Sin Nombre Virus Research Articles

Human Orthohantavirus disease prevalence and genotype distribution in the U.S., 2008–2020: a retrospective observational study

In the United States (U.S.), hantavirus pulmonary syndrome (HPS) and non-HPS hantavirus infection are nationally notifiable diseases. Criteria for identifying human cases are based on clinical symptoms (HPS or non-HPS) and acute diagnostic results (IgM+, rising IgG+ titers, RT-PCR+, or immunohistochemistry (IHC)+). Here we provide an overview of diagnostic testing and summarize human Hantavirus disease occurrence and genotype distribution in the U.S. from 2008 to2020. Epidemiological data from the national hantavirus registry was merged with laboratory diagnostic testing results performed at the CDC. Residual hantavirus-positive specimens were sequenced, and the available epidemiological and genetic data sets were linked to conduct a genomic epidemiological study of hantavirus disease in the U.S. From 1993 to 2020, 833 human hantavirus cases have been identified, and from 2008 to 2020, 335 human cases have occurred. Among New World (NW) hantavirus cases detected at the CDC diagnostic laboratory (representing 29.2% of total cases), most (85.0%) were detected during acute disease, however, some convalescent cases were detected in states not traditionally associated with hantavirus infections (Connecticut, Missouri, New Jersey, Pennsylvania, Tennessee, and Vermont). From 1993 to 2020, 94.9% (745/785) of U.S. hantaviruses cases were detected west of the Mississippi with 45.7% (359/785) in the Four Corners region of the U.S. From 2008 to 2020, 67.7% of NW hantavirus cases were detected between the months of March and August. Sequencing of RT-PCR-positive cases demonstrates a geographic separation of Orthohantavirus sinnombreense species [Sin Nombre virus (SNV), New York virus, and Monongahela virus]; however, there is a large gap in viral sequence data from the Northwestern and Central U.S. Finally, these data indicate that commercial IgM assays are not concordant with CDC-developed assays, and that "concordant positive" (i.e., commercial IgM+ and CDC IgM+ results) specimens exhibit clinical characteristics of hantavirus disease. Hantaviral disease is broadly distributed in the contiguous U.S, viral variants are localised to specific geographic regions, and hantaviral disease infrequently detected in most Southeastern states. Discordant results between two diagnostic detection methods highlight the need for an improved standardised testing plan in the U.S. Hantavirus surveillance and detection will continue to improve with clearly defined, systematic reporting methods, as well as explicit guidelines for clinical characterization and diagnostic criteria. This work was funded by core funds provided to the Viral Special Pathogens Branch at CDC.

A Systematic Review of the Distribution and Prevalence of Viruses Detected in the Peromyscus maniculatus Species Complex (Rodentia: Cricetidae).

The North American Deermouse, Peromyscus maniculatus, is one of the most widespread and abundant mammals on the continent. It is of public health interest as a known host of several viruses that are transmissible to humans and can cause illness, including the acute respiratory disease Hantavirus Pulmonary Syndrome (HPS). However, recent taxonomic studies indicate that P. maniculatus is a complex of multiple species, raising questions about how to identify and interpret three decades of hantavirus monitoring data. We conducted a systematic review investigating the prevalence and spatial distribution of viral taxa detected in wild populations allocated to P. maniculatus. From the 46 relevant studies published from 2000 to 2022, we extracted and analyzed spatial occurrence data to calculate weighted populational prevalences for hantaviruses. We found that detection efforts have been concentrated in the Western United States and Mexico with a focus on the spread of Sin Nombre virus, the primary causative agent of HPS. There are significant gaps in the existing literature both geographically and in regard to the types of hantaviruses being sampled. These results are significantly impacted by a recent taxonomic split of P. maniculatus into four species, which results in the relabeling of 92% of hantavirus observations. Considering the uncertain, and likely multiple, phylogenetic histories of these viral hosts should be a key emphasis of future modeling efforts.

