Hantaviruses: an overview

Hantaviruses are a newly emerging group of rodent-borne viruses that have significant zoonotic potential. Human infection by hantaviruses can result in profound morbidity and mortality, with death rates as high as 50%, and potentially long-term cardiovascular consequences. Hantaviruses are carried by peridomestic and wild rodents worldwide and have occasionally been linked to infections in laboratory rodents. Because these viruses have been associated with significant human disease, they have become the subject of intense scientific investigation. In this review the reader is introduced to the hantaviruses, including hantavirus diseases and their pathogenesis. A review of the biology, morphology, and molecular biology of the hantaviruses with a brief overview of the ecology and biology of hantavirus-rodent pairs is also included. The risks of occupational exposure to hantaviruses, diagnosis of hantavirus infections, and methods for handling potentially infected rodents and tissues are discussed as well.     

Brush mouse (Peromyscus boylii) population dynamics and hantavirus infection during a warm, drought period in southern Arizona

We monitored Limestone Canyon hantavirus (LSCV) antibody prevalence, host (brush mouse, Peromyscus boylii) abundance, and environmental variables (temperature and rainfall) in brush mice captured on three trapping webs in southern Arizona for 5 yr. Although seasonal patterns were subtle, we observed large multiyear variation in population abundance and antibody prevalence. Limestone Canyon hantavirus infection in brush mouse populations varied over time with prevalence ranging from 0% to 33%. At all trapping webs, evidence of infection disappeared completely for an extended period (up to 2 yr) and eventually reappeared, suggesting that dispersal may play a role in maintaining infection in brush mouse metapopulations. Weather during the study period was drier and warmer than average and these conditions, especially during spring through fall, may have contributed to low brush mouse population density and the local extinction of LSCV during the second year of the study. Nevertheless, population growth was associated with relatively warm, dry conditions during winter periods and a cool, wet spring and summer period in the fifth year of the study. After prolonged absence, LSCV infection was consistently detected only when brush mouse population abundance reached relatively high levels during that fifth year. Comparison of our results to similar studies suggests that stochastic events resulting in the loss or survival of a few infected mice in low-density host populations may result in local extinction of virus; reestablishment of infection may occur via immigration of infected individuals from adjacent populations, but may be successful only when populations are of sufficient density to support frequent rodent-to-rodent interactions and virus transmission.     

Hantaviruses: molecular biology, evolution and pathogenesis

Hantaviruses are tri-segmented negative sense single stranded RNA viruses that belong to the family Bunyaviridae. In nature, hantaviruses are exclusively maintained in the populations of their specific rodent hosts. In their natural host species, hantaviruses usually develop a persistent infection with prolonged virus shedding in excreta. Humans become infected by inhaling virus contaminated aerosol. Unlike asymptomatic infection in rodents, hantaviruses cause two acute febrile diseases in humans: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). The mortality rate varies from 0.1% to 40% depending on the virus involved. Hantaviruses are distributed world wide, with over 150,000 HFRS and HPS cases being registered annually. In this review we summarize current knowledge on hantavirus molecular biology, epidemiology, genetic diversity and co-evolution with rodent hosts. In addition, special attention was given in this review to describing clinical manifestation of HFRS and HPS, and advances in our current understanding of the host immune response, treatment, and prevention.     

Distribution and abundance of sigmodontine rodents in relation to hantavirus in Neuquén, Argentina.

In order to estimate spatial distribution, temporal variation, and prevalence of Andes hantavirus antibody in the rodent community, and especially in Oligoryzomys longicaudatus populations, four different ecosystems were trapped seasonally between spring 2001 and winter 2002 in Neuquen, northwestern Argentinean Patagonia. Five peridomestic settings were sampled within the same period. The rodent O. longicaudatus had the widest distribution in Neuquen, as it was the only species captured at every sample site except for the High Andean steppe, and it was also the most common species captured. Rodents of 13 species were tested for hantavirus antibody prevalence, but O. longicaudatus and Abrothrix longipilis were the only seropositive species. Seropositive individuals were captured during spring and summer in the Subantarctic forest and in winter 2001 in a peridomestic setting in the Patagonian steppe. The dominant presence of O. longicaudatus throughout Neuquen must be incorporated into strategies to prevent human exposure to hantavirus.     

