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Key Points Hantaviruses are negative-sense single-stranded RNA viruses that infect many species of rodents, shrews, moles and bats. Hantaviruses primarily replicate in the endothelium and might use integrins to enter cells. Following entry, the virus synthesizes viral mRNA to produce viral proteins and replicate the genome (comprising small, medium and large segments), although the exact details of these processes remain unclear. The viral genome is encapsided by nucleocapsid protein to form ribonucleoproteins, which interact with viral glycoprotein to form virus particles. The three segments of viral RNA encode nucleocapsid protein, glycoprotein and RNA-dependent RNA polymerase. Infection of reservoir hosts is asymptomatic, possibly owing to immunosuppression. Infection of humans causes either haemorrhagic fever with renal syndrome or hantavirus cardiopulmonary syndrome. Disease pathology is characterized by increased permeability of the endothelial cells lining capillaries and is also thought to be mediated by enhanced immune responses, such as increased production of cytokines and expansion of cytotoxic T cells. Vaheri and colleagues discuss the molecular and cell biology of hantavirus infection and provide an overview of the virus-induced and immune-mediated pathology caused by this virus family in humans. Hantaviruses are negative-sense single-stranded RNA viruses that infect many species of rodents, shrews, moles and bats. Infection in these reservoir hosts is almost asymptomatic, but some rodent-borne hantaviruses also infect humans, causing either haemorrhagic fever with renal syndrome (HFRS) or hantavirus cardiopulmonary syndrome (HCPS). In this Review, we discuss the basic molecular properties and cell biology of hantaviruses and offer an overview of virus-induced pathology, in particular vascular leakage and immunopathology.

The zoonotic transmission of hantaviruses from their rodent hosts to humans in North and South America is associated with a severe and frequently fatal respiratory disease, hantavirus pulmonary syndrome (HPS) 1 , 2 . No specific antiviral treatments for HPS are available, and no molecular determinants of in vivo susceptibility to hantavirus infection and HPS are known. Here we identify the human asthma-associated gene protocadherin-1 ( PCDH1 ) 3 – 6 as an essential determinant of entry and infection in pulmonary endothelial cells by two hantaviruses that cause HPS, Andes virus (ANDV) and Sin Nombre virus (SNV). In vitro, we show that the surface glycoproteins of ANDV and SNV directly recognize the outermost extracellular repeat domain of PCDH1—a member of the cadherin superfamily 7 , 8 —to exploit PCDH1 for entry. In vivo, genetic ablation of PCDH1 renders Syrian golden hamsters highly resistant to a usually lethal ANDV challenge. Targeting PCDH1 could provide strategies to reduce infection and disease caused by New World hantaviruses. New World hantaviruses—which cause a severe human respiratory disease—use surface glycoproteins to bind to the human protocadherin-1 protein and enter endothelial cells in vitro; depleting protocadherin-1 in Syrian golden hamsters largely protects against disease.

Dobrava-Belgrade virus (DOBV) is a human pathogen that has evolved in, and is hosted by, mice of several species of the genus Apodemus . We propose a subdivision of the species Dobrava-Belgrade virus into four related genotypes – Dobrava, Kurkino, Saaremaa, and Sochi – that show characteristic differences in their phylogeny, specific host reservoirs, geographical distribution, and pathogenicity for humans.

Abstract Background Hantavirus pulmonary syndrome (HPS) is caused by Andes virus (ANDV) and related hantaviruses in the Americas. Despite a fatality rate of 40%, the pathogenesis of HPS is poorly understood and factors associated with severity, fatality, and survival remain elusive. Methods Ninety-three ANDV-infected HPS patients, of whom 34 had a fatal outcome, were retrospectively studied. Serum levels of cytokines and other inflammation-associated markers were analyzed using multiplex immunoassay and enzyme-linked immunosorbent assay. Associations with disease severity, fatal outcome, and survival were identified using logistic regression. Results HPS patients exhibited increased serum levels of markers associated with inflammation, intestinal damage, and microbial translocation compared to controls. Patients with fatal outcome displayed higher levels of interleukin (IL) 6, IL-10, interferon-γ, soluble tumor necrosis factor-related apoptosis-inducing ligand, and intestinal fatty acid–binding protein (I-FABP) than survivors. Levels of complement factor 5/5a were higher in survivors compared with fatal cases. IL-6 and I-FABP, the latter a marker for intestinal damage, were by multivariate analyses identified as independent markers associated with disease severity (odds ratio [OR], 2.25; 95% confidence interval [CI], 1.01–5.01) and fatal outcome (OR, 1.64; 95% CI, 1.01–2.64), respectively. Conclusions HPS patients displayed a multifaceted, systemic inflammatory response, with IL-6 and I-FABP as independent markers of disease severity and fatality, respectively. Patients with hantavirus pulmonary syndrome exhibited strong inflammatory responses and increased serum levels of markers associated with microbial translocation and intestinal damage. Interleukin 6 and intestinal fatty acid–binding protein were identified as markers independently associated with severe disease and fatal outcome.