Genome sequencing identifies “Limestone Canyon virus” as Montaño virus (Hantaviridae: Orthohantavirus montanoense) circulating in brush deermice in New Mexico

Orthohantaviruses infect distinct eulipotyphlan and rodent reservoirs throughout the world; some rodent orthohantaviruses can cause disease in humans. In the United States, a primary rodent reservoir for the human-pathogenic Sin Nombre virus (SNV) is the western deermouse (Peromyscus sonoriensis; formerly included in Peromyscus maniculatus). Deermice (rodents of genus Peromyscus) carry presumably distinct orthohantaviruses but, although deermice of ten species have been recorded in New Mexico, only SNV has been reported in rodents from that state. Using a set of pan-orthohantavirus primers, we discovered a non-SNV orthohantavirus in a brush deermouse (P. boylii), trapped in central New Mexico in 2019. Sequencing enabled the generation of a consensus coding-complete genome sequence, revealing similarity to the known partial sequences of the unclassified “Limestone Canyon virus (LSCV)” in GenBank and aligning with the information in an unpublished study of wild-caught brush deermice trapped in southwestern New Mexico in 2006. Phylogenetic analysis of these combined data revealed geospatial clades and overall identity of “LSCV”, uncovering its association with the classified Montaño virus (MTNV), which is known to infect Aztec and Orizaba deermice in central Mexico. Our work emphasizes the importance of determining coding-complete viral genome sequences as a framework for rigorous virus classification as the basis for epidemiological studies.

Distribution and prevalence of Sin Nombre hantavirus in rodent species in eastern New Mexico.

Orthohantaviruses are diverse zoonotic RNA viruses. Small mammals, such as mice and rats are common chronic, asymptomatic hosts that transmit the virus through their feces and urine. In North America, hantavirus infection primarily causes hantavirus cardiopulmonary syndrome (HCPS), which has a mortality rate of nearly 36%. In the United States of America, New Mexico (NM) is leading the nation in the number of HCPS-reported cases (N = 129). However, no reported cases of HCPS have occurred within eastern NM. In this study, we assessed the prevalence of Sin Nombre virus (SNV) in rodent assemblages across eastern NM, using RT-qPCR. We screened for potential rodent hosts in the region, as well as identified areas that may pose significant infection risk to humans. We captured and collected blood and lung tissues from 738 rodents belonging to 23 species. 167 individuals from 16 different species were positive for SNV RNA by RT-qPCR, including 6 species unreported in the literature: Onychomys leucogaster (Northern grasshopper mouse), Dipodomys merriami (Merriam's kangaroo rat), Dipodomys ordii (Ord's kangaroo rat), Dipodomys spectabilis (Banner-tailed kangaroo rat), Perognathus flavus (Silky pocket mouse), and Chaetodipus hispidus (Hispid pocket mouse). The infection rates did not differ between sexes or rodent families (i.e., Cricetidae vs. Heteromyidae). Generalized linear model showed that disturbed habitat types positively influenced the prevalence of SNV at sites of survey. Overall, the results of this study indicate that many rodent species in east New Mexico have the potential to maintain SNV in the environment, but further research is needed to assess species specific infectivity mechanisms and potential risk to humans.

Sin Nombre Virus and the Emergence of Other Hantaviruses: A Review of the Biology, Ecology, and Disease of a Zoonotic Pathogen.

Sin Nombre virus (SNV) is an emerging virus that was first discovered in the Four Corners region of the United States in 1993. The virus causes a disease known as Hantavirus Pulmonary Syndrome (HPS), sometimes called Hantavirus Cardiopulmonary Syndrome (HCPS), a life-threatening illness named for the predominance of infection of pulmonary endothelial cells. SNV is one of several rodent-borne hantaviruses found in the western hemisphere with the capability of causing this disease. The primary reservoir of SNV is the deer mouse (Peromyscus maniculatus), and the virus is transmitted primarily through aerosolized rodent excreta and secreta. Here, we review the history of SNV emergence and its virus biology and relationship to other New World hantaviruses, disease, treatment, and prevention options.

Zoonotic Hantaviridae with Global Public Health Significance.

