Comparison of transcriptional responses between pathogenic and nonpathogenic hantavirus infections in Syrian hamsters using NanoString.

BACKGROUND: Syrian hamsters infected with Andes virus (ANDV) develop a disease that recapitulates many of the salient features of human hantavirus pulmonary syndrome (HPS), including lethality. Infection of hamsters with Hantaan virus (HTNV) results in an asymptomatic, disseminated infection. In order to explore this dichotomy, we examined the transcriptome of ANDV- and HTNV-infected hamsters. RESULTS: Using NanoString technology, we examined kinetic transcriptional responses in whole blood collected from ANDV- and HTNV-infected hamsters. Of the 770 genes analyzed, key differences were noted in the kinetics of type I interferon sensing and signaling responses, complement activation, and apoptosis pathways between ANDV- and HTNV-infected hamsters. CONCLUSIONS: Delayed activation of type I interferon responses in ANDV-infected hamsters represents a potential mechanism that ANDV uses to subvert host immune responses and enhance disease. This is the first genome-wide analysis of hantavirus-infected hamsters and provides insight into potential avenues for therapeutics to hantavirus disease.

MAIT cell activation is associated with disease severity markers in acute hantavirus infection.

Hantaviruses are zoonotic RNA viruses that cause severe acute disease in humans. Infected individuals have strong inflammatory responses that likely cause immunopathology. Here, we studied the response of mucosal-associated invariant T (MAIT) cells in peripheral blood of individuals with hemorrhagic fever with renal syndrome (HFRS) caused by Puumala orthohantavirus, a hantavirus endemic in Europe. We show that MAIT cell levels decrease in the blood during HFRS and that residual MAIT cells are highly activated. This activation correlates with HFRS severity markers. In vitro activation of MAIT cells by hantavirus-exposed antigen-presenting cells is dependent on type I interferons (IFNs) and independent of interleukin-18 (IL-18). These findings highlight the role of type I IFNs in virus-driven MAIT cell activation and suggest a potential role of MAIT cells in the disease pathogenesis of viral infections.

Hantavirus infection in type I interferon receptor-deficient (A129) mice.

Type I interferon receptor knockout mice (strain A129) were assessed as a disease model of hantavirus infection. A range of infection routes (intramuscular, intraperitoneal and intranasal) were assessed using minimally passaged Seoul virus (strain Humber). Dissemination of virus to the spleen, kidney and lung was observed at 5 days after intramuscular and intraperitoneal challenge, which was resolved by day 14. In contrast, intranasal challenge of A129 mice demonstrated virus tropism to the lung, which was maintained to day 14 post-challenge. These data support the use of the A129 mouse model for future infection studies and the in vivo evaluation of interventions.

Hantavirus Inhibits TRAIL-Mediated Killing of Infected Cells by Downregulating Death Receptor 5.

Cytotoxic lymphocytes normally kill virus-infected cells by apoptosis induction. Cytotoxic granule-dependent apoptosis induction engages the intrinsic apoptosis pathway, whereas death receptor (DR)-dependent apoptosis triggers the extrinsic apoptosis pathway. Hantaviruses, single-stranded RNA viruses of the order Bunyavirales, induce strong cytotoxic lymphocyte responses in infected humans. Cytotoxic lymphocytes, however, are largely incapable of eradicating hantavirus-infected cells. Here, we show that the prototypic hantavirus, Hantaan virus (HTNV), induces TRAIL production but strongly inhibits TRAIL-mediated extrinsic apoptosis induction in infected cells by downregulating DR5 cell surface expression. Mechanistic analyses revealed that HTNV triggers both 26S proteasome-dependent degradation of DR5 through direct ubiquitination of DR5 and hampers DR5 transport to the cell surface. These results corroborate earlier findings, demonstrating that hantavirus also inhibits cytotoxic cell granule-dependent apoptosis induction. Together, these findings show that HTNV counteracts intrinsic and extrinsic apoptosis induction pathways, providing a defense mechanism utilized by hantaviruses to inhibit cytotoxic cell-mediated eradication of infected cells.

Revisiting the genetic diversity of emerging hantaviruses circulating in Europe using a pan-viral resequencing microarray.

