A global perspective on hantavirus ecology, epidemiology, and disease

doi:10.1128/CMR.00062-09. 23(2):412-441. Clin. Microbiol. Rev.Epidemiology, and Disease. A Global Perspective on Hantavirus Ecology,2010. and Olli Vapalahti Colleen B. Jonsson, Luiz Tadeu Moraes Figueiredo, Disease Ecology, Epidemiology, and A Global Perspective on Hantavirus http://cmr.asm.org/cgi/content/full/23/2/412 Updated information and services can be found at: These include: CONTENT ALERTS more>>cite this article), eTOCs, free email alerts (when new articlesRSS Feeds,Receive: http://journals.asm.org/subscriptions/To subscribe to an ASM journal go to: http://journals.asm.org/misc/reprints.dtlInformation about commercial reprint orders: at UNIVERSITAT DE BARCELO NA July 21, 2010 cm r.ASM .O RG - DO W NLO ADED FRO M CLINICAL MICROBIOLOGY REVIEWS, Apr. 2010, p. 412–441 Vol. 23, No. 2 0893-8512/10/$12.00 doi:10.1128/CMR.00062-09 Copyright © 2010, American Society for Microbiology. All Rights Reserved. A Global Perspective on Hantavirus Ecology, Epidemiology, and Disease Colleen B. Jonsson,1,2* Luiz Tadeu Moraes Figueiredo,3 and Olli Vapalahti4 Department of Microbiology and Immunology,1 and the Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases,2 University of Louisville, Louisville, Kentucky; Virology Research Center, School of Medicine of the University of Sa˜o Paulo, Ribeira˜o Preto City, Sa˜o Paulo, Brazil3; and Department of Virology, Haartman Institute, and Department of Basic Veterinary Sciences, University of Helsinki, HUSLAB, Helsinki, Finland4 INTRODUCTION .......................................................................................................................................................412 HANTAVIRUS LIFE CYCLE....................................................................................................................................413 Genome Organization and Virion Structure.......................................................................................................414 Replication of Hantaviruses ..................................................................................................................................414 ECOLOGY AND EVOLUTION OF HANTAVIRUS..............................................................................................416 Rodent Reservoirs of Old World Hantaviruses ..................................................................................................417 Rodent Reservoirs of New World Hantaviruses .................................................................................................419 Evolution of Hantaviruses .....................................................................................................................................420 EPIDEMIOLOGY OF HANTAVIRUS INFECTIONS...........................................................................................422 Epidemiology of Old World Hantaviruses...........................................................................................................422 Epidemiology of New World Hantaviruses..........................................................................................................424 CLINCAL COURSE OF HANTAVIRAL ILLNESSES AND PATHOLOGY......................................................425 Spectrum of HFRS Disease in Europe and Asia................................................................................................425 Spectrum of HPS Disease in the Americas.........................................................................................................426 Pathogenesis ............................................................................................................................................................427 LABORATORY DIAGNOSIS....................................................................................................................................428 Serological Tests .....................................................................................................................................................428 Molecular Diagnostics............................................................................................................................................429 TREATMENT AND PREVENTION.........................................................................................................................429 FUTURE PROSPECTS AND CONCLUDING REMARKS..................................................................................430 ACKNOWLEDGMENTS ...........................................................................................................................................430 REFERENCES ............................................................................................................................................................430 INTRODUCTION In the past century, two major outbreaks of disease led to the discovery