Transmission Of Sin Nombre Virus Research Articles

Oral Vaccination With Recombinant Vesicular Stomatitis Virus Expressing Sin Nombre Virus Glycoprotein Prevents Sin Nombre Virus Transmission in Deer Mice.

Sin Nombre virus (SNV) is the major cause of hantavirus cardiopulmonary syndrome (HCPS) in North America, a severe respiratory disease with a high fatality rate. SNV is carried by Peromyscus maniculatus, or deer mice, and human infection occurs following inhalation of aerosolized virus in mouse excreta or secreta, often in peri-domestic settings. Currently there are no FDA approved vaccines or therapeutics for SNV or any other hantaviruses, therefore prevention of infection is an important means of reducing the disease burden of HCPS. One approach for preventing HCPS cases is to prevent the spread of the virus amongst the rodent reservoir population through bait vaccination. However, bait style vaccines for rodent-borne viruses have not been employed in the field, unlike those targeting larger species. Here we utilized a recombinant vesicular stomatitis virus expressing SNV glycoprotein precursor (rVSVΔG/SNVGPC) in an attempt to prevent SNV transmission. Vaccination of deer mice with rVSVΔG/SNVGPC was able to reduce viral RNA copy numbers in the blood and lungs of directly infected animals. More importantly, vaccination, either intramuscularly or orally, significantly reduced the number of transmission events in a SNV transmission model compared with control animals. This provides a proof-of-concept in which oral vaccination of deer mice results in protection against acquiring the virus following direct contact with infected deer mice. Further development of bait style vaccines for SNV or other rodent-borne viruses could provide an effective means of reducing disease burden.

Development and Characterization of a Sin Nombre Virus Transmission Model in Peromyscus maniculatus.

In North America, Sin Nombre virus (SNV) is the main cause of hantavirus cardiopulmonary syndrome (HCPS), a severe respiratory disease with a fatality rate of 35–40%. SNV is a zoonotic pathogen carried by deer mice (Peromyscus maniculatus), and few studies have been performed examining its transmission in deer mouse populations. Studying SNV and other hantaviruses can be difficult due to the need to propagate the virus in vivo for subsequent experiments. We show that when compared with standard intramuscular infection, the intraperitoneal infection of deer mice can be as effective in producing SNV stocks with a high viral RNA copy number, and this method of infection provides a more reproducible infection model. Furthermore, the age and sex of the infected deer mice have little effect on viral replication and shedding. We also describe a reliable model of direct experimental SNV transmission. We examined the transmission of SNV between deer mice and found that direct contact between deer mice is the main driver of SNV transmission rather than exposure to contaminated excreta/secreta, which is thought to be the main driver of transmission of the virus to humans. Furthermore, increases in heat shock responses or testosterone levels in SNV-infected deer mice do not increase the replication, shedding, or rate of transmission. Here, we have demonstrated a model for the transmission of SNV between deer mice, the natural rodent reservoir for the virus. The use of this model will have important implications for further examining SNV transmission and in developing strategies for the prevention of SNV infection in deer mouse populations.

The role of behavioural heterogeneity on infection patterns: implications for pathogen transmission

Animals infected with pathogens often differ in behaviour from their uninfected counterparts, and these differences may be key to understanding zoonotic pathogen transmission. To explore behavioural heterogeneity and its role in pathogen transmission, we studied deer mice, Peromyscus maniculatus, under field conditions. Deer mice are the natural host of Sin Nombre virus (SNV), a zoonotic pathogen with high human mortality. We live-trapped mice in May, July and September of 2009 and 2010, marked captures with passive integrated transponder (PIT) tags, recorded physical characteristics and collected blood samples for SNV analysis. For 4 nights after each trapping session, we observed behaviour with a novel surveillance system of nine camera stations, each consisting of a foraging tray, infrared camera, PIT antenna and data logger. We found that deer mice infected with SNV (30.0%) engaged more frequently in behaviours that increased the probability of intraspecific encounters and SNV transmission than did uninfected deer mice. When deer mice were categorized as bold (31.7%) or shy (68.3%) based on these behaviours, bold behaviour was predictive of positive SNV status. Bold deer mice were three times more likely to be infected with SNV than were shy deer mice. These results suggest that a small percentage of bold individuals are responsible for a majority of SNV transmission events, and that behavioural phenotype is an important consideration in transmission dynamics of zoonotic diseases.

