Nlrc3 Knockout Mice Showed Renal Pathological Changes After HTNV Infection.

Hantaan virus (HTNV) infects humans and causes hemorrhagic fever with renal syndrome (HFRS). The development of well-characterized animal models of HFRS could accelerate the testing of vaccine candidates and therapeutic agents and provide a useful tool for studying the pathogenesis of HFRS. Because NLRC3 has multiple immunoregulatory roles, we investigated the susceptibility of Nlrc3-/- mice to HTNV infection in order to establish a new model of HFRS. Nlrc3-/- mice developed weight loss, renal hemorrhage, and tubule dilation after HTNV infection, recapitulating many clinical symptoms of human HFRS. Moreover, infected Nlrc3-/- mice showed higher viral loads in serum, spleen, and kidney than wild type C57BL/6 (WT) mice, and some of them manifested more hematological disorders and significant pathological changes within multiple organs than WT mice. Our results identify that HTNV infected Nlrc3-/- mice can develop clinical symptoms and pathological changes resembling patients with HFRS, suggesting a new model for studying the pathogenesis and testing of candidate vaccines and therapeutics.

Macropinocytosis and Clathrin-Dependent Endocytosis Play Pivotal Roles for the Infectious Entry of Puumala Virus.

Viruses from the family Hantaviridae are encountered as emerging pathogens causing two life-threatening human zoonoses: hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS), with case fatality rates of up to 50%. Here, we comprehensively investigated entry of the Old World hantavirus Puumala virus (PUUV) into mammalian cells, showing that upon treatment with pharmacological inhibitors of macropinocytosis and clathrin-mediated endocytosis, PUUV infections are greatly reduced. We demonstrate that the inhibitors did not interfere with viral replication and that RNA interference, targeting cellular mediators of macropinocytosis, decreases PUUV infection levels significantly. Moreover, we established lipophilic tracer staining of PUUV particles and show colocalization of stained virions and markers of macropinosomes. Finally, we report a significant increase in the fluid-phase uptake of cells infected with PUUV, indicative of a virus-triggered promotion of macropinocytosis.IMPORTANCE The family Hantaviridae comprises a diverse group of virus species and is considered an emerging global public health threat. Individual hantavirus species differ considerably in terms of their pathogenicity but also in their cell biology and host-pathogen interactions. In this study, we focused on the most prevalent pathogenic hantavirus in Europe, Puumala virus (PUUV), and investigated the entry and internalization of PUUV into mammalian cells. We show that both clathrin-mediated endocytosis and macropinocytosis are cellular pathways exploited by the virus to establish productive infections and demonstrate that pharmacological inhibition of macropinocytosis or a targeted knockdown using RNA interference significantly reduced viral infections. We also found indications of an increase of macropinocytic uptake upon PUUV infection, suggesting that the virus triggers specific cellular mechanisms in order to stimulate its own internalization, thus facilitating infection.

Hantavirus inhibits apoptosis by preventing mitochondrial membrane potential loss through up-regulation of the pro-survival factor BCL-2.

Hantaviruses, zoonotic RNA viruses belonging to the order Bunyavirales, cause two severe acute diseases in humans, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Hantavirus-infected patients show strong cytotoxic lymphocyte responses and hyperinflammation; however, infected cells remain mostly intact. Hantaviruses were recently shown to inhibit apoptosis in infected cells. By inhibiting granzyme B- and TRAIL-mediated apoptosis, hantaviruses specifically and efficiently inhibit cytotoxic lymphocyte-mediated killing of infected cells. Hantaviruses also strongly inhibit apoptosis triggered intrinsically; i.e., initiated through intracellular activation pathways different from those used by cytotoxic lymphocytes. However, insights into the latter mechanisms are currently largely unknown. Here, we dissected the mechanism behind how hantavirus infection, represented by the HFRS-causing Hantaan virus and the HPS-causing Andes virus, results in resistance to staurosporine-induced apoptosis. Less active caspase-8 and caspase-9, and consequently less active caspase-3, was observed in infected compared to uninfected staurosporine-exposed cells. While staurosporine-exposed uninfected cells showed massive release of pro-apoptotic cytochrome C into the cytosol, this was not observed in infected cells. Further, hantaviruses prevented activation of BAX and mitochondrial outer membrane permeabilization (MOMP). In parallel, a significant increase in levels of the pro-survival factor BCL-2 was observed in hantavirus-infected cells. Importantly, direct inhibition of BCL-2 by the inhibitor ABT-737, as well as silencing of BCL-2 by siRNA, resulted in apoptosis in staurosporine-exposed hantavirus-infected cells. Overall, we here provide a tentative mechanism by which hantaviruses protect infected cells from intrinsic apoptosis at the mitochondrial level by inducing an increased expression of the pro-survival factor BCL-2, thereby preventing MOMPs and subsequent activation of caspases. The variety of mechanisms used by hantaviruses to ensure survival of infected cells likely contribute to the persistent infection in natural hosts and may play a role in immunopathogenesis of HFRS and HPS in humans.

Dentin matrix protein 1 correlates with the severity of hemorrhagic fever with renal syndrome and promotes hyper-permeability of endothelial cells infected by Hantaan virus.

Hantaviruses are the major causative agents of hemorrhagic fever with renal syndrome (HFRS) in humans, which is characterized by increased capillary permeability. Dentin matrix protein 1