Orthohantaviruses, Emerging Zoonotic Pathogens

Abstract

Orthohantaviruses give rise to the emerging infections such as of hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS) in Eurasia and the Americas, respectively. In this review we will provide a comprehensive analysis of orthohantaviruses distribution and circulation in Eurasia and address the genetic diversity and evolution of Puumala orthohantavirus (PUUV), which causes HFRS in this region. Current data indicate that the geographical location and migration of the natural hosts can lead to the orthohantaviruses genetic diversity as the rodents adapt to the new environmental conditions. The data shows that a high level of diversity characterizes the genome of orthohantaviruses, and the PUUV genome is the most divergent. The reasons for the high genome diversity are mainly caused by point mutations and reassortment, which occur in the genome segments. However, it still remains unclear whether this diversity is linked to the disease's severity. We anticipate that the information provided in this review will be useful for optimizing and developing preventive strategies of HFRS, an emerging zoonosis with potentially very high mortality rates.

Keywords: HFRS and HPS; Puumala orthohantavirus; emerging; hantavirus pulmonary syndrome; hemorrhagic fever with renal syndrome; nephropathia epidemica; reassortment; recombination; zoonosis.

Figure 1

Virion structure of orthohantaviruses. The orthohantavirus virion (ø 80–120 nm) is enveloped. The surface of the virion is surrounded by glycoprotein (Gn and Gc) layer. Inside the virion are three negative-sense segments of single-stranded RNA (the (S) small, (M) medium and (L) large segments).

Figure 2

The genome structure of orthohantaviruses, based on Puu/Kazan strain, accession numbers, Z84204, Z84205, and EF405801 for the S, M, and L segments, respectively. The S segment encodes for 433, M-1138, and L-2155 aa. The ends of the segments contain three trinucleotide repeats at the 3′- and 5′-terminal (5′ UAGUAGUAG), which form a panhandle like structure, and it is suggested they are involved in the regulation of viral transcription and replication.

Figure 3

Schematic presentation of orthohantavirus infection cycle. As the rodent population densities increase, the spread of orthohantaviruses among rodents increases proportionally. In rodent and or insectivore populations, orthohantaviruses are horizontally transmitted through aggressive behavior and exposure to aerosolized contaminated droppings. Usually, humans are considered to be the dead-end hosts of orthohantaviruses and become infected by breathing aerosolized rodent excreta containing the virus.

Figure 4

Geographical distribution of human associated pathogenic orthohantaviruses. Seoul orthohantavirus has been detected worldwide.

Figure 5

Schematic presentation of recombination and reassortment processes in the tri-segmented orthohantaviruses resulting from the co-infection of a cell by two parental viral strains A and B. The S, M, and L capital letters inside the parental virion strains stands for the S (small), M (medium), and L (large) genomic segments. Parenthesized A and B represent origin of the given segment from one of the two parents. The reassortment and recombination events frequently occur naturally in nature and can also be shown in in vitro experiments.

Figure 6

Phylogenetic tree of rodent, shrew, and bat orthohantaviruses based on the full S segment. All PCR confirmed orthohantaviruses associated with human pathogens are marked in bold (HFRS; dark circle and HPS; dark square) and those not associated with the infection. (1) Sigmodontinae-borne orthohantaviruses (Andes, ANDV; Laguna Negra, LANV; Sin Nombre, SNV; Montano, MTNV; Bayou, BAYV; Black Creek Canal, BCCV; Choclo, CHOV; Cano Delgadito, CADV, Maporal, MPRLV, Nicocli, NECV). (2) Crocidura orthohantaviruses (Bowe BOWV). (3) Murinae-borne orthohantaviruses (Hantaan, HTNV; Dobrava-Belgrade, DOBV; Seoul, SEOV; Thailand, THAIV; Cao Bang, CBNV; Sangassou, SANGV). (4) Crocidurinae orthohantaviruses (Nova, NVAV). (5) Arvicolinae-borne orthohantaviruses (Tula, TULV; Puumala, PUUV; Prospect Hill, PHV). (6) Cricetidae orthohantaviruses (Rockport, RKPV; Khabarovsk, KHAV; EL Moro Canyon, ELMC; Tigray, TIGV). (7) Soricinae orthohantaviruses (Asama, ASAV; Asikkala, ASIV; Jeju, JJUV; Kenkeme, KKMV; Seewis, SWSV; Oxbow, OXBV; Yakeshi, YKSV).