Hantaviruses in Rodents: Veterinary and One Health Reference

Introduction

Orthohantaviruses (family Hantaviridae, genus Orthohantavirus) are enveloped negative-sense single-stranded RNA viruses maintained primarily in rodent hosts. These viruses establish persistent, largely asymptomatic infections in their reservoir species, with spillover to incidental hosts including humans and domestic animals [1, 2]. The veterinary and One Health importance of hantaviruses derives from their tight ecological linkage to rodent population dynamics, environmental determinants, and the potential for zoonotic transmission that may affect companion animals, livestock, and wildlife [3, 38]. This reference provides a comprehensive overview of hantavirus biology in rodent systems, diagnostic approaches, surveillance methodologies, and the conceptual framework of One Health as applied to these pathogens. Emphasis is placed on molecular virology, host-pathogen interactions, and the biophysical principles underlying detection and monitoring.

Virology and Genomic Organization

Orthohantaviruses possess a tripartite genome comprising the large (L), medium (M), and small (S) segments. The L segment encodes the RNA-dependent RNA polymerase (RdRp); the M segment encodes a glycoprotein precursor (GPC) that is post-translationally cleaved into Gn and Gc envelope glycoproteins; and the S segment encodes the nucleocapsid (N) protein [4, 5]. The N protein is the primary antigen targeted in serological assays, while Gn and Gc mediate host cell entry through interaction with protocadherin-1 (PCDH1) and other surface receptors [55]. Two point mutations in PCDH1 can disrupt hantavirus recognition and confer protection against lethal infection in experimental models [55].

Genetic diversity among orthohantaviruses is substantial, driven by high mutation rates and reassortment potential [6, 5]. Phylogenetic analyses have delineated distinct clades corresponding to reservoir host families, with rodent-borne lineages broadly divided into those associated with subfamilies Arvicolinae, Murinae, and Sigmodontinae/Neotominae [7, 8, 83]. For example, Hantaan virus (HTNV) is harbored by Apodemus agrarius and related species in Asia [9, 6], while Sin Nombre virus (SNV) is maintained by Peromyscus maniculatus in North America [10, 11, 45]. Puumala virus (PUUV) circulates in Myodes glareolus (bank voles) across Europe [39, 43, 53], and Seoul virus (SEOV) is globally distributed in Rattus norvegicus and R. rattus [12, 41, 67].

Rodent Reservoir Hosts and Ecology

A diverse array of rodent species serve as primary reservoirs for orthohantaviruses. The association between virus and host is typically coevolved, with each viral species or genotype exhibiting a narrow host range [1, 83]. However, spillover infections into sympatric non-reservoir rodents have been documented, as observed in the Czech Republic [75] and in multiple rodent species infected with SNV in North America [90]. Host switching and evolutionary plasticity are also evident, as demonstrated by the broad host range of Tula virus (TULV) in arvicoline rodents [8].

Ecological determinants of hantavirus prevalence in rodent populations include habitat type, climate, food availability, and interspecific competition [13, 3, 63]. Community assembly processes, particularly competition among rodent species, drive deer mouse density and consequently SNV infection prevalence [13]. Habitat management practices, such as vegetation clearing and prescribed burning, can alter rodent diversity and abundance, thereby affecting virus infection dynamics [60]. Climatic variables, including temperature and precipitation, influence rodent population cycles and virus transmission rates, enabling predictive modeling of outbreak risk [14, 38, 63].

Transmission Dynamics in Rodent Populations

Transmission of orthohantaviruses among rodents occurs primarily through direct contact, including aggressive interactions, grooming, and inhalation of aerosolized excreta (urine, feces, saliva) from infected individuals [15, 65]. Indirect transmission via contaminated fomites and environmental surfaces is also recognized [53]. The virus is shed in high concentrations in rodent excreta, particularly during the early phase of infection, and can persist in the environment under favorable temperature and humidity conditions [65].

Longitudinal studies have demonstrated persistent infection in reservoir hosts with periodic recrudescence of shedding, which maintains viral circulation within populations [9, 81]. In bank voles, PUUV infection does not affect trapping success, indicating that behavioral changes induced by infection are minimal and that infected animals remain active participants in social networks [81]. Maternal antibody-mediated elimination of an outbreak has been documented in bank vole colonies, suggesting that population immunity plays a critical role in modulating transmission [16].