Hantaviruses are zoonotic agents transmitted from small mammals, mainly rodents, to humans, where they provoke diseases such as Hemorrhagic fever with Renal Syndrome (HFRS) and its mild form, Nephropathia Epidemica (NE), or Hantavirus Cardio-Pulmonary Syndrome (HCPS). Hantaviruses are spread worldwide and monitoring animal reservoirs is of primary importance to control the zoonotic risk. Here, we describe the development of a pan-viral resequencing microarray (PathogenID v3.0) able to explore the genetic diversity of rodent-borne hantaviruses endemic in Europe. Among about 800 sequences tiled on the microarray, 52 correspond to a tight molecular sieve of hantavirus probes covering a large genetic landscape. RNAs from infected animal tissues or from laboratory strains have been reverse transcribed, amplified, then hybridized to the microarray. A classical BLASTN analysis applied to the sequence delivered through the microarray allows to identify the hantavirus species up to the exact geographical variant present in the tested samples. Geographical variants of the most common European hantaviruses from France, Germany, Slovenia and Finland, such as Puumala virus, Dobrava virus and Tula virus, were genetically discriminated. Furthermore, we precisely characterized geographical variants still unknown when the chip was conceived, such as Seoul virus isolates, recently emerged in France and the United Kingdom.

Hantavirus infections.

Over the past few decades understanding and recognition of hantavirus infection has greatly improved worldwide, but both the amplitude and the magnitude of hantavirus outbreaks have been increasing. Several novel hantaviruses with unknown pathogenic potential have been identified in a variety of insectivore hosts. With the new hosts, new geographical distributions of hantaviruses have also been discovered and several new species were found in Africa. Hantavirus infection in humans can result in two clinical syndromes: haemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS) caused by Old World and New World hantaviruses, respectively. The clinical presentation of HFRS varies from subclinical, mild, and moderate to severe, depending in part on the causative agent of the disease. In general, HFRS caused by Hantaan virus, Amur virus and Dobrava virus are more severe with mortality rates from 5 to 15%, whereas Seoul virus causes moderate and Puumala virus and Saaremaa virus cause mild forms of disease with mortality rates <1%. The central phenomena behind the pathogenesis of both HFRS and HCPS are increased vascular permeability and acute thrombocytopenia. The pathogenesis is likely to be a complex multifactorial process that includes contributions from immune responses, platelet dysfunction and the deregulation of endothelial cell barrier functions. Also a genetic predisposition, related to HLA type, seems to be important for the severity of the disease. As there is no effective treatment or vaccine approved for use in the USA and Europe, public awareness and precautionary measures are the only ways to minimize the risk of hantavirus disease.

Motility of human renal cells is disturbed by infection with pathogenic hantaviruses.

BACKGROUND: Hemorrhagic fever with renal syndrome (HFRS) caused by pathogenic hantaviruses in Europe and Asia is often characterized by acute kidney injury (AKI) with massive proteinuria. Renal filtration depends on the integrity of epithelial and endothelial monolayers in the tubular and glomerular apparatus. Tubular and glomerular cells represent target cells of hantavirus infection. However, the detailed mechanisms of renal impairment induced by hantaviruses are not well understood. METHODS: We analyzed the cellular consequences of hantavirus infection by measuring adhesion and migration capacity of human renal cells infected with Puumala (PUUV) or Hantaan (HTNV) virus. The impact of hantaviral nucleocapsid proteins (N proteins) on motility was examined by transfection of podocytes. RESULTS: Infection of kidney cells with hantavirus species PUUV and HTNV causes a significant reduction of migration capacity. The impaired motility depends on viral replication and transfection of podocytes with N protein of PUUV or HTNV reveals that the expression of N protein alone is sufficient to deteriorate podocyte function. The cellular effects are more pronounced for the more pathogenic HTNV than for PUUV that causes a milder form of HFRS. CONCLUSIONS: The direct impairment of migration capacity of renal cells by hantaviral N proteins may contribute substantially to proteinuria observed in the clinical picture of hantavirus infection.

Upregulation of P2Y2R, Active uPA, and PAI-1 Are Essential Components of Hantavirus Cardiopulmonary Syndrome.