Finland has the highest incidence of hantavirus infections globally, with a significant impact on public health. The large coverage of boreal forests and the cyclic dynamics of the dominant forest rodent species, the bank vole Myodes glareolus, explain most of this. We review the relationships between Puumala hantavirus (PUUV), its host rodent, and the hantavirus disease, nephropathia epidemica (NE), in Finland. We describe the history of NE and its diagnostic research in Finland, the seasonal and multiannual cyclic dynamics of PUUV in bank voles impacting human epidemiology, and we compare our northern epidemiological patterns with those in temperate Europe. The long survival of PUUV outside the host and the life-long shedding of PUUV by the bank voles are highlighted. In humans, the infection has unique features in pathobiology but rarely long-term consequences. NE is affected by specific host genetics and risk behavior (smoking), and certain biomarkers can predict the outcome. Unlike many other hantaviruses, PUUV causes a relatively mild disease and is rarely fatal. Reinfections do not exist. Antiviral therapy is complicated by the fact that when symptoms appear, the patient already has a generalized infection. Blocking vascular leakage measures counteracting pathobiology, offer a real therapeutic approach.

The Bunyaviridae comprise a large family of RNA viruses with worldwide distribution and includes the pathogenic New World hantavirus, Andes virus (ANDV). Host factors needed for hantavirus entry remain largely enigmatic and therapeutics are unavailable. To identify cellular requirements for ANDV infection, we performed two parallel genetic screens. Analysis of a large library of insertionally mutagenized human haploid cells and a siRNA genomic screen converged on components (SREBP-2, SCAP, S1P and S2P) of the sterol regulatory pathway as critically important for infection by ANDV. The significance of this pathway was confirmed using functionally deficient cells, TALEN-mediated gene disruption, RNA interference and pharmacologic inhibition. Disruption of sterol regulatory complex function impaired ANDV internalization without affecting virus binding. Pharmacologic manipulation of cholesterol levels demonstrated that ANDV entry is sensitive to changes in cellular cholesterol and raises the possibility that clinically approved regulators of sterol synthesis may prove useful for combating ANDV infection.

The discovery of genetically distinct hantaviruses (family Hantaviridae) in multiple species of shrews, moles and bats has revealed a complex evolutionary history involving cross-species transmission. Seewis virus (SWSV) is widely distributed throughout the geographic ranges of its soricid hosts, including the Eurasian common shrew (Sorex araneus), tundra shrew (Sorex tundrensis) and Siberian large-toothed shrew (Sorex daphaenodon), suggesting host sharing. In addition, genetic variants of SWSV, previously named Artybash virus (ARTV) and Amga virus, have been detected in the Laxmann’s shrew (Sorex caecutiens). Here, we describe the geographic distribution and phylogeny of SWSV and Altai virus (ALTV) in Asian Russia. The complete genomic sequence analysis showed that ALTV, also harbored by the Eurasian common shrew, is a new hantavirus species, distantly related to SWSV. Moreover, Lena River virus (LENV) appears to be a distinct hantavirus species, harbored by Laxmann’s shrews and flat-skulled shrews (Sorex roboratus) in Eastern Siberia and far-eastern Russia. Another ALTV-related virus, which is more closely related to Camp Ripley virus from the United States, has been identified in the Eurasian least shrew (Sorex minutissimus) from far-eastern Russia. Two highly divergent viruses, ALTV and SWSV co-circulate among common shrews in Western Siberia, while LENV and the ARTV variant of SWSV co-circulate among Laxmann’s shrews in Eastern Siberia and far-eastern Russia. ALTV and ALTV-related viruses appear to belong to the Mobatvirus genus, while SWSV is a member of the Orthohantavirus genus. These findings suggest that ALTV and ALTV-related hantaviruses might have emerged from ancient cross-species transmission with subsequent diversification within Sorex shrews in Eurasia.