DELAYED DENSITY-DEPENDENT PREVALENCE OF SIN NOMBRE VIRUS INFECTION IN DEER MICE (PEROMYSCUS MANICULATUS) IN CENTRAL AND WESTERN MONTANA

Understanding how transmission of zoonoses takes place within reservoir populations, such as Sin Nombre virus (SNV) among deer mice (Peromyscus maniculatus), is important in determining the risk of exposure to other hosts, including humans. In this study, we examined the relationship between deer mouse populations and the prevalence of antibodies to SNV, a system where the effect of host population abundance on transmission is debated. We examined the relationship between abundance of deer mice in late summer-early autumn and SNV antibody prevalence the following spring-early summer (termed delayed density-dependent [DDD] prevalence of infection) at both regional and local scales, using 12 live-trapping grids for 11-14 yr, across central and western Montana. When all trapping grids were combined (regional scale), there was a significant DDD relationship for individual months and when months within seasons were averaged. However, within individual grids (local scale), evidence of DDD prevalence of infection was observed consistently at only one location. These findings suggest that, although there is evidence of DDD prevalence of infection at regional scales, it is not always apparent at local scales, possibly because the regional pattern of DDD infection prevalence is driven by differences in abundance and prevalence among sites, rather than in autumn-spring delays. Transmission of SNV may be more complex than the original hypothesis of autumn-spring delayed density dependence suggests. This complexity is also supported by recent modeling studies. Empirical investigations are needed to determine the duration and determinants of time-lagged abundance and antibody prevalence. Our study suggests predicting local, human exposure risk to SNV in spring, based on deer mouse abundance in autumn, is unlikely to be a reliable public health tool, particularly at local scales.

Deer Mouse (Peromyscus maniculatus) Home-Range Size and Fidelity in Sage-Steppe Habitat

Within a species, home-range size can vary due to factors such as sex, mass, age, and breeding condition of individuals as well as habitat type, food availability, population density, and season. The objectives of this study were to estimate home ranges of deer mice (Peromyscus maniculatus) in sage-steppe habitat and to test the hypothesis that several factors (sex, mass, reproductive status, and seasonality) affect home-range size. We also tested the hypothesis that deer mice exhibit home-range fidelity over time. Passive integrated transponder (PIT) technology was used to estimate home ranges in June and September 2006. Home-range estimates varied from 360 m2 to 5868 m2 (65 individuals, 753 observations). Home-range size increased by approximately 60% from June to September. Besides seasonality, none of the other predictors of home range were informative in explaining the variation in home range. Deer mice recaptured in September (3 months after initial capture) had high fidelity in home-range use (42.1% [SE = 8.4%] overlap with 74.1% [SE = 8.7%] area conserved; n = 9). All animals for which home range was estimated in both seasons retained some fraction of their June home range in September. Results support the use of combined location data collected over long periods, such as weeks or months, to estimate home range for deer mice. The results have implications for deer mouse—pathogen ecology, particularly with respect to modeling transmission of Sin Nombre virus—a pathogen that is directly transmitted by deer mice.