Hantaviridae currently encompasses seven genera and 53 species. Multiple hantaviruses such as Hantaan virus, Seoul virus, Dobrava-Belgrade virus, Puumala virus, Andes virus, and Sin Nombre virus are highly pathogenic to humans. They cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome or hantavirus pulmonary syndrome (HCPS/HPS) in many countries. Some hantaviruses infect wild or domestic animals without causing severe symptoms. Rodents, shrews, and bats are reservoirs of various mammalian hantaviruses. Recent years have witnessed significant advancements in the study of hantaviruses including genomics, taxonomy, evolution, replication, transmission, pathogenicity, control, and patient treatment. Additionally, new hantaviruses infecting bats, rodents, shrews, amphibians, and fish have been identified. This review compiles these advancements to aid researchers and the public in better recognizing this zoonotic virus family with global public health significance.

Structural and functional characterization of the Sin Nombre virus L protein.

The Bunyavirales order is a large and diverse group of segmented negative-strand RNA viruses. Several virus families within this order contain important human pathogens, including Sin Nombre virus (SNV) of the Hantaviridae. Despite the high epidemic potential of bunyaviruses, specific medical countermeasures such as vaccines or antivirals are missing. The multifunctional ~250 kDa L protein of hantaviruses, amongst other functional domains, harbors the RNA-dependent RNA polymerase (RdRp) and an endonuclease and catalyzes transcription as well as replication of the viral RNA genome, making it a promising therapeutic target. The development of inhibitors targeting these key processes requires a profound understanding of the catalytic mechanisms. Here, we established expression and purification protocols of the full-length SNV L protein bearing the endonuclease mutation K124A. We applied different biochemical in vitro assays to provide an extensive characterization of the different enzymatic functions as well as the capacity of the hantavirus L protein to interact with the viral RNA. By using single-particle cryo-EM, we obtained a 3D model including the L protein core region containing the RdRp, in complex with the 5' promoter RNA. This first high-resolution model of a New World hantavirus L protein shows striking similarity to related bunyavirus L proteins. The interaction of the L protein with the 5' RNA observed in the structural model confirms our hypothesis of protein-RNA binding based on our biochemical data. Taken together, this study provides an excellent basis for future structural and functional studies on the hantavirus L protein and for the development of antiviral compounds.

Two point mutations in protocadherin-1 disrupt hantavirus recognition and afford protection against lethal infection

Andes virus (ANDV) and Sin Nombre virus (SNV) are the etiologic agents of severe hantavirus cardiopulmonary syndrome (HCPS) in the Americas for which no FDA-approved countermeasures are available. Protocadherin-1 (PCDH1), a cadherin-superfamily protein recently identified as a critical host factor for ANDV and SNV, represents a new antiviral target; however, its precise role remains to be elucidated. Here, we use computational and experimental approaches to delineate the binding surface of the hantavirus glycoprotein complex on PCDH1’s first extracellular cadherin repeat domain. Strikingly, a single amino acid residue in this PCDH1 surface influences the host species-specificity of SNV glycoprotein-PCDH1 interaction and cell entry. Mutation of this and a neighboring residue substantially protects Syrian hamsters from pulmonary disease and death caused by ANDV. We conclude that PCDH1 is a bona fide entry receptor for ANDV and SNV whose direct interaction with hantavirus glycoproteins could be targeted to develop new interventions against HCPS.

Hantavirus Infections among Military Forces.

Hantaviruses cause two kinds of clinical syndromes. Hemorrhagic fever with renal syndrome is caused by Hantaan virus in Asia, Puumala virus (PUUV) and Dobrava virus in Europe, and Seoul virus worldwide. Hantavirus cardiopulmonary syndrome is caused by Sin Nombre virus in North America and Andes virus and related viruses in Latin America. All hantaviruses are carried by rodents and insectivores. Humans are infected via inhaled aerosols of rodent excreta. In the history, there are several epidemics of acute infectious diseases during many wars, which have been suggested or proven to be caused by various hantaviruses. Literature review of 41 original publications and reviews published between 1943 and 2022 was performed. Among them, 23 publications handle hantavirus infections among military forces, and the rest 17 hantavirus infections themselves. A large epidemic during World War II in 1942 among German and Finnish soldiers in Northern Finland with more than 1,000 patients was most probably caused by PUUV. During Korean War in 1951-1954,∼ 3,200 cases occurred among United Nations soldiers in an epidemic caused by Hantaan virus. During Balkan war from 1991 to 1995, numerous soldiers got ill because of hantavirus infection caused by PUUV and Dobrava virus. Several other reports of cases of various hantavirus infections especially among U.S. soldiers acting in South Korea, Germany, Bosnia, and Kosovo have been described in the literature. Military maneuvers usually include soil removal, spreading, digging with accompanied dust, and living in field and other harsh conditions, which easily expose soldiers to rodents and their excreta. Therefore, the risks of hantavirus infections in military context are obvious. All military infections have been caused by hantaviruses leading to hemorrhagic fever with renal syndrome.