Echinococcus multilocularis--a zoonosis of anthropogenic environments?

Transmission of the fox tapeworm Echinococcus multilocularis, the causative agent of human alveolar echinococcosis, is known to depend on various environmental factors which are subject to human influence. Epidemiological data suggest that in most endemic regions anthropogenic landscape changes (e.g. deforestation and agricultural practices) have led to more favourable conditions for the parasite's animal hosts, especially arvicolid rodents, thereby increasing the risk for parasite transmission and human disease. Examples are the conversion of forests or crop fields into meadows and pastures in Europe, China and North America, and overgrazing of natural grassland in central Asia. Other anthropogenic factors include interference with host population densities by wildlife disease control, changing hunting pressure and provision of new habitats, e.g. in urban areas. Domestic dogs may, under certain conditions, get involved in the otherwise largely wildlife-based transmission, and thereby greatly increase the infection pressure to humans. The introduction of neozootic host species may increase transmission, or even initiate the parasite's life-cycle in previously non-endemic regions. Lastly, the parasite itself may be accidentally introduced into non-endemic areas, if suitable host populations are present (e.g. in northern Japan).     

Emergence of hantaviral disease in the southwestern United States.

Hantaviruses are parasites of small mammals, predominantly peridomestic and commensal rodents. They have a worldwide distribution. Hantavirus-related illness occurs in rural areas where humans come into contact with rodents. In most cases human infection is manifested by one of a variety of acute illnesses involving hemorrhagic fever and renal disease. In May 1993, a cluster of patients with an acute pulmonary disease with high mortality was noted in the Four Corners region of the southwestern United States. Serologic and genetic studies indicated that the etiologic agent was a novel hantavirus. The uncertainty engendered by the emergence of a new disease with high mortality forced a rapid response by state and federal agencies and by the University of New Mexico Medical Center, Albuquerque, where most patients from this region were referred. Considerable progress has been made in identifying infected cases on clinical and laboratory grounds and in ensuring that appropriate supportive care is made available to patients as soon as they are suspected of having hantaviral infection. Cases of hantavirus pulmonary syndrome--both new and retrospectively diagnosed--are still being recognized throughout the western United States. Many important questions remain unanswered.     

Detection and characterization of three zoonotic viruses in wild rodents and shrews from Shenzhen city,China

Diverse species of rodents and shrews, which are abundant worldwide, harbor a variety of viruses;some of these are closely related to human viruses and possess zoonotic potential. Previously studies have demonstrated that the mammarenavirus and hantavirus carried by rodents or shrews could cause diseases in human population. To determine the distribution of zoonotic viruses in Shenzhen city, the major city in southern China with a high population density, we analyzed 225 rodents(Rattus norvegicus and Rattus flavipectus) and 196 shrews(Suncus murinus) from urban and rural districts for the presence of mammarenavirus, hantavirus, and hepatitis E virus(HEV) by RT-PCR targeting the conserved regions. The infection rates for mammarenavirus, hantaviruses,and HEV in rodents and shrews were 3.56%, 6.89%, and 1.66%, respectively. Partial genome fragment analysis indicated that mammarenavirus and hantavirus strains had more than 90% and 99% nucleic acid identity with Cardamones virus and Seoul virus, respectively, which cause diseases in humans. Although the present HEV strains identified are typically found worldwide,phylogenetic analysis demonstrated a divergence of 16%. To our knowledge, the present work is the first report of the prevalence of mammarenavirus, hantaviruses, and rat HEV strains in rodents and shrews from Shenzhen city, China. Our findings highlight the zoonotic potential of rodent-and shrew-borne mammarenavirus and hantavirus, and the biodiversity of rat HEV isolates in Shenzhen city. The present work suggests that utilization of good hygiene habits is important to minimize the risk of zoonosis.     