Relationship of Human Behavior within Outbuildings to Potential Exposure to Sin Nombre Virus in Western Montana

Sin Nombre virus (SNV) causes hantavirus cardiopulmonary syndrome (HCPS) in humans. Transmission of SNV among the deer mouse (Peromyscus maniculatus) host predominates during spring and summer, and is greater in peridomestic than sylvan settings where, protected from UV light, SNV may survive longer. Incidence of HCPS reflects these times and settings and is associated with inhalation of mouse excreta. Little is known, however, about how human use of outbuildings contributes to potential exposure to SNV. Here, the frequency and seasonality of outbuilding use by humans was evaluated, via a survey of rural residents in western Montana, to quantify human behaviors and potential risk of exposure to SNV. Retrieving or return of tools and scooping feed/grain were the most frequently undertaken activities. Seasonal activities coinciding with seasons of highest HCPS incidence and times of potentially high viral shedding by deer mice, included retrieving or returning tools, calving or lambing, and, to a lesser extent, feeding livestock and sweeping or cleaning. Human behavior is a component of SNV transmission risk and this preliminary study provides a basis from which to further evaluate this route of exposure.

NATURAL HISTORY OF SIN NOMBRE VIRUS INFECTION IN DEER MICE IN URBAN PARKS IN OREGON

Sin Nombre virus (SNV), one of at least 45 hantaviruses described worldwide, is hosted by the deer mouse, Peromyscus maniculatus, a common species throughout most of North America. Herein, we describe general life-history characteristics of deer mice and the ways in which these factors relate to the incidence of SNV infections among populations of this host species in and around Portland, Oregon. In total, 3,175 deer mice were captured from October 2002 to September 2005. Transmission of SNV appears to be associated with male breeding behaviors, as more males and adults were infected than expected by capture rate; spring and summer had the highest infection prevalence, as well as scrotal male captures. Wounding rates between infected and uninfected deer mice were not different in any age or sex class. Capture rates were significantly and positively related to the interaction of temperature departure from normal, total precipitation, and number of clear days from two seasons previous (P=0.029), while infection prevalence was significantly and negatively related to the capture rate of juveniles from two seasons previous (P=0.029).

Contact heterogeneity in deer mice: implications for Sin Nombre virus transmission.

Heterogeneities within disease hosts suggest that not all individuals have the same probability of transmitting disease or becoming infected. This heterogeneity is thought to be due to dissimilarity in susceptibility and exposure among hosts. As such, it has been proposed that many host-pathogen systems follow the general pattern whereby a small fraction of the population accounts for a large fraction of the pathogen transmission. This disparity in transmission dynamics is often referred to as '20/80 Rule', i.e. approximately 20 per cent of the hosts are responsible for 80 per cent of pathogen transmission. We investigated the role of heterogeneity in contact rates among potential hosts of a directly transmitted pathogen by examining Sin Nombre virus (SNV) in deer mice (Peromyscus maniculatus). Using foraging arenas and powder marking, we documented contacts between wild deer mice in Great Basin Desert, central Utah. Our findings demonstrated heterogeneity among deer mice, both in frequency and in duration of contacts with other deer mice. Contact dynamics appear to follow the general pattern that a minority of the population accounts for a majority of the contacts. We found that 20 per cent of individuals in the population were responsible for roughly 80 per cent of the contacts observed. Larger-bodied individuals appear to be the functional group with the greatest SNV transmission potential. Contrary to our predictions, transmission potential was not influenced by breeding condition or sex.

USE OF IgG AVIDITY TO INDIRECTLY MONITOR EPIZOOTIC TRANSMISSION OF SIN NOMBRE VIRUS IN DEER MICE (PEROMYSCUS MANICULATUS)

An IgG avidity assay was developed to differentiate deer mice that had recently acquired Sin Nombre virus (SNV) from those that were infected in the distant past. Using this procedure, low avidity antibodies were predominantly detected in experimentally infected deer mice (89.5%) within the first 30 days post-inoculation. The assay was then applied to sera from naturally infected deer mice collected during a field investigation associated with a cluster of hantavirus pulmonary syndrome cases. A higher proportion of seropositive mice collected during the outbreak had serum with low avidity antibodies (16.7%) when compared with mice trapped four months later (5.7%). Sin Nombre virus RNA was detectable in blood in a similar fraction of low- (45%) and high- (38.7%) avidity groups. Non-adult mice were more likely to contain low-avidity antibodies (44.4%) than were adults (9.6%). Our results indicate that the IgG avidity assay shows promise as a tool to better characterize epizootic intensity and to identify factors involved in SNV transmission.