High species diversity of the potential animal host community for a zoonotic pathogen may reduce pathogen transmission among the most competent host, a phenomenon called the “dilution effect”, but the mechanisms driving this effect have been little studied. One proposed mechanism is “encounter reduction” where host species of low-competency decrease contact rates between infected and susceptible competent hosts, especially in directly transmitted diseases. We conducted an experiment in outdoor enclosures in northwestern Mexico where we manipulated rodent assemblages to assess the effect of species richness on the frequency of intra- and interspecific interactions and activity patterns of a hantavirus reservoir host (North American deermouse; Peromyscus maniculatus). Trials consisted of three treatments of rodent assemblages that differed in species richness, but had equal abundance of deermice; treatment 1 consisted of only deermice, treatment 2 included deermice and one non-competent host species, and treatment 3 included two non-competent host species in addition to deermice. To measure interactions and temporal activity, we strategically deployed foraging stations and infrared cameras. We did not find differences in the frequency of intraspecific interactions of deermice among treatments, but there were significantly more interspecific interactions between deermouse and non-competent hosts in treatment 2 than treatment 3, which is explained by the identity of the non-competent host species. In addition, there were differences in activity patterns between rodent species, and also between deermice from treatment 1 and treatment 2. These results indicate that at least at a small-scale analysis, the co-occurrence with other species in the study area does not influence the frequency of intraspecific interactions of deermice, and that deermice may be changing their activity patterns to avoid a particular non-competent host species (Dipodomys merriami). In conclusion, in this deermouse-hantavirus system a potential dilution effect would not be through intraspecific encounter reduction in the most competent hantavirus host. To identify variables of host assemblages that can influence pathogen transmission, we highlight the need to address the identity of species and the composition of assemblages, not only host species richness or diversity.

Hantaviruses cause hemorrhagic fever with renal syndrome (HFRS) in Europe and Asia. Interferon (IFN) responses play an important role in HFRS pathogenesis and early IFN-β response is delayed by pathogenic hantaviruses. The severity of HFRS caused by Dobrava virus (DOBV) and Puumala virus (PUUV) varies. Our aim was to determine whether differences in early activation of IFN type 1-induced antiviral state influence HFRS severity. Peripheral blood mononuclear cells (PBMCs) from healthy donors and HFRS patients were stimulated with DOBV or PUUV and expression of selected genes was measured. PUUV, but not DOBV, activated IFN type 1-induced antiviral state in stimulated PBMCs, and IFNβ, STAT-1, and MxA were highly upregulated. Upregulation of MxA was earlier in acute-phase PBMCs and higher in convalescent-phase PBMCs from patients with mild compared with severe PUUV infection. Our study showed that delayed IFN type 1-induced antiviral state could contribute to HFRS severity, particularly in PUUV infection.

Hantavirus pulmonary syndrome (HPS), also referred to as hantavirus cardiopulmonary syndrome (HCPS), is a rare but frequently fatal disease caused by New World hantaviruses. In humans HPS is associated with severe pulmonary edema and cardiogenic shock; however, the pathogenesis of this disease remains unclear largely due to a lack of suitable animal models for the study of disease progression. In this study we monitored clinical, virological, pathophysiological parameters and host immunological responses to decipher pathological factors and events in the lethal Syrian hamster model of HPS following intranasal inoculation of Andes virus. Transcriptional profiling of the host gene responses demonstrated a suppression of innate immune responses in most organs analyzed during the early stage of infection, except for in the lung which had low level activation of several pro-inflammatory genes. During this phase Andes virus established a systemic infection in hamsters, with viral antigen readily detectable in the endothelium of the majority of tissues analyzed by 7-8 days post-inoculation. Despite wide-spread infection, histological analysis confirmed pathological abnormalities were almost exclusively found in the lungs. Immediately preceding clinical signs of disease, intense activation of pro-inflammatory and Th1/Th2 responses were observed in the lungs as well as the heart, but not in peripheral organs, suggesting that localized immune-modulations by infection is paramount to pathogenesis. Throughout the course of infection a strong suppression of regulatory T-cell responses was noted and is hypothesized to be the basis of the aberrant immune activations. The unique and comprehensive monitoring of host immune responses to hantavirus infection increases our understanding of the immuno-pathogenesis of HPS and will facilitate the development of treatment strategies targeting deleterious host immunological responses.