Sin Nombre virus (SNV) causes hantavirus cardiopulmonary pulmonary syndrome (HCPS) with the loss of pulmonary vascular endothelial integrity, and pulmonary edema without causing cytopathic effects on the vascular endothelium. HCPS is associated primarily with a dysregulated immune response. We previously found occult signs of hemostatic imbalance in the form of a sharp >30-100 fold increase in the expression of plasminogen activator inhibitor type 1 (PAI-1), in serial blood plasma draws of terminal stage-patients. However, the mechanism of the increase in PAI-1 remains unclear. PAI-1 is a primary inhibitor of fibrinolysis caused by tissue plasminogen activator (tPA) and urokinase plasminogen activator plasma (uPA). Here, we investigate factors that contribute to PAI-1 upregulation during HCPS. Using zymography, we found evidence of PAI-1-refractory uPA activity and no tPA activity in plasma samples drawn from HCPS patients. The sole prevalence of uPA activity suggested that severe inflammation drove PAI-1 activity. We have recently reported that the P2Y2 receptor (P2Y2R) mediates SNV infectivity by interacting in cis with ß3 integrins, which activates the latter during infection. P2Y2R is a known effector for several biological processes relevant to HCPS pathogenesis, such as upregulation of tissue factor (TF), a primary initiator of the coagulation cascade, stimulating vascular permeability and leukocyte homing to sites of infection. As P2Y2R is prone to upregulation under conditions of inflammation, we compared the expression level of P2Y2R in formalin fixed tissues of HCPS decedents using a TaqMan assay and immunohistochemistry. Our TaqMan results show that the expression of P2Y2R is upregulated significantly in HCPS cases compared to non- HCPS controls (P < 0.001). Immunohistochemistry showed that lung macrophages were the primary reservoir of high and coincident localization of P2Y2R, uPA, PAI-1, and TF antigens. We also observed increased staining for SNV antigens in the same tissue segments where P2Y2R expression was upregulated. Conversely, sections of low P2Y2R expression showed weak manifestations of macrophages, SNV, PAI-1, and TF. Coincident localization of P2Y2R and PAI-1 on macrophage deposits suggests an inflammation-dependent mechanism of increasing pro-coagulant activity in HCPS in the absence of tissue injury.

Severe hantavirus disease in children.

BACKGROUND: Very recently, a novel European hantavirus, Sochi virus, has been discovered which causes severe courses of hantavirus disease with a case fatality rate of about 15 percent. OBJECTIVES: We aimed to study to which extent and with which clinical severity children were affected by Sochi virus infection. STUDY DESIGN: Sochi virus infection of patients was confirmed by molecular, serological, and epizoonotic studies. Clinical and laboratory parameters were analyzed for the age group of up to 15 years (n = 6) in comparison to all older patients (n = 56). RESULTS: 9.7 percent of patients with hantavirus disease studied (6/62) were up to 15 years old. The children showed moderate to severe clinical courses similarly to the situation in adults. CONCLUSIONS: While children are in general considered to be less affected by hantavirus infections than adults, in case of highly pathogenic hantaviruses, such as Sochi virus, frequency of clinical cases as well as their clinical course are comparable between children and adults. Therefore, hantavirus disease, particularly in regions endemic to highly pathogenic hantaviruses, should be considered in cases of unclear fever and kidney/pulmonary failure in children.

Hantavirus Gc induces long-term immune protection via LAMP-targeting DNA vaccine strategy.