Genetic relatedness of deer mice (Peromyscus maniculatus) infected with Sin Nombre virus.

The deer mouse (Peromyscus maniculatus) is the primary rodent host of Sin Nombre virus (SNV), the principal etiologic agent of hantavirus pulmonary syndrome in the United States. Many characteristics of SNV infections of deer mice are unknown. To better understand the transmission mechanisms of SNV in deer mice, we conducted mark-recapture sampling and genetic analyses to study deer mouse population density and genetic relatedness from 2001 to 2002. We genotyped each deer mouse at 10 microsatellite loci to estimate relatedness among SNV-infected and SNV-uninfected groups, demographic categories, and individuals. Estimates of average overall population densities ranged from 1.15 to 14.95 deer mice/ha. Estimates of average population densities of SNV-infected deer mice ranged from 0 to 1.55 deer mice/ha. When evaluated as groups at one of two study sites, SNV-infected deer mice were more related to one another, on average, than they were to their uninfected cohorts. Pairwise coefficients of relatedness among individuals indicated that several deer mice infected with SNV were closely related. Most infected mice were males. These results are consistent with the hypothesis that transmission of SNV often is associated with breeding activities and aggression among males during the breeding season and suggest that post-birth behavioral associations among adults and juveniles may be a factor in the transmission of SNV.

Satellite imagery characterizes local animal reservoir populations of Sin Nombre virus in the southwestern United States.

The relationship between the risk of hantaviral pulmonary syndrome (HPS), as estimated from satellite imagery, and local rodent populations was examined. HPS risk, predicted before rodent sampling, was highly associated with the abundance of Peromyscus maniculatus, the reservoir of Sin Nombre virus (SNV). P. maniculatus were common in high-risk sites, and populations in high-risk areas were skewed toward adult males, the subclass most frequently infected with SNV. In the year after an El Niño Southern Oscillation (ENSO), captures of P. maniculatus increased only in high-risk areas. During 1998, few sites had infected mice, but by 1999, 1820 of the high-risk sites contained infected mice and the crude prevalence was 30.8%. Only 118 of the low-risk sites contained infected rodents, and the prevalence of infection was lower (8.3%). Satellite imagery identified environmental features associated with SNV transmission within its reservoir population, but at least 2 years of high-risk conditions were needed for SNV to reach high prevalence. Areas with persistently high-risk environmental conditions may serve as refugia for the survival of SNV in local mouse populations.

Shedding and intracage transmission of Sin Nombre hantavirus in the deer mouse (Peromyscus maniculatus) model.

The mechanism(s) by which Sin Nombre (SN) hantavirus is maintained in deer mouse populations is unclear. Field studies indicate that transmission occurs primarily if not exclusively via a horizontal mechanism. Using an experimental deer mouse infection model in an outdoor laboratory, we tested whether infected rodents shed SN virus in urine, feces, and saliva, whether infected mice transmit infection to naïve cage mates, and whether infected dams are able to vertically transmit virus or antibody to offspring. Using pooled samples of urine, feces, and saliva collected from mice infected 8 to 120 days postinoculation (p.i.), we found that a subset of saliva samples, collected between 15 and 90 days p.i., contained viral RNA. Parallel studies conducted on wild-caught, naturally infected deer mice showed a similar pattern of intermittent positivity, also only in saliva samples. Attempts to isolate virus through inoculation of cells or naïve deer mice with the secreta or excreta of infected mice were uniformly negative. Of 54 attempts to transmit infection by cohousing infected deer mice with seronegative cage mates, we observed only a single case of transmission, which occurred between 29 and 42 days p.i. Dams passively transferred antibodies to neonatal pups via milk, and those antibodies persisted for at least 2 months after weaning, but none transmitted infection to their pups. Compared to other hantavirus models, SN virus is shed less efficiently and transmits inefficiently among cage mates. Transmission of SN virus among reservoir rodents may require factors that are not required for other hantaviruses.