A comparison of infestation patterns by Ixodes ticks in urban and rural populations of the Common Blackbird Turdus merula

Although spatial variation in the patterns of parasite infestations among host populations may have important ecological and epidemiological consequences, the causes underlying such variation are poorly known. In the context of a long-term study on the population biology of Common Blackbirds Turdus merula , we examined the prevalence and intensity of infestation by Ixodes ticks between birds living in rural vs. urban habitats. The overall prevalence of tick infestations was significantly higher in the rural habitat where 74% of individuals ( n  = 130) were infested. This result contrasted markedly with the situation in the urban habitat where less than 2% of individuals ( n  = 360) carried ticks. There was no significant effect of the sex of the host on the intensity or prevalence of tick infestations. There was a significant effect of the age of the host on tick infestations essentially due to the absence of ticks on nestlings. Possible mechanisms responsible for the differences between habitats could include differences in tick survival and/or host resistance towards ticks. Previous studies have shown higher population densities and suggested longer survival for Blackbirds in urban than in rural habitats. Given that ixodid ticks are known to transmit pathogens like Borrelia spp. to wild birds, and that Blackbirds can act as reservoirs for these pathogens, the infection patterns observed in our study area provide a suitable situation to study the interrelations between ticks, Blackbirds and pathogens.     

Biological control agents elevate hantavirus by subsidizing deer mouse populations

Biological control of exotic invasive plants using exotic insects is practiced under the assumption that biological control agents are safe if they do not directly attack non-target species. We tested this assumption by evaluating the potential for two host-specific biological control agents ( Urophora spp.), widely established in North America for spotted knapweed ( Centaurea maculosa ) control, to indirectly elevate Sin Nombre hantavirus by providing food subsidies to populations of deer mice ( Peromyscus maniculatus ), the primary reservoir for the virus. We show that seropositive deer mice (mice testing positive for hantavirus) were over three times more abundant in the presence of the biocontrol food subsidy. Elevating densities of seropositive mice may increase risk of hantavirus infection in humans and significantly alter hantavirus ecology. Host specificity alone does not ensure safe biological control. To minimize indirect risks to non-target species, biological control agents must suppress pest populations enough to reduce their own numbers.     

Study of hantavirus infection in captive breed colonies of wild rodents

Wild sigmondontine rodents are known to be the reservoir of several serotypes of New World hantaviruses. The mechanism of viral transmission is by aerosol inhalation of the excreta from infected rodents. Considering that the captive breed colonies of various wild mammals may present a potential risk for hantaviral transmission, we examined 85 specimens of Thrichomys spp. (Echimyidae) and 17 speciemens of Nectomys squamipes (Sigmodontinae) from our colony for the presence of hantavirus infections. Blood samples were assayed for the presence of antibodies to Andes nucleocapsid antigen using enzyme-linked immunosorbent assay (ELISA). Additionally, serum samples from workers previously exposed to wild rodents, in the laboratories where the study was conducted, were also tested by ELISA to investigate prevalence of anti-hantavirus IgG antibodies. All blood samples were negative for hantavirus antibodies. Although these results suggest that those rodent's colonies are hantavirus free, the work emphasizes the need for hantavirus serological monitoring in wild colonized rodents and secure handling potentially infected rodents as important biosafety measures.     

Transmission Ecology of Sin Nombre Hantavirus in Naturally Infected North American Deermouse Populations in Outdoor Enclosures

Sin Nombre hantavirus (SNV), hosted by the North American deermouse (Peromyscus maniculatus), causes hantavirus pulmonary syndrome (HPS) in North America. Most transmission studies in the host were conducted under artificial conditions, or extrapolated information from mark-recapture data. Previous studies using experimentally infected deermice were unable to demonstrate SNV transmission. We explored SNV transmission in outdoor enclosures using naturally infected deermice. Deermice acquiring SNV in enclosures had detectable viral RNA in blood throughout the acute phase of infection and acquired significantly more new wounds (indicating aggressive encounters) than uninfected deermice. Naturally-infected wild deermice had a highly variable antibody response to infection, and levels of viral RNA sustained in blood varied as much as 100-fold, even in individuals infected with identical strains of virus. Deermice that infected other susceptible individuals tended to have a higher viral RNA load than those that did not infect other deermice. Our study is a first step in exploring the transmission ecology of SNV infection in deermice and provides new knowledge about the factors contributing to the increase of the prevalence of a zoonotic pathogen in its reservoir host and to changes in the risk of HPS to human populations. The techniques pioneered in this study have implications for a wide range of zoonotic disease studies.     