Hemorrhagic fever with renal syndrome (HFRS) occurs widely throughout Eurasia. Unfortunately, there is no effective treatment, and prophylaxis remains the best option against the major pathogenic agent, hantaan virus (HTNV), which is an Old World hantavirus. However, the absence of cellular immune responses and immunological memory hampers acceptance of the current inactivated HFRS vaccine. Previous studies revealed that a lysosome-associated membrane protein 1 (LAMP1)-targeting strategy involving a DNA vaccine based on the HTNV glycoprotein Gn successfully conferred long-term immunity, and indicated that further research on Gc, another HTNV antigen, was warranted. Plasmids encoding Gc and lysosome-targeted Gc, designated pVAX-Gc and pVAX-LAMP/Gc, respectively, were constructed. Proteins of interest were identified by fluorescence microscopy following cell line transfection. Five groups of 20 female BALB/c mice were subjected to the following inoculations: inactivated HTNV vaccine, pVAX-LAMP/Gc, pVAX-Gc, and, as the negative controls, pVAX-LAMP or the blank vector pVAX1. Humoral and cellular immunity were assessed by enzyme-linked immunosorbent assays (ELISAs) and 15-mer peptide enzyme-linked immunospot (ELISpot) epitope mapping assays. Repeated immunization with pVAX-LAMP/Gc enhanced adaptive immune responses, as demonstrated by the specific and neutralizing antibody titers and increased IFN-γ production. The inactivated vaccine induced a comparable humoral reaction, but the negative controls only elicited insignificant responses. Using a mouse model of HTNV challenge, the in vivo protection conferred by the inactivated vaccine and Gc-based constructs (with/without LAMP recombination) was confirmed. Evidence of pan-epitope reactions highlighted the long-term cellular response to the LAMP-targeting strategy, and histological observations indicated the safety of the LAMP-targeting vaccines. The long-term protective immune responses induced by pVAX-LAMP/Gc may be due to the advantage afforded by lysosomal targeting after exogenous antigen processing initiation and major histocompatibility complex (MHC) class II antigen presentation trafficking. MHC II-restricted antigen recognition effectively primes HTNV-specific CD4+ T-cells, leading to the promotion of significant immune responses and immunological memory. An epitope-spreading phenomenon was observed, which mirrors the previous result from the Gn study, in which the dominant IFN-γ-responsive hot-spot epitopes were shared between HLA-II and H2d. Importantly, the pan-epitope reaction to Gc indicated that Gc should be with potential for use in further hantavirus DNA vaccine investigations.

Hantavirus and tuberculosis co-infection in an Indian child.

Hantaviruses are a group of antigenically distinct viruses carried out in rodents and insectivores. Humans are accidental hosts and get infected by aerosols generated from contaminated urine, faeces and saliva of infected rodents. Hantaviruses are identified as aetiological agents of two human diseases, haemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. Hantavirus causing pulmonary renal disease has rarely been reported in children in India. Hantavirus infection is uncommon under the age of 12 years. We report a 9-year-old girl from Mumbai, India with fever, bilateral pleural effusion, thrombocytopaenia, haemoconcentration and oliguria due to hantavirus infection. She also had associated tuberculosis.

Clinical and virological characteristics of hantavirus infections in a 2014 Croatian outbreak.

INTRODUCTION: Croatia is endemic for hemorrhagic fever with renal syndrome (HFRS), with both Puumala (PUUV) and Dobrava virus (DOBV) documented. Several large outbreaks were recorded in 1995, 2002, and 2012. We analyzed demographic, clinical, laboratory, and virological characteristics of HFRS cases detected in three geographically close natural foci (Ogulin, Slunj, and the Plitvice Lakes surroundings) during the 2014 outbreak. METHODOLOGY: From January to December 2014, 122 patients with suspected HFRS were tested for hantavirus IgM/IgG antibodies using an indirect immunofluorescence assay (IFA). Cross-reactive samples were further tested using a western blot (WB). For hospitalized patients from Ogulin area, clinical and laboratory data were analyzed. RESULTS: Acute infection was documented in 57 (46.7%) patients, of whom 75.4% were hospitalized. Ten (8.2%) patients were found to be IgG seropositive. Patients were 15-69 years of age and predominantly male (74.5%). The outbreak started in winter months, with most cases recorded from May to July (80.7%). The most frequently reported symptoms were fever (96.3%), chills/shivering (62.9%), and lumbar pain (48.1%). Mild clinical form was found in 66.7% patients, moderate in 18.5%, and severe in 14.8% patients (all but one infected with PUUV). One patient died. Using IFA, 48.8% patients showed monotypic antibody response, while in 51.2%, cross-reactive antibodies were found. PUUV was confirmed in 94.7% and DOBV in 5.3% HFRS cases by WB. CONCLUSIONS: Central mountainous Croatian regions are still highly endemic areas for HFRS. A higher percentage of severe PUUV infections could be at least partly associated with a patient's immune status.

Maporal Hantavirus Causes Mild Pathology in Deer Mice (Peromyscus maniculatus).