Mechanistic basis for potent neutralization of Sin Nombre hantavirus by a human monoclonal antibody

Rodent-borne hantaviruses are prevalent worldwide and upon spillover to human populations, cause severe disease for which no specific treatment is available. A potent antibody response is key for recovery from hantavirus infection. Here we study a highly neutralizing human monoclonal antibody, termed SNV-42, which was derived from a memory B cell isolated from an individual with previous Sin Nombre virus (SNV) infection. Crystallographic analysis demonstrates that SNV-42 targets the Gn subcomponent of the tetrameric (Gn−Gc)4 glycoprotein assembly that is relevant for viral entry. Integration of our 1.8 Å structure with the (Gn−Gc)4 ultrastructure arrangement indicates that SNV-42 targets the membrane-distal region of the virus envelope. Comparison of the SNV-42 paratope encoding variable genes with inferred germline gene segments reveals high sequence conservation, suggesting that germline-encoded antibodies inhibit SNV. Furthermore, mechanistic assays reveal that SNV-42 interferes with both receptor recognition and fusion during host-cell entry. This work provides a molecular-level blueprint for understanding the human neutralizing antibody response to hantavirus infection.

Development of a novel minigenome and recombinant VSV expressing Seoul hantavirus glycoprotein-based assays to identify anti-hantavirus therapeutics

Seoul virus (SEOV) is an emerging global health threat that can cause hemorrhagic fever with renal syndrome (HFRS), which results in case fatality rates of ∼2%. There are no approved treatments for SEOV infections. We developed a cell-based assay system to identify potential antiviral compounds for SEOV and generated additional assays to characterize the mode of action of any promising antivirals. To test if candidate antivirals targeted SEOV glycoprotein-mediated entry, we developed a recombinant reporter vesicular stomatitis virus expressing SEOV glycoproteins. To facilitate the identification of candidate antiviral compounds targeting viral transcription/replication, we successfully generated the first reported minigenome system for SEOV. This SEOV minigenome (SEOV-MG) screening assay will also serve as a prototype assay for discovery of small molecules inhibiting replication of other hantaviruses, including Andes and Sin Nombre viruses. Ours is a proof-of-concept study in which we tested several compounds previously reported to have activity against other negative-strand RNA viruses using our newly developed hantavirus antiviral screening systems. These systems can be used under lower biocontainment conditions than those needed for infectious viruses, and identified several compounds with robust anti-SEOV activity. Our findings have important implications for the development of anti-hantavirus therapeutics.

Bunyaviral N Proteins Localize at RNA Processing Bodies and Stress Granules: The Enigma of Cytoplasmic Sources of Capped RNA for Cap Snatching