Silent <Emphasis Type="Italic">Orthohantavirus</Emphasis> Circulation Among Humans and Small Mammals from Central Minas Gerais,Brazil

New World orthohantaviruses are emerging RNA viruses that cause hantavirus cardiopulmonary syndrome (HCPS). These viruses are a burden to public health around the world with a lethality rate of around 60%. In South America, rodents of Sigmodontinae subfamily are the main reservoirs of orthohantaviruses. We described a serosurvey for orthohantaviruses circulation in an apparently healthy human population and small mammals from rural areas in Central Minas Gerais State, Brazil. A total of 240 individuals and 50 small mammals (26 rodents belonging to 10 different species and 24 marsupials from 4 different species) were sampled during 2012–2013. The seroprevalence rates of IgG/IgM antibodies in humans were 7.1 and 1.6%, respectively. Only one rodent, an Oligoryzomys nigripes captured in peridomestic area, tested positive for IgG antibodies and viral RNA. Our findings suggest a silent circulation of orthohantaviruses in a region of intensive agriculture production. The detection of seropositive humans in an area with a lack of previous HCPS reports highlights potential oligosymptomatic cases and the need for surveillance strategies that could reduce the risk of future outbreaks.     

Loss of Wolbachia infection during colonisation in the invasive Argentine ant Linepithema humile

WOLBACHIA are maternally inherited bacteria, which are very common in arthropods and nematodes. Wolbachia infection may affect host reproduction through feminisation, parthenogenesis, male-killing, cytoplasmic incompatibility and increased fecundity. Previous studies showing discrepancies between the phylogenies of Wolbachia and its arthropod hosts indicate that infection is frequently lost, but the causes of symbiont extinction have so far remained elusive. Here, we report data showing that colonisation of new habitats is a possible mechanism leading to the loss of infection. The presence and prevalence of Wolbachia were studied in three native and eight introduced populations of the Argentine ant Linepithema humile. The screening shows that the symbiont is common in the three native L. humile populations analysed. In contrast, Wolbachia was detected in only one of the introduced populations. The loss of infection associated with colonisation of new habitats may result from drift (founder effect) or altered selection pressures in the new habitat. Furthermore, a molecular phylogeny based on sequences of the Wolbachia wsp gene indicates that L. humile has been infected by a single strain. Horizontal transmission of the symbiont may be important in ants as suggested by the sequence similarity of strains in the three genera Linepithema, Acromyrmex, and Solenopsis native from South and Central America.     

Effects of anthropogenic habitat disturbance and Giardia duodenalis infection on a sentinel species' gut bacteria

Habitat disturbance, a common consequence of anthropogenic land use practices, creates human–animal interfaces where humans, wildlife, and domestic species can interact. These altered habitats can influence host–microbe dynamics, leading to potential downstream effects on host physiology and health. Here, we explored the effect of ecological overlap with humans and domestic species and infection with the protozoan parasite Giardia duodenalis on the bacteria of black and gold howler monkeys (Alouatta caraya), a key sentinel species, in northeastern Argentina. Fecal samples were screened for Giardia duodenalis infection using a nested PCR reaction, and the gut bacterial community was characterized using 16S rRNA gene amplicon sequencing. Habitat type was correlated with variation in A. caraya gut bacterial community composition but did not affect gut bacterial diversity. Giardia presence did not have a universal effect on A. caraya gut bacteria across habitats, perhaps due to the high infection prevalence across all habitats. However, some bacterial taxa were found to vary with Giardia infection. While A. caraya's behavioral plasticity and dietary flexibility allow them to exploit a range of habitat conditions, habitats are generally becoming more anthropogenically disturbed and, thus, less hospitable. Alterations in gut bacterial community dynamics are one possible indicator of negative health outcomes for A. caraya in these environments, since changes in host–microbe relationships due to stressors from habitat disturbance may lead to negative repercussions for host health. These dynamics are likely relevant for understanding organism responses to environmental change in other mammals.     