Rodent-borne hantaviruses can cause two human diseases with many pathological similarities: hantavirus cardiopulmonary syndrome (HCPS) in the western hemisphere and hemorrhagic fever with renal syndrome in the eastern hemisphere. Each virus is hosted by specific reservoir species without conspicuous disease. HCPS-causing hantaviruses require animal biosafety level-4 (ABSL-4) containment, which substantially limits experimental research of interactions between the viruses and their reservoir hosts. Maporal virus (MAPV) is a South American hantavirus not known to cause disease in humans, thus it can be manipulated under ABSL-3 conditions. The aim of this study was to develop an ABSL-3 hantavirus infection model using the deer mouse (Peromyscus maniculatus), the natural reservoir host of Sin Nombre virus (SNV), and a virus that is pathogenic in another animal model to examine immune response of a reservoir host species. Deer mice were inoculated with MAPV, and viral RNA was detected in several organs of all deer mice during the 56 day experiment. Infected animals generated both nucleocapsid-specific and neutralizing antibodies. Histopathological lesions were minimal to mild with the peak of the lesions detected at 7-14 days postinfection, mainly in the lungs, heart, and liver. Low to modest levels of cytokine gene expression were detected in spleens and lungs of infected deer mice, and deer mouse primary pulmonary cells generated with endothelial cell growth factors were susceptible to MAPV with viral RNA accumulating in the cellular fraction compared to infected Vero cells. Most features resembled that of SNV infection of deer mice, suggesting this model may be an ABSL-3 surrogate for studying the host response of a New World hantavirus reservoir.

What Do We Know about How Hantaviruses Interact with Their Different Hosts?

Hantaviruses, like other members of the Bunyaviridae family, are emerging viruses that are able to cause hemorrhagic fevers. Occasional transmission to humans is due to inhalation of contaminated aerosolized excreta from infected rodents. Hantaviruses are asymptomatic in their rodent or insectivore natural hosts with which they have co-evolved for millions of years. In contrast, hantaviruses cause different pathologies in humans with varying mortality rates, depending on the hantavirus species and its geographic origin. Cases of hemorrhagic fever with renal syndrome (HFRS) have been reported in Europe and Asia, while hantavirus cardiopulmonary syndromes (HCPS) are observed in the Americas. In some cases, diseases caused by Old World hantaviruses exhibit HCPS-like symptoms. Although the etiologic agents of HFRS were identified in the early 1980s, the way hantaviruses interact with their different hosts still remains elusive. What are the entry receptors? How do hantaviruses propagate in the organism and how do they cope with the immune system? This review summarizes recent data documenting interactions established by pathogenic and nonpathogenic hantaviruses with their natural or human hosts that could highlight their different outcomes.

Depletion of Alveolar Macrophages Does Not Prevent Hantavirus Disease Pathogenesis in Golden Syrian Hamsters.

UNLABELLED: Andes virus (ANDV) is associated with a lethal vascular leak syndrome in humans termed hantavirus pulmonary syndrome (HPS). The mechanism for the massive vascular leakage associated with HPS is poorly understood; however, dysregulation of components of the immune response is often suggested as a possible cause. Alveolar macrophages are found in the alveoli of the lung and represent the first line of defense to many airborne pathogens. To determine whether alveolar macrophages play a role in HPS pathogenesis, alveolar macrophages were depleted in an adult rodent model of HPS that closely resembles human HPS. Syrian hamsters were treated, intratracheally, with clodronate-encapsulated liposomes or control liposomes and were then challenged with ANDV. Treatment with clodronate-encapsulated liposomes resulted in significant reduction in alveolar macrophages, but depletion did not prevent pathogenesis or prolong disease. Depletion also did not significantly reduce the amount of virus in the lung of ANDV-infected hamsters but altered neutrophil recruitment, MIP-1α and MIP-2 chemokine expression, and vascular endothelial growth factor (VEGF) levels in hamster bronchoalveolar lavage (BAL) fluid early after intranasal challenge. These data demonstrate that alveolar macrophages may play a limited protective role early after exposure to aerosolized ANDV but do not directly contribute to hantavirus disease pathogenesis in the hamster model of HPS. IMPORTANCE: Hantaviruses continue to cause disease worldwide for which there are no FDA-licensed vaccines, effective postexposure prophylactics, or therapeutics. Much of this can be attributed to a poor understanding of the mechanism of hantavirus disease pathogenesis. Hantavirus disease has long been considered an immune-mediated disease; however, by directly manipulating the Syrian hamster model, we continue to eliminate individual immune cell types. As the most numerous immune cells present in the respiratory tract, alveolar macrophages are poised to defend against hantavirus infection, but those antiviral responses may also contribute to hantavirus disease. Here, we demonstrate that, like in our prior T and B cell studies, alveolar macrophages neither prevent hantavirus infection nor cause hantavirus disease. While these studies reflect pathogenesis in the hamster model, they should help us rule out specific cell types and prompt us to consider other potential mechanisms of disease in an effort to improve the outcome of human HPS.