Most cytoplasmic-replicating negative-strand RNA viruses (NSVs) initiate genome transcription by cap snatching. The source of host mRNAs from which the cytoplasmic NSVs snatch capped-RNA leader sequences has remained elusive. Earlier reports have pointed towards cytoplasmic-RNA processing bodies (P body, PB), although several questions have remained unsolved. Here, the nucleocapsid (N) protein of plant- and animal-infecting members of the order Bunyavirales, in casu Tomato spotted wilt virus (TSWV), Rice stripe virus (RSV), Sin nombre virus (SNV), Crimean-Congo hemorrhagic fever virus (CCHFV) and Schmallenberg virus (SBV) have been expressed and localized in cells of their respective plant and animal hosts. All N proteins localized to PBs as well as stress granules (SGs), but extensively to docking stages of PB and SG. TSWV and RSV N proteins also co-localized with Ran GTPase-activating protein 2 (RanGAP2), a nucleo-cytoplasmic shuttling factor, in the perinuclear region, and partly in the nucleus when co-expressed with its WPP domain containing a nuclear-localization signal. Upon silencing of PB and SG components individually or concomitantly, replication levels of a TSWV minireplicon, as measured by the expression of a GFP reporter gene, ranged from a 30% reduction to a four-fold increase. Upon the silencing of RanGAP homologs in planta, replication of the TSWV minireplicon was reduced by 75%. During in vivo cap-donor competition experiments, TSWV used transcripts destined to PB and SG, but also functional transcripts engaged in translation. Altogether, the results implicate a more complex situation in which, besides PB, additional cytoplasmic sources are used during transcription/cap snatching of cytoplasmic-replicating and segmented NSVs.

Human antibody recognizing a quaternary epitope in the Puumala virus glycoprotein provides broad protection against orthohantaviruses.

The rodent-borne hantavirus Puumala virus (PUUV) and related agents cause hemorrhagic fever with renal syndrome (HFRS) in humans. Other hantaviruses, including Andes virus (ANDV) and Sin Nombre virus, cause a distinct zoonotic disease, hantavirus cardiopulmonary syndrome (HCPS). Although these infections are severe and have substantial case fatality rates, no FDA-approved hantavirus countermeasures are available. Recent work suggests that monoclonal antibodies may have therapeutic utility. We describe here the isolation of human neutralizing antibodies (nAbs) against tetrameric Gn/Gc glycoprotein spikes from PUUV-experienced donors. We define a dominant class of nAbs recognizing the "capping loop" of Gn that masks the hydrophobic fusion loops in Gc. A subset of nAbs in this class, including ADI-42898, bound Gn/Gc complexes but not Gn alone, strongly suggesting that they recognize a quaternary epitope encompassing both Gn and Gc. ADI-42898 blocked the cell entry of seven HCPS- and HFRS-associated hantaviruses, and single doses of this nAb could protect Syrian hamsters and bank voles challenged with the highly virulent HCPS-causing ANDV and HFRS-causing PUUV, respectively. ADI-42898 is a promising candidate for clinical development as a countermeasure for both HCPS and HFRS, and its mode of Gn/Gc recognition informs the development of broadly protective hantavirus vaccines.

Environmental and occupational health on the Navajo Nation: a scoping review.

A scoping review was performed to answer: what environmental health concerns have been associated with adverse health outcomes in the Navajo Nation? The review focused on occupational and ambient environmental exposures associated with human industrial activities. The search strategy was implemented in PubMed, and two investigators screened the retrieved literature. Thirteen studies were included for review. Data were extracted using the matrix method. Six studies described associations between work in uranium mining and cancer. Six studies focused on environmental exposures to uraniummine waste and other metals, with outcomes that included biological markers, kidney disease, diabetes and hypertension, and adverse birth outcomes. One study explored occupational exposure to Sin Nombre Virus and infection. Most research has focused on the health effects of uranium, where occupational exposures occurred among miners and environmental exposures are a legacy of uranium mining and milling. Gaps exist with respect to health outcomes associated with current occupations and the psychosocial impact of environmental hazards. Other environmental exposures and hazards are known to exist on the Navajo Nation, which may warrant epidemiologic research.

Exome sequencing of deer mice on two California Channel Islands identifies potential adaptation to strongly contrasting ecological conditions.

