development, including the development of hantavirus mRNA vaccine. The combinational therapies specifically targeted to inhibit hantavirus replication and vascular permeability in infected patients will likely improve the disease outcome.

Keywords: HFRS; acute kidney injury; bunyavirus; hantavirus; hemorrhagic fever.

Figure 1

A simple graphical sketch of the hantavirus replication cycle. Hantavirus particles harboring the three nucleocapsids (blue) bind the host cell surface receptor. After entry virus uncoating takes place and capped viral mRNAs are synthesized by transcription. Viral RdRp replicates the viral genome. Viral proteins are synthesized by the host translation machinery. Glycoprotein Gn and Gc are transported to Golgi. During virus assembly, the nucleocapsids meet the glycoprotein on the Golgi surface and new virus particles are born inside the Golgi, which then egress the cell through secretary mechanisms. In some hantaviruses, the assembly occurs on the host cell membrane (red line). In this case, nucleocapsids meet the glycoprotein on the cell membrane that are transported through Golgi.

Figure 2

Hantavirus infection damages the contacts between endothelial cells. Human renal glomerular endothelial cells were infected with puumala hantavirus. Cells were examined by immunofluorescence microscopy. Hantavirus nucleocapsid protein is shown by red color and the tight junction marker protein (ZO-1) is shown by green color. The uninfected cells on the left show well-organized cell-to-cell contacts evident from continuous peripheral staining of ZO-1. The uninfected cells form an intact monolayer. The virus-infected cells on the right display discontinue ZO-1 staining, demonstrating the breakdown of endothelial barrier function. This picture was borrowed from (5) and is reused with permission from the Nature publishing group.

Figure 3

Brief overview of Hantavirus replication cycle and therapeutic targets. The virus binds to the host cell's receptor. After entry, virus uncoating takes place and virus replication is initiated. N protein binds to the host mRNA caps (36). RdRp binds to the N protein through C-terminus (33). The N-terminal endonuclease domain of RdRp cleaves the host cell mRNA at a “G” residue 14 nucleotides downstream of the 5′ cap to generate the capped RNA primer (30). The primer anneals with the 3′ terminus of the viral genome and transcription is initiated by the prime and re-align mechanism. Potential therapeutic targets are shown by the arrow.

Figure 4

Hantavirus induced kidney injury. A flow chart showing the involvement of cytokines [IL-1, IL-2, IL-6, IL-10, IL-12, TNF-, INF-, and vascular endothelial growth factor (VEGF) and chemokines] [RANTES, monocyte chemoattractant protein-1 (MCP-1), IP-10, and IL-8. ICAM-1, intercellular adhesion molecule-1; PECAM-1, platelet-endothelial cell adhesion molecule-1; VCAM, vascular cell adhesion molecule-1] in hantavirus induced kidney injury (64). Increased bradykinin levels can also trigger cytokine storms during hantavirus infection (65). the most severe vascular affection includes congestion and permeability disturbances during the early phases, followed by severe blood stasis accompanied by leakage, extensive interstitial hemorrhage, severe endothelial degenerative changes, and occasionally anemic necrosis in the deeper medulla that culminate into kidney injury (, –69).