Andes Hantavirus-Infection of a 3D Human Lung Tissue Model Reveals a Late Peak in Progeny Virus Production Followed by Increased Levels of Proinflammatory Cytokines and VEGF-A.

Andes virus (ANDV) causes hantavirus pulmonary syndrome (HPS), a severe acute disease with a 40% case fatality rate. Humans are infected via inhalation, and the lungs are severely affected during HPS, but little is known regarding the effects of ANDV-infection of the lung. Using a 3-dimensional air-exposed organotypic human lung tissue model, we analyzed progeny virus production and cytokine-responses after ANDV-infection. After a 7-10 day period of low progeny virus production, a sudden peak in progeny virus levels was observed during approximately one week. This peak in ANDV-production coincided in time with activation of innate immune responses, as shown by induction of type I and III interferons and ISG56. After the peak in ANDV production a low, but stable, level of ANDV progeny was observed until 39 days after infection. Compared to uninfected models, ANDV caused long-term elevated levels of eotaxin-1, IL-6, IL-8, IP-10, and VEGF-A that peaked 20-25 days after infection, i.e., after the observed peak in progeny virus production. Notably, eotaxin-1 was only detected in supernatants from infected models. In conclusion, these findings suggest that ANDV replication in lung tissue elicits a late proinflammatory immune response with possible long-term effects on the local lung cytokine milieu. The change from an innate to a proinflammatory response might be important for the transition from initial asymptomatic infection to severe clinical disease, HPS.

Isolation and partial characterization of a highly divergent lineage of hantavirus from the European mole (Talpa europaea).

Genetically distinct hantaviruses have been identified in five species of fossorial moles (order Eulipotyphla, family Talpidae) from Eurasia and North America. Here, we report the isolation and partial characterization of a highly divergent hantavirus, named Nova virus (NVAV), from lung tissue of a European mole (Talpa europaea), captured in central Poland in August 2013. Typical hantavirus-like particles, measuring 80-120 nm in diameter, were found in NVAV-infected Vero E6 cells by transmission electron microscopy. Whole-genome sequences of the isolate, designated NVAV strain Te34, were identical to that amplified from the original lung tissue, and phylogenetic analysis of the full-length L, M and S segments, using maximum-likelihood and Bayesian methods, showed that NVAV was most closely related to hantaviruses harbored by insectivorous bats, consistent with an ancient evolutionary origin. Infant Swiss Webster mice, inoculated with NVAV by the intraperitoneal route, developed weight loss and hyperactivity, beginning at 16 days, followed by hind-limb paralysis and death. High NVAV RNA copies were detected in lung, liver, kidney, spleen and brain by quantitative real-time RT-PCR. Neuropathological examination showed astrocytic and microglial activation and neuronal loss. The first mole-borne hantavirus isolate will facilitate long-overdue studies on its infectivity and pathogenic potential in humans.

[Pathomorphism of Hantavirus infection under prolonged heat stress]. / Patomorfoz khantavirusnoi infektsii na fone prolongirovannogo teplovogo stressa.