Hantavirus pulmonary syndrome in pregnancy.

This comprehensive case review of hantavirus pulmonary syndrome (HPS) during pregnancy in 5 women characterizes the effect of Sin Nombre virus infection on maternal and fetal outcomes. Histopathologic, serological, and clinical information were evaluated for evidence of vertical transmission. Maternal ages ranged from 20 to 34 years and gestational ages from 13 to 29 weeks. Symptoms, physical findings, and laboratory values other than those related to pregnancy were not noticeably different from those of nonpregnant patients with HPS, although fevers were somewhat lower. One maternal death and 2 fetal losses occurred. Gross, microscopic, and immunohistochemical examination for hantavirus antigen were done on 2 fetal autopsies and 3 placentas showing no evidence of transplacental hantavirus transmission. There was no serological evidence of conversion in the 3 surviving children. Maternal and fetal outcomes of HPS appear similar to those of nonpregnant HPS patients and of pregnant patients with other causes of acute respiratory distress syndrome. No evidence of vertical transmission of Sin Nombre virus was found.

Serologic survey for hantavirus infection in domestic animals and coyotes from New Mexico and northeastern Arizona

Objective To determine whether animals had serologic evidence of infection with Sin Nombre virus (SNV). Design Prospective serosurvey. Sample Population Serum samples were obtained from 145 cats, 85 dogs, 120 horses, and 24 cattle between April 1993 and August 1994 and 54 coyotes between December 1994 and February 1995. Procedure Serum samples were analyzed by western immunoblot assays for reaction with SNV nucleocapsid antigen. Samples with reactivity to SNV nucleocapsid proteins were used to probe multiple-antigen blots containing recombinant fusion proteins derived from prototypic hantaviruses. Lung tissue or blood clots were used in nested reverse-transcriptase polymerase chain reaction assays for a 320-nucleotide portion of the SNV G1 gene. Results Sera from 4 of 145 (2.8%) cats and 4 of 85 (3.5%) dogs had trace reactivity to full-length SNV-encoded nucleocapsid proteins. All samples from horses, cattle, and coyotes were nonreactive. Sera from cats and dogs that had trace IgG-antibody reactivity to nucleocapsid proteins were then tested for IgG-antibody reactivity to nucleocapsid proteins of prototypic hantaviruses. One cat had multiple cross-reactivities with these hantaviruses, consistent with exposure to a hantavirus; however, epitope mapping studies did not support this conclusion. Reverse-transcriptase polymerase chain reaction studies of blood clots or lung tissue from 2 animals that had weak reactivity to SNV failed to amplify any hantavirus sequence. Clinical Implications Domestic animals, particularly dogs and cats, as well as coyotes do not appear to have a major role in the maintenance and transmission of SNV. (J Am Vet Med Assoc 1998;212:970–973)

Evidence Against Person-to-Person Transmission of Hantavirus to Health Care Workers

Unusual, primarily pulmonary, manifestations of hantaviral illness occurring in the southwestern United States raised the possibility of person-to-person transmission of a recently recognized hantavirus, Sin Nombre virus. To determine whether such transmission had occurred among health care workers (HCWs) exposed to patients with confirmed hantavirus pulmonary syndrome, we evaluated HCWs who had cared for patients with hantavirus pulmonary syndrome or who had processed specimens from these patients. Information about exposure to these patients and about recent illnesses was obtained via a standardized questionnaire. Serum specimens were tested for IgM and IgG antibodies to hantaviruses with use of ELISAs. Of the 396 HCWs, 266 (67%) reported that they had been exposed to patients with hantavirus pulmonary syndrome or to their body fluids or that they had processed laboratory specimens from these patients. Although 108 (27%) of the HCWs reported fever, myalgias, or respiratory illnesses during the 3 months before the serum specimens were obtained, hantavirus antibodies were not detected in any HCW. These data suggest that person-to-person transmission of Sin Nombre virus is unlikely to occur in health care settings.