Understanding the forces that drive genotypic and phenotypic change in wild populations is a central goal of evolutionary biology. We examined exome variation in populations of deer mice from two of the California Channel Islands: Peromyscus maniculatus elusus from Santa Barbara Island and P. m. santacruzae from Santa Cruz Island exhibit significant differences in olfactory predator recognition, activity timing, aggressive behavior, morphology, prevalence of Sin Nombre virus, and population densities. We characterized variation in protein‐coding regions using exome capture and sequencing of 25 mice from Santa Barbara Island and 22 mice from Santa Cruz Island. We identified and examined 386,256 SNPs using three complementary methods (BayeScan, pcadapt, and LFMM). We found strong differences in molecular variation between the two populations and 710 outlier SNPs in protein‐coding genes that were detected by all three methods. We identified 35 candidate genes from this outlier set that were related to differences in phenotypes between island populations. Enrichment analyses demonstrated that patterns of molecular variation were associated with biological processes related to response to chemical stimuli and regulation of immune processes. Candidate genes associated with olfaction (Gfy, Tlr2, Vmn13r2, numerous olfactory receptor genes), circadian activity (Cry1), anxiety (Brca1), immunity (Cd28, Eif2ak4, Il12a, Syne1), aggression (Cyp19a, Lama2), and body size (Bc16, Syne1) exhibited non‐synonymous mutations predicted to have moderate to large effects. Variation in olfaction‐related genes, including a stop codon in the Santa Barbara Island population, suggests loss of predator‐recognition traits at the molecular level, consistent with a lack of behavioral aversion to fox feces. These findings also suggest that divergent pathogen prevalence and population density may have influenced adaptive immunity and behavioral phenotypes, such as reduced aggression. Overall, our study indicates that ecological differences between islands are associated with signatures of selection in protein‐coding genes underlying phenotypes that promote success in those environments.

Hantavirus outbreaks in the American Southwest: Propagation and retraction of rodent and virus diffusion waves from sky-island refugia

Hantavirus outbreaks in the American Southwest are hypothesized to be driven by episodic seasonal events of high precipitation, promoting rapid increases in virus-reservoir rodent species that then move across the landscape from high quality montane forested habitats (refugia), eventually over-running human residences and increasing disease risk. In this study, the velocities of rodents and virus diffusion wave propagation and retraction were documented and quantified in the sky-islands of northern New Mexico and related to rodent-virus relationships in refugia versus nonrefugia habitats. Deer mouse (Peromyscus maniculatus) refugia populations exhibited higher Sin Nombre Virus (SNV) infection prevalence than nonrefugia populations. The velocity of propagating diffusion waves of Peromyscus from montane to lower grassland habitats was measured at [Formula: see text] m/day (SE), with wave retraction velocities of [Formula: see text] m/day. SNV infection diffusion wave propagation velocity within a deer mouse population averaged [Formula: see text] m/day, with a faster retraction wave velocity of [Formula: see text] m/day. A spatio-temporal analysis of human Hantavirus Pulmonary Syndrome (HPS) cases during the initial 1993 epidemic revealed a positive linear relationship between the time during the epidemic and the distance of human cases from the nearest deer mouse refugium, with a landscape diffusion wave velocity of [Formula: see text] m/day ([Formula: see text]). These consistent diffusion propagation wave velocity results support the traveling wave component of the HPS outbreak theory and can provide information on space–time constraints for future outbreak forecasts.

Heterospecific competitors and seasonality can affect host physiology and behavior: key factors in disease transmission

AbstractEcological and environmental factors can influence the transmission of infectious diseases. They can accomplish this via effects on host susceptibility and exposure to infection, which are governed by host physiology and behavior, respectively. To better inform disease control, more information is needed about how extrinsic factors affect physiological and behavioral processes that determine transmission. We investigated how heterospecific competitors and seasonality may influence host susceptibility and intraspecific contact rates using a directly transmitted disease system, the North American deer mouse (Peromyscus maniculatus)—Sin Nombre hantavirus (SNV) system. In grasslands of western Montana, USA, deer mice compete with dominant voles (Microtus spp.) and shrews (Sorex spp.) and experience a seasonal temperate climate. Higher SNV transmission occurs primarily during spring/summer, when changes in physiology and behavior may serve as influential contributors. We hypothesized that (1) voles, and to a lesser extent shrews, will induce chronic stress, suppress immunity, and may change contact rates of deer mice; and (2) during spring/summer, deer mice may experience chronic stress, suppressed immunity, and higher contact rates, which may help explain the reported seasonality in SNV transmission. Over two years, we trapped small mammals at four grids in western Montana. Deer mice were sampled for feces and blood and evaluated for scar numbers, demography, and body condition scores (BCSs). We evaluated stress physiology with fecal corticosterone metabolites (FCMs), neutrophil/lymphocyte (N/L) ratios and BCSs, immunity with white blood cell (WBC) counts, and contact rates with scar numbers. We found that shrew density was negatively associated with stress response FCMs, suggestive of chronic stress. Additionally, although complex interactions existed, shrew and vole densities were negatively associated with BCSs, but differentially with scar numbers. N/L ratios were higher in spring/summer, whereas WBC counts were lower in summer, suggestive of chronic stress and suppressed immunity, respectively. Our results suggest that (1) heterospecific competitors may differentially influence disease transmission via stress physiology and contact rates, and that (2) chronic stress, suppressed immunity, and higher contact rates may help explain why higher SNV transmission has been previously reported during spring/summer in Montana. Our findings may extend to other directly transmitted disease systems.