AIM: to provide the morphological characteristics of experimental Hantavirus infection under heat stress conditions to identify the possibilities of its modeling in resistant laboratory animals. MATERIAL AND METHODS: Experiments were carried out on outbred albino mice that were divided into 4 groups: 1) intact mice unexposed to heating; 2) those exposed to heating; 3) Hantavirus-infected animals unexposed to preheating; 4) those exposed to preheating. The animals in Groups 2-4 were long exposed to heat stress at a temperature of 30 °C for 3 hours during 3 days. Strain Aa 60343 (PM-79-95) of the Far East genovariant of Hantaan virus (the genus Hantavirus, family Bunyaviridae) from the collection of the G.P. Somov Research Institute of Epidemiology and Microbiology was used to induce infection. The animals in Groups 3 and 4 were intraperitoneally injected with 700 FFU of Hantavirus per mouse. Materials (lung, liver, kidney, and spleen) taken from Groups 2-4 animals were collected for histological examination on days 1, 3, 7 and 14 of observation. RESULTS: The intact albino mice in Group 1 showed no histopathological changes in the organs. After heat exposure, Group 2 animals were found to have an immunomorphological response in the interstitial tissues of the lung, liver and kidney in partial lymphoid hypoplasia of the spleen. There were no signs of inapparent infection in the presence of marked immunomorphological changes in the organs in Group 3 of hantavirus-infected animals unexposed to preheating. In Group 4, those exposed to preheating exhibited dystrophic and destructive changes in the target organs (lungs, kidneys) in the presence of immunodeficiency manifestations of manifestations that were more pronounced in dead animals. CONCLUSION: In an unresponsive model (adult albino mice), Hantavirus infection caused only obvious immunomorphological changes in the organs. Prolonged preheat stress in the hantavirus-infected animals promoted inapparent infection and morphological manifestations of induced secondary immunodeficiency that was responsible for the manifestation of an infectious process in some animals.

Association of Single-Nucleotide Polymorphisms in IL28B, but Not TNF-α, With Severity of Disease Caused by Andes Virus.

BACKGROUND: Andes virus (ANDV) is the sole etiologic agent of hantavirus cardiopulmonary syndrome (HCPS) in Chile, with a fatality rate of about 35%. Individual host factors affecting ANDV infection outcome are poorly understood. In this case-control genetic association analysis, we explored the link between single-nucleotide polymorphisms (SNPs) rs12979860, rs8099917 and rs1800629 and the clinical outcome of ANDV-induced disease. The SNPs rs12979860 and rs8099917 are known to play a role in the differential expression of the interleukin 28B gene (IL28B), whereas SNP rs1800629 is implicated in the expression of tumor necrosis factor α gene (TNF-α). METHODS: A total of 238 samples from confirmed ANDV-infected patients collected between 2006 and 2014, and categorized according to the severity of the disease, were genotyped for SNPs rs12979860, rs8099917, and rs1800629. RESULTS: Analysis of IL28B SNPs rs12979860 and rs8099917 revealed a link between homozygosity of the minor alleles (TT and GG, respectively), displaying a mild disease progression, whereas heterozygosity or homozygosity for the major alleles (CT/CC and TG/TT, respectively) in both IL28B SNPs is associated with severe disease. No association with the clinical outcome of HCPS was observed for TNF-α SNP rs1800629 (TNF -308G>A). CONCLUSIONS: The IL28B SNPs rs12979860 and rs8099917, but not TNF-α SNP rs1800629, are associated with the clinical outcome of ANDV-induced disease, suggesting a possible link between IL28B expression and ANDV pathogenesis.

Animal Models for the Study of Rodent-Borne Hemorrhagic Fever Viruses: Arenaviruses and Hantaviruses.

Human pathogenic hantaviruses and arenaviruses are maintained in nature by persistent infection of rodent carrier populations. Several members of these virus groups can cause significant disease in humans that is generically termed viral hemorrhagic fever (HF) and is characterized as a febrile illness with an increased propensity to cause acute inflammation. Human interaction with rodent carrier populations leads to infection. Arenaviruses are also viewed as potential biological weapons threat agents. There is an increased interest in studying these viruses in animal models to gain a deeper understating not only of viral pathogenesis, but also for the evaluation of medical countermeasures (MCM) to mitigate disease threats. In this review, we examine current knowledge regarding animal models employed in the study of these viruses. We include analysis of infection models in natural reservoirs and also discuss the impact of strain heterogeneity on the susceptibility of animals to infection. This information should provide a comprehensive reference for those interested in the study of arenaviruses and hantaviruses not only for MCM development but also in the study of viral pathogenesis and the biology of these viruses in their natural reservoirs.