Mathematical models of seroconversion have been developed to better understand hantavirus transmission dynamics and to estimate the force of infection based on cross-sectional serological data [15]. These models incorporate density-dependent or frequency-dependent transmission and account for the long duration of antibody persistence in reservoir hosts.

Pathogenesis in Rodents

In their natural reservoir hosts, orthohantaviruses typically cause persistent, asymptomatic infections. The virus replicates primarily in vascular endothelial cells and macrophages, with tropism varying by host and virus genotype [65]. In bank voles, PUUV exhibits broad tissue tropism, including lung, kidney, spleen, and liver, and coinfection with endoparasites modulates viral loads and tissue distribution [65]. Histopathological changes are generally mild, with evidence of perivascular infiltration and focal inflammation [73].

In non-reservoir rodent species, hantavirus infection can result in clinical disease that mirrors aspects of human hemorrhagic fever with renal syndrome (HFRS) or hantavirus pulmonary syndrome (HPS). For example, HTNV infection in laboratory mice (e.g., BALB/c) produces renal pathology, including tubular necrosis, proteinuria, and elevated blood urea nitrogen, which can serve as a model for human HFRS [17, 73]. The development of a HPS model using human lung xenografts in immunodeficient mice has provided a platform for studying pathogenesis and evaluating therapeutic interventions [18]. Urinalysis in HTNV-infected mice reveals marked proteinuria and hematuria, correlating with renal damage [17].

Genetic factors in the reservoir host also influence infection outcome. In Peromyscus maniculatus, single nucleotide polymorphisms in genes related to inflammation and immune surveillance are associated with SNV infection status, highlighting host genetic control of viral replication and persistence [48].

Diagnostic Approaches in Rodents

Serological Detection

Detection of anti-hantavirus antibodies in rodent blood or serum is achieved primarily through enzyme-linked immunosorbent assays (ELISAs) using recombinant N protein as antigen [19, 20, 82]. These assays are genus-reactive, detecting antibodies across multiple orthohantavirus species due to conserved epitopes on the N protein [19, 50]. Cross-reactivity among rodent-borne and bat-borne hantaviruses has been observed, necessitating careful assay validation for specific host-virus combinations [19, 20].

Indirect immunofluorescence assays and western blotting serve as confirmatory methods [50]. External quality assessment programs for orthohantavirus serology in Europe have demonstrated variable performance among laboratories, emphasizing the need for standardized protocols [50].

Molecular Detection

Reverse transcription polymerase chain reaction (RT-PCR) targeting conserved regions of the L or S segment is the primary molecular tool for hantavirus detection in rodent tissues [21, 22, 4, 70]. Real-time RT-PCR with specific probes allows quantification of viral RNA loads in various organs [12, 75]. Nested RT-PCR enhances sensitivity for samples with low viral burden [47]. High-fidelity nanopore sequencing has been employed for full-genome characterization of HTNV from field-collected rodents, enabling phylogeographic analysis without prior virus isolation [4].

A novel molecular detection tool using duplex RT-PCR with an internal control has been validated for SNV surveillance in wild-caught rodents, improving diagnostic accuracy [82]. Generic pan-hantavirus primers targeting the L segment allow detection of divergent viruses, including those discovered in shrews and moles [23, 61].

Virus Isolation

Virus isolation from rodent tissues, while technically challenging, remains the gold standard for definitive identification and phenotypic characterization [83]. Isolation success rates vary by virus-host combination and tissue tropism. SEOV has been isolated from multiple organs of Rattus norvegicus, including lung, kidney, and liver, with highest viral RNA loads in kidney [12]. Isolation data improve host predictions for New World rodent orthohantaviruses and inform reservoir competence assessments [83].

Surveillance and One Health Implications

Rodent Surveillance Networks

Systematic rodent surveillance is a cornerstone of One Health approaches to hantavirus risk assessment [35, 58, 78]. Longitudinal monitoring of rodent populations for seroprevalence and viral RNA prevalence provides early warning signals for potential human spillover [58, 59]. In Panama, twenty years of epidemiological surveillance in Oligoryzomys costaricensis have documented stable Choclo orthohantavirus circulation with periodic increases in prevalence correlating with human case clusters [58]. Similarly, monitoring of Apodemus agrarius in the Republic of Korea over two decades has demonstrated the role of rodent density and environmental factors in HTNV transmission risk [9].