Hantavirus-specific antibodies in rodents and humans living in Kuwait

Hantaviruses are found in widely scattered areas of the world and are transmitted by inhalation of virus-contaminated aerosols of rodent excreta. The present study was undertaken in Kuwait to investigate the serological evidence for hantavirus infection in rodents and humans. Sera were collected from 283 wild rodents and 183 human subjects (46 Kuwaitis and 137 non-Kuwaitis). The rodent sera were investigated for the presence of antibodies against the Seoul and Puumala strains of the hantaviruses by enzyme-linked immunosorbent assay and immunofluorescence technique using the virus-infected Vero E6 cells. The findings showed the presence of anti-hantavirus antibodies in seven out of the 283 (2.8%) rodents. Antibodies against the Seoul strain were present in six (2.1%) and against the Puumala strain in three (1%) rodents. Further, it was observed that three out of 84 (3.6%) of the Rattus norvegicus and four out of 174 (2.3%) Mus musculus had anti-hantavirus antibodies. Two rodents belonging to species Mus musculus had antibodies against both strains of the hantaviruses. Out of 183 human sera, 13 (7%) were positive for hantavirus antibodies. Among the Kuwaitis 5/46 (11%) and among the non-Kuwaitis 8/137 (6%) were positive for the hantavirus antibodies. Antibodies to both Puumala and Hantaan strains were detected in Kuwaitis as well as in non-Kuwaitis. Although no human case of hantavirus illness has yet been reported in Kuwait, the serological evidence of infection suggests a constant vigil.     

Land cover associated with hantavirus presence in Paraguay

Aims  Hantaviruses are zoonotic, aetiological agents maintained by rodents of the family Muridae. The occurrence of hantavirus in rodent hosts has been correlated to a number of climatic and environmental factors, including landscape structure. To date, most of these correlative studies have been conducted at moderate to fine spatial resolution. Our aim is to determine whether land cover classes defined at a mapping resolution of 1 km² are associated with rodents with antibodies to hantavirus in Paraguay.
Location  The Republic of Paraguay.
Methods  A total of 362 rodents from 10 species known to host hantaviruses were tested for the presence of hantavirus antibodies, resulting in 27 seropositive individuals. This data base was then combined with a map of six land cover types derived from coarse resolution remote sensing data to create a series of contingency tables, which were used to relate serostatus to land cover type using nonparametric tests of proportions and qualitative comparison of observed and expected values.
Results  There was a significant difference in habitat association between seropositive and seronegative rodents when species were pooled. Seropositive rodents were found with disproportionately high frequency in areas where human disturbance in the form of intensive and mosaic agricultural landscapes was present.
Main conclusions  Human-disturbed land cover classes have a detectable relationship to the hantavirus serostatus of host population rodents when observed at coarse spatial resolutions. Although coarse-grained analysis does not lead to any conclusions as to why agricultural land cover is more likely to harbour seropositive rodents, the relationship between them could form the basis for a monitoring system designed to relate land cover change to potential viral outbreaks in rodents and humans.     

Infestation of rural houses by Triatoma infestans in the region of Los Llanos (La Rioja, Argentina)

Vectorial transmission of Chagas disease has been strongly reduced in most parts of the Southern Cone countries of South America, except in the Gran Chaco region of Argentina, Bolivia, and Paraguay. Given periodical interruptions of the vector control programmes in the endemic region of the Gran Chaco of Argentina, the vectorial transmission of the disease has been increasing during the last years. From the beginning of 2004, the provincial Ministry of Health of La Rioja, Argentina, started a vector control programme to cover the rural houses of the Los Llanos area in the southwestern area of the Gran Chaco region. This article reports the result of a standardized entomological survey and insecticide application against Chagas disease vectors in the intra and peridomestic structures of the rural houses of Los Llanos. A total of 4062 houses were inspected, of which 46.8% were found to be infested by Triatoma infestans. Infestation by vector species other than T. infestans was less than 0.5%(T. eratyrusiformis and T. platensis). Intradomestic infestation was found in 27.2%, whereas peridomestic infestation was found in 39.3% of the houses. The lowest figure of intradomestic infestation was 6.6% (Department F Varela), and the highest value of intradomestic infestation was 45.1% (Department Independencia). In spite of the demonstrated success of vector control elsewhere, this study shows that the vector populations are susceptible to pyrethroid insecticides in the southern area of the Gran Chaco of Argentina, that there still are regions where rural houses show heavy infestation by T. infestans associated with big peridomestic structures and that the vectorial transmission of the Chagas disease will continue, unless a sustained and well organized vector control effort is installed in the region.     