of hantaviruses in the Old and New Worlds. The first outbreak occurred during the Korean War (1950 to 1953), wherein more than 3,000 United Nations troops fell ill with Korean hemorrhagic fever, which is commonly referred to as hemorrhagic fever with renal syndrome (HFRS). The second outbreak of disease occurred in the Four Corners region of the United States in 1993 and was initially referred to as Four Corners disease, which is now called hantavirus pulmonary syndrome (HPS) or hantavirus cardiopulmonary syndrome (HCPS). These viruses can cause serious diseases in humans and have reached mortality rates of 12% (HFRS) and 60% (HPS) in some outbreaks. In 1978, nearly 25 years after the recognition of HFRS, the etiological agent for this disease, Hantaan virus (HTNV), and its reservoir, the striped field mouse (Apodemus agrarius), were reported by Lee et al. (239). This landmark study launched the recognition of additional HFRS-related viruses in Asia, Europe, and the United States (Table 1). Surveillance efforts showed the presence of HTNV and HTNV-like viruses in Apodemus agrarius and A. peninsulae rodents in Far East Russia, China, and South Korea and a distinct virus, Dobrava virus (DOBV), and Dobrava-like vi- ruses harbored by Apodemus flavicollis, A. agrarius, and A. ponticus in Europe (18, 21, 125, 173, 211–213, 324). In the 1980s, it was discovered that urban cases of HFRS were caused by the rat-borne Seoul virus (SEOV) in Asia (57, 203), and in Europe, nephropathia epidemica (NE), which is a milder form of HFRS described in the 1930s (304, 465), was discovered to be caused by another hantavirus, Puumala virus (PUUV), har- bored by the bank vole, Myodes glareolus (previously known as Clethrionomys glareolus) (76). The discovery of these hantavi- ruses has led to the appreciation that worldwide, there may be as many as 150,000 cases of HFRS each year, with more than half occurring in China (231, 403). In contrast to these early pioneering efforts that led to the discovery of HTNV, the etiological agent of HPS, Sin Nombre virus (SNV) was identified within weeks of the Four Corners outbreak (148, 308). Technological advancements in molecular biology contributed largely to the ability of investigators to rapidly isolate and characterize this newly discovered virus. However, it was the weak cross-reactivity of human sera with the antigen from an Old World hantavirus that provided the first clue to the possible causative agent of HPS. Since the Four Corners outbreak, more than 2,000 cases of HPS have oc- * Corresponding author. Mailing address: Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville, 950 N. Hurstbourne Parkway, Louisville, KY 40222. Phone: (502) 852-1339. Fax: (502) 852-5468. E-mail: cbjons01 @louisville.edu. 412 at UNIVERSITAT DE BARCELO NA July 21, 2010 cm r.ASM .O RG - DO W NLO ADED FRO M curred in sporadic clusters throughout the Americas and have led to the discovery of many different strains of these viruses and their rodent reservoirs (26, 28, 37, 70, 107, 110, 151, 179, 180, 441, 450). At present, over 21 hantaviruses that cause illness in humans ranging from proteinuria to pulmonary edema and frank hem- orrhage illnesses when transmitted from their rodent reservoirs to humans have been identified across the globe (Table 1). Additional hantaviruses may remain undiscovered, since in many countries, hantaviral infections are likely to go undetec- ted and not reported, especially in Africa, the Middle East, and the Indian subcontinent. This is especially evident with the recent discovery of shrew-borne hantaviruses around the globe (192). Until these seminal discoveries, Thottapalayam virus (TPMV), a long-unclassified virus isolated from the Asian house shrew (Suncus murinus), was the only known shrew- borne hantavirus (406). Clearly, these and other hantaviruses deserve the attention of research scientists and public health officials with respect to their impact on public health and the quest for treatments and to promote public awareness of those hantaviruses that cause illness in humans (383). Here, we present a review of these fascinating viruses, with our major focus being on the ecology of and disease caused by these serious human pathogens. Finally, in our future prospects, we address new approaches to the study of hantaviruses that seek to integrate the ecology and evolution of these and other host-virus ecosystems through modeling. First, however, we introduce the basic biology of the virus. HANTAVIRUS LIFE CYCLE The genus Hantavirus resides in the family Bunyaviridae, a large family of over 300 viruses that infect animals, plants, humans, and arthropods (36, 100, 388). In general, hantavi- TABLE 1. Geographic distribution of and disease associated with Old World and New World strains of hantavirus Group and subfamily Virus isolate or strain Abbreviation a Geographic distribution Rodent host Associateddisease Old World Murinae Hantaan virus