Surveillance efforts in urban environments, particularly among Rattus norvegicus, have revealed high seroprevalence rates and co-circulation of SEOV with other zoonotic pathogens such as Leptospira and Bartonella [24, 25, 42, 46, 78]. Rats in markets and seaports serve as important sentinels for virus introduction and spread [67, 72, 86]. The relationship between urban green space and increased rat-borne zoonotic disease hazard underscores the need for integrated rodent management [56].

Coinfection Ecology

Orthohantavirus infections in rodents do not occur in isolation. Coinfection with viral, bacterial, and parasitic agents is common and can modulate infection outcomes and transmission dynamics. SEOV and Leptospira spp. coinfections have been documented in rats from Indonesian markets [24] and in Chinese reservoir regions [42]. PUUV coinfection with endoparasites influences viral tropism and tissue-specific viral loads in bank voles [65]. Coinfection with hantavirus and severe fever with thrombocytopenia syndrome virus has been reported in humans, but such dual infections in rodents remain poorly characterized [26]. The gut microbiota of bank voles is also affected by coinfection status, suggesting complex interactions between systemic pathogens and the intestinal microbiome [68].

One Health Framework

The One Health perspective recognizes the interconnectedness of human, animal, and environmental health. For hantaviruses, this framework encompasses rodent population ecology, landscape epidemiology, climate change impacts, and the potential for companion animal exposure [63, 84]. Domestic rats and pet rats have been implicated as sources of SEOV infection in humans, indicating that veterinary professionals should be aware of hantavirus risks in urban and peri-domestic settings [66, 37]. Occupational exposure among feeder rodent breeding farm workers has been documented, highlighting the need for biosecurity measures [37].

Bats and shrews also harbor divergent hantaviruses, and serological evidence suggests possible cross-species exposure in neotropical bats [19, 69]. However, the role of non-rodent hosts in the maintenance and transmission of orthohantaviruses remains to be fully elucidated [20, 27, 69].

Computational Modeling and Spatial Epidemiology

Species distribution models and ecological niche modeling have been applied to predict the geographic range of hantavirus reservoirs and to forecast spillover risk. For Oligoryzomys flavescens, a host of Lechiguanas virus in South America, models incorporating environmental variables have identified areas of high reservoir abundance and infection prevalence [62, 77]. Bayesian spatiotemporal models have been used to analyze HFRS outbreaks in China, linking rodent abundance and climatic data to human case distributions [76].

Phylogeographic analyses based on complete genomic sequencing reveal transmission pathways and the geographic structuring of viral lineages. For example, SNV sequences from northwestern United States cluster by region, reflecting limited dispersal of infected rodents [10]. In Europe, PUUV genome variants correlate with regional landscapes and habitat fragmentation [89]. These computational approaches are essential for predicting emergence and informing surveillance priorities.

The following Mermaid diagram summarizes the integrated One Health surveillance workflow for hantaviruses in rodents:

flowchart TD
    A[Rodent Trapping & Sampling], > B[Serology: ELISA / IFA]
    A, > C[Molecular Detection: RT-PCR / qRT-PCR]
    B, > D{Antibody Positive?}
    C, > E{RNA Positive?}
    D, >|Yes| F[Confirmatory Western Blot]
    E, >|Yes| G[Sequencing & Phylogenetics]
    F, > H[Seroprevalence Estimation]
    G, > I[Genotype Assignment]
    H, > J[Risk Assessment & Modeling]
    I, > J
    J, > K[One Health Intervention: Rodent Control, Biosecurity, Public Awareness]

Key Rodent Hosts and Associated Orthohantaviruses

The following table summarizes major orthohantavirus species, their principal rodent reservoirs, and geographic distribution, based on published literature [21, 10, 7, 28, 8, 29, 5, 30, 39, 41, 45, 51, 57, 70, 74, 86, 89].

Conclusions

Hantaviruses in rodents represent a paradigm of persistent, emerging zoonotic pathogens that require integrated veterinary, ecological, and computational approaches for effective management. The coevolutionary relationship between virus and reservoir host, combined with environmental and anthropogenic drivers, dictates the dynamics of transmission and the risk of spillover. Veterinary professionals are uniquely positioned to contribute to surveillance through sampling of urban and peri-domestic rodent populations, diagnostic testing of companion rodents, and participation in One Health networks. Advances in molecular diagnostics, including high-throughput sequencing and generic detection assays, continue to expand the known diversity of orthohantaviruses and their hosts. Continued research on host genetics, coinfection ecology, and predictive modeling will refine risk assessment and enable proactive intervention strategies.

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