Hemorrhagic Fever-Associated Orthohantaviruses

Introduction

Orthohantaviruses have a worldwide distribution. The infectious agent Hantaan orthohantavirus was first identified in the Hantan River area of South Korea. At present more than fifty different orthohantaviruses, whereof twenty are pathogenic to humans, have been identified.

The genus of Orthohantavirus is a member of the family of Hantaviridae belonging to the recently reclassified order of Bunyavirales. Orthohantaviruses, previously known as hantaviruses, are zoonotic viruses that can cause hantavirus pulmonary syndrome (HPS) and hemorrhagic fever with renal syndrome (HFRS) in humans. HFRS is caused by several orthohantaviruses including Hantaan (HTNV), Seoul (SEOV), Puumala (PUUV), and Dobrava-Belgrade (DOBV).

Structure and Morphogenesis

Orthohantavirus is an enveloped negative-sense single-stranded RNA virus containing large (L), medium (M), and small (S) genome segments. The tripartite segments encode an RNA-dependent RNA polymerase (RdRp), two membrane glycoproteins (Gn and Gc), and a nucleocapsid (N) protein. The virus particles generally appear spherical or pleomorphic in electron micrographs, ranging 120 to 160 nm in diameter. The virion comprises a lipid envelope that is 5 nm thick and covered with spikes that protrude approximately 10 nm from the membrane.

Fig.1 Hantavirus particles, genes, and proteins. (Vaheri, 2013)

Pathogenesis

The basic mechanisms behind HFRS pathogenesis relate to increased vascular permeability. orthohantaviruses infect and replicate in the vascular endothelial cells (ECs) and dendritic cells (DCs) but do not seem to cause direct cytopathic effects. Orthohantavirus particles cluster on the surface of ECs and this accumulation recruits quiescent platelets to ECs. This increased consumption of blood platelets may contribute in part to thrombocytopenia, promoting vascular leakage and hemorrhaging. In addition, antiviral and inflammatory responses aid in eliminating the virus, thereby concurrently impairing EC function by secreting large amounts of cytokines.

Fig.2 Mechanisms of vasculopathy in hantavirus infections. (Hepojoki, 2014)

Epidemiology

Orthohantaviruses cause a significant number of human illnesses, making it a global public health threat. The virus is spread by brown Norway rats and by ship rats all over the world. Some evidence suggests that the virus rarely spreads from person to person. HFRS is endemic in Asia, mostly in China, North Korea, and South Korea, and clinical cases of HFRS caused by HTNV and SEOV have been identified. The highest incidence and prevalence of orthohantavirus infection is documented in Russia, Finland, and Swede. In Europe, PUUV causes most HFRS cases.

Fig.3 Geographical distribution of human associated pathogenic orthohantaviruses. (Kabwe, 2020)

Humans do not belong to the natural host range of Orthohantaviruses. The rodents shed the virus in their urine, droppings, and saliva. The virus is mainly transmitted to people when they breathe in air contaminated with the virus.

Prevention and Treatment

No vaccines against Orthohantaviruses have been approved by the U.S. FDA, but the whole virus inactivated bivalent vaccines against HTNV and SEOV are available in China and South Korea. Eliminating or minimizing contact with rodents is the best way to prevent infection. There is no specific treatment, cure, or drug for the infection. Orthohantaviruses are still a significant public health threat in endemic countries.

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References

1. Vaheri, A.; et al. Uncovering the mysteries of hantavirus infections. Nat Rev Microbiol. 2013, 11(8): 539-550.
2. Hepojoki, J.; et al. The fundamental role of endothelial cells in hantavirus pathogenesis. Front Microbiol. 2014, 5: 727.
3. Kabwe, E.; et al. Orthohantaviruses, Emerging Zoonotic Pathogens. Pathogens. 2020, 9(9).

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