HTNV China, South Korea, Russia Apodemus agrarius HFRS Dobrava-Belgrade virus DOBV Balkans Apodemus flavicollis HFRS Seoul virus SEOV Worldwide Rattus HFRS Saaremaa virus SAAV Europe Apodemus agrarius HFRS Amur virus AMRV Far East Russia Apodemus peninsulae HFRS Soochong virus — South Korea Apodemus peninsulae Unknown Arvicolinae Puumala virus PUUV Europe, Asia, and Americas Clethrionomys glareolus HFRS/NE Khabarovsk virus KHAV Far East Russia Microtus fortis Unknown Muju virus MUJV South Korea Myodes regulus Unknown Prospect Hill virus PHV Maryland Microtus pennsylvanicus Unknown Tula virus TULV Russia/Europe Microtus arvalis Unknown Isla Vista virus ISLAV North America Microtus californicus Unknown Topografov virus TOPV Siberia Lemmus sibericus Unknown New World Sigmodontinae Sin Nombre virus SNV North America Peromyscus maniculatus HPS Monongahela virus MGLV North America Peromyscus leucopus HPS New York virus NYV North America Peromyscus leucopus HPS Black Creek Canal virus BCCV North America Sigmodon hispidus HPS Bayou virus BAYV North America Oryzomys palustris HPS Limestone Canyon virus — North America Peromyscus boylii Unknown Playa de Oro virus — Mexico Oryzomys couesi Unknown Catacamas virus — Honduras Oryzomys couesi Unknown Choclo virus — Panama Oligoryzomys fulvescens HPS Calabazo virus — Panama Zygodontomys brevicauda Unknown Rio Segundo virus RIOSV Cost Rica Reithrodontomys mexicanus Unknown Cano Delgadito virus CADV Venezuela Sigmodon alstoni Unknown Andes virus ANDV Argentina, Chile Oligoryzomys longicaudatus HPS Bermejo virus BMJV Argentina Oligoryzomys chocoensis HPS Pergamino virus PRGV Argentina Akodon azarae Unknown Lechiguanas virus LECV Argentina Oligoryzomys flavescens HPS Maciel virus MCLV Argentina Bolomys obscurus HPS Oran virus ORNV Argentina Oligoryzomys longicaudatus HPS Laguna Negra virus LANV Paraguay, Bolivia, Argentina Calomys laucha HPS Alto Paraguay virus — Paraguayan Chaco Holochilus chacoensis Unknown Ape Aime virus — Eastern Paraguay Akodon montensis Unknown Itapúa virus — Eastern Paraguay Oligoryzomys nigripes Unknown Rio Mamore virus — Bolivia, Peru Oligoryzomys microtis Unknown Araraquara virus — Brazil Bolomys lasiurus HPS Juquitiba virus — Brazil Oligoryzomys nigripes HPS Jabora´ virus — Brazil, Paraguay Akodon montensis a —, an abbreviation has not yet been designated by the ICTVdb Index of Viruses. VOL. 23, 2010 HANTAVIRUS ECOLOGY, EPIDEMIOLOGY, AND DISEASE 413 at UNIVERSITAT DE BARCELO NA July 21, 2010 cm r.ASM .O RG - DO W NLO ADED FRO M ruses are commonly referred to as Old World and New World hantaviruses due to the geographic distribution of their rodent reservoirs and the type of illness (HFRS or HPS) that mani- fests upon transmission to humans (382). Despite the differ- ences in geographic locations and illnesses, the Old World and New World hantaviruses share high homology in the organi- zations of their nucleic sequences and exhibit similar aspects of their life cycles. Genome Organization and Virion Structure The first molecular analyses of HTNV showed that the ge- nome comprises three negative-sense, single-stranded RNAs that share a 3� terminal sequence of the three genome seg- ments (385). The three segments, S (small), M (medium), and L (large), encode the nucleoprotein (N), envelope glycopro- teins (Gn, formerly G1, and Gc, formerly G2), and the L protein or viral RNA (vRNA)-dependent RNA polymerase (RdRp), respectively (389). The total size of the RNA genome ranges from 11,845 nucleotides (nt) for HTNV to 12,317 nt for SNV. The treatment of HTNV with nonionic detergents re- leases three ribonucleoproteins (RNPs) that sediment to den- sities of 1.18 and 1.25 g/cm3 in sucrose and CsCl, respectively, by using rate-zonal centrifugation methods (387). The RNP structures within the virion each consist of one viral RNA segment complexed with the N protein (82, 311). It is widely held for all of the viruses in the family Bunyaviridae that each genomic RNA forms a circular molecule that forms by base pairing between inverted complementary sequences at the 3� and 5� ends of linear viral RNA (140). The RNP complexes may contribute to the virion’s internal filamentous appearance (86). The tomographic reconstruction of an HTNV virion shows a set of parallel rod-like densities (Fig. 1) that can be seen beneath the membrane, which presumably represent the three RNPs (A. J. Battisti and P. R. Chipman, Purdue Uni- versity, unpublished data). Hantaviruses of the HTNV/SEOV lineage do not have a nonstructural (NSs) protein, which oc- curs in other genera within the Bunyaviridae (389). However, the New World hantaviruses and vole-borne PUUV-Tula virus (TULV) branch of hantaviruses contain an evolutionarily conserved NSs open reading frame (ORF) in an overlapping reading frame similar to that of the orthobunyaviruses. The expression of this ORF in PUUV-infected cells has been demonstrated and was suggested to influence the interferon response (171, 172). Hantaviruses lack a matrix protein, and therefore, the N protein may provide this function to facilitate physical interactions with the glycoprotein projections on the inner leaf of the lipid membrane and the RNPs. Hantavirus virions are generally spherical in nature, with an average diameter of approximately 80 to 120 nm (168, 236, 268, 271, 390, 449). Ultrastructural studies of HTNV suggest that the virion has a surface structure composed of a grid-like pattern distinct from that of other genera of the family Bunyaviridae (168, 268, 449). The grid-like pattern of the outer surface reflects the glycoprotein projections, which extend �12 nm from the lipid bilayer. Biochemical studies confirmed that these projections are composed of heterodimers of Gn and Gc (11). Replication of Hantaviruses Hantaviruses infect endothelial, epithelial, macrophage, fol- licular dendritic, and lymphocyte cells via the attachment of the viral glycoprotein to the host’s cell surface receptor(s) (262, 266, 353, 409, 461), as illustrated in Fig. 2. Several studies suggested that the receptors that interact with the larger viral glycoprotein (Gn) for entry are integrins: �1 integrin for Microtus-borne hantaviruses considered to be apathogenic and �3 integrin for pathogenic hantaviruses causing HFRS and HPS (116, 118, 227). However, these may not be the sole receptors, since cells without �3 integrin proteins permit infection (299, 407). The pretreatment of cells with antibodies to decay-accel- erating factor (DAF)/CD55 blocks infection by Old World hantaviruses, suggesting that DAF is a critical cofactor for infection (221). DAF is a glycosylphosphatidylinositol (GPI)- anchored protein of the complement regulatory system. Han- taviruses can enter polarized target cells from the apical and basolateral membrane surfaces (359, 370). HTNV enters via clathrin-coated pits, followed by movement to early endosomes and subsequent delivery to late endosomes or lysosomes (178). Within the endolysosomal compartments, the virus is uncoated to liberate the three RNPs into the cytoplasm. Viral RdRp initiates primary transcription to give rise to the S, M, and L mRNAs. The translation of the S and L mRNA transcripts occurs on free ribosomes, and the M-segment transcript occurs on membrane-bound ribosomes, which is cotranslated on rough endoplasmic reticulum (ER) (RER). For hantaviruses, the N protein is the most abundant viral protein and is syn- thesized early in infection (388). N plays key roles in several important steps in the virus life cycle, including translation, trafficking, and assembly (31, 182, 291, 323, 354, 355, 397, 398). Furthermore, recent evidence suggests that the N protein interacts with and can modulate the host immune response to infection (419, 420). The glycoprotein precursor is pro- teolytically processed into Gn and Gc during import into the ER (374, 409). For most hantaviruses, a conserved amino acid motif, WAASA, located at the end of Gn is presumed to be the proteolytic cleavage site (254). The Gn and Gc proteins FIG. 1. Tomography of an HTNV virion particle. Shown is a near- tangential section through a tomographic reconstruction of a virion. A set of parallel rod-like densities (indicated by green arrows) can be seen beneath the membrane. Anisotropy is in the direction perpendic- ular to the page. The section is 5.1 nm thick, and the scale bar repre- sents 25 nm. The tomogram was denoised by using nonlinear aniso- tropic diffusion as implemented in BSOFT (142a). (Photograph courtesy of Anthony J. Battisti and Paul R. Chipman, Purdue Univer- sity; reproduced with permission.) 414 JONSSON ET AL. CLIN. MICROBIOL. REV. at UNIVERSITAT DE BARCELO NA July 21, 2010 cm r.ASM .O RG - DO W NLO ADED FRO M are glycosylated in the ER and subsequently transported to the Golgi complex (11, 360, 374, 382, 434). Soon after the initial burst of transcription, the viral poly- merase switches from transcription to the replication of the S, M, and L genomic RNAs (Fig. 2). The newly synthesized vRNAs are encapsidated by the N protein to form the RNPs (388). The HTNV N protein traffics via microtubule dynein to the ER-Golgi-intermediate compartment (ERGIC) but not the ER, Golgi complex, or endosomes in HTNV-infected Vero E6 cells (354). Viral proteins and virion particles of other members of the Bunyaviridae, such as Uukuniemi virus (UUKV) (111, 175, 223) and Bunyamwera virus (375), accu- mulate at the Golgi complex. The UUKV N protein associates with cis-Golgi elements and accumulates in peripheral ele- ments that could also include the ERGIC (175). This suggests that the ERGIC and the Golgi complex may be important for some aspects of virus assembly. Fascinating questions remain as to where or how the assembly of the RNPs takes place, whether the RdRp is part of the RNP complex, how the RNPs traffic to the Golgi complex, and the mechanisms that drive budding into and out of the Go