Sin Nombre virus prevalence from 2014–2017 in wild deer mice,Peromyscus maniculatus, on five of the California Channel Islands

Sin Nombre virus (SNV) is a zoonotic virus that is highly pathogenic to humans. The deer mouse, Peromyscus maniculatus, is the primary host of SNV, and SNV prevalence in P.maniculatus is an important indicator of human disease risk. Because the California Channel Islands contain permanent human settlements, receive hundreds of thousands of visitors each year, and can have extremely high densities of P.maniculatus, surveillance for SNV in island P.maniculatus is important for understanding the human risk of zoonotic disease. Despite the importance of surveillance on these heavily utilized islands, SNV prevalence (i.e. the proportion of P.maniculatus that test positive to antibodies to SNV) has not been examined in the last 13-27years. We present data on 1,610 mice sampled for four consecutive years (2014-2017) on five of the California Channel Islands: East Anacapa, Santa Barbara, Santa Catalina, San Nicolas, and San Clemente. Despite historical data indicating SNV-positive mice on San Clemente and Santa Catalina, we detected no SNV-positive mice on these islands, suggesting very low prevalence or possible loss of SNV. Islands historically free of SNV (East Anacapa, Santa Barbara, and San Nicolas) remained free of SNV, suggesting that rates of pathogen introduction from other islands and/or the mainland are low. Although continued surveillance is warranted to determine whether SNV establishes on these islands, our work helps inform current human disease risk in these locations and suggests that SNV prevalence on these islands is currently very low.

Broad and potently neutralizing monoclonal antibodies isolated from human survivors of New World hantavirus infection

SUMMARYNew World hantaviruses (NWHs) are endemic in North and South America and cause hantavirus cardiopulmonary syndrome (HCPS), with a case fatality rate of up to 40%. Knowledge of the natural humoral immune response to NWH infection is limited. Here, we describe human monoclonal antibodies (mAbs) isolated from individuals previously infected with Sin Nombre virus (SNV) or Andes virus (ANDV). Most SNV-reactive antibodies show broad recognition and cross-neutralization of both New and Old World hantaviruses, while many ANDV-reactive antibodies show activity for ANDV only. mAbs ANDV-44 and SNV-53 compete for binding to a distinct site on the ANDV surface glycoprotein and show potently neutralizing activity to New and Old World hantaviruses. Four mAbs show therapeutic efficacy at clinically relevant doses in hamsters. These studies reveal a convergent and potently neutralizing human antibody response to NWHs and suggest therapeutic potential for human mAbs against HCPS.

Experimental parasite community perturbation reveals associations between Sin Nombre virus and gastrointestinal nematodes in a rodent reservoir host.

Individuals are often co-infected with several parasite species, yet measuring within-host interactions remains difficult in the wild. Consequently, the impacts of such interactions on host fitness and epidemiology are often unknown. We used anthelmintic drugs to experimentally reduce nematode infection and measured the effects on both nematodes and the important zoonosis Sin Nombre virus (SNV) in its primary reservoir (Peromyscus spp.). Treatment significantly reduced nematode infection, but increased SNV seroprevalence. Furthermore, mice that were co-infected with both nematodes and SNV were in better condition and survived up to four times longer than uninfected or singly infected mice. These results highlight the importance of investigating multiple parasites for understanding interindividual variation and epidemiological dynamics in reservoir populations with zoonotic transmission potential.