Transmission study of Andes hantavirus infection in wild sigmodontine rodents

Our study was designed to contribute to an understanding of the timing and conditions under which transmission of Andes hantavirus in Oligoryzomys longicaudatus reservoir populations takes place. Mice were caged in test habitats consisting of steel drums containing holding cages, where seronegative rodents were exposed to wild seropositive individuals by freely sharing the same cage or being separated by a wire mesh. Tests were also performed for potential viral transmission to mice from excrement-tainted bedding in the cages. Andes virus transmitted efficiently; from 130 attempts with direct contact, 12.3% resulted in virus transmission. However, if we consider only those rodents that proved to be infectious, from 93 attempts we obtained 16 infected animals (17.2%). Twelve of them resulted from intraspecies O. longicaudatus encounters where male mice were differentially affected and 4 resulted from O. longicaudatus to Abrothrix olivaceus. Experiments using Abrothrix longipilis as receptors were not successful. Transmission was not observed between wire mesh-separated animals, and mice were not infected from excrement-tainted bedding. Bites seemed not to be a requisite for oral transmission. Genomic viral RNA was amplified in two out of three saliva samples from seropositive rodents, but it was not detected in urine samples obtained by vesicle puncture from two other infected rodents. Immunohistochemistry, using antibodies against Andes (AND) hantavirus proteins, revealed strong reactions in the lung and salivary glands, supporting the possibility of oral transmission. Our study suggests that AND hantavirus may be principally transmitted via saliva or saliva aerosols rather than via feces and urine.     

Microhabitat characteristics of Akodon montensis,a reservoir for hantavirus,and hantaviral seroprevalence in an Atlantic forest site in eastern Paraguay

Hantaviruses may cause serious disease when transmitted to humans by their rodent hosts. Since their emergence in the Americas in 1993, there have been extensive efforts to understand the role of environmental factors on the presence of these viruses in their host rodent populations. HPS outbreaks have been linked to precipitation, but climatic factors alone have not been sufficient to predict the spatial‐temporal dynamics of the environment‐reservoir‐virus system. Using a series of mark‐recapture sampling sites located at the Mbaracayú Biosphere Reserve, an Atlantic Forest site in eastern Paraguay, we investigated the hypothesis that microhabitat might also influence the prevalence of Jaborá hantavirus within populations of its reservoir species, Akodon montensis. Seven trapping sessions were conducted during 2005‐2006 at four sites chosen to capture variable microhabitat conditions within the study site. Analysis of microhabitat preferences showed that A. montensis preferred areas with little forest overstory and denser vegetation cover on and near the ground. Moreover, there was a significant difference in the microhabitat occupied by antibody‐positive vs antibody‐negative rodents, indicating that microhabitats with greater overstory cover may promote transmission and maintenance of hantavirus in A. montensis.     

Human Exposure to Particulate Matter Potentially Contaminated with Sin Nombre Virus

The most common mechanism for human exposure to hantaviruses throughout North America is inhalation of virally contaminated particulates. However, risk factors associated with exposure to particulates potentially contaminated with hantaviruses are generally not well understood. In North America, Sin Nombre virus (SNV) is the most common hantavirus that infects humans, causing hantavirus pulmonary syndrome, which has a significant mortality rate (approximately 35%). We investigated human exposure to particulate matter and evaluated the effects of season, location (sylvan and peridomestic environment), and activity (walking and sweeping) on generation of particulates at the breathing zone (1.5 m above the ground). We found greater volumes of small inhalable particulates during the spring and summer compared to the fall and winter seasons and greater volumes of small inhalable particulates produced in peridomestic, compared to sylvan, environments. Also, greater volumes of particulates were generated at the breathing zone while walking compared to sweeping. Results suggest that more aerosolized particles were generated during the spring and summer months. Our findings suggest that simply moving around in buildings is a significant source of human exposure to particulates, potentially contaminated with SNV, during spring and summer seasons. These findings could be advanced by investigation of what particle sizes SNV is most likely to attach to, and where in the respiratory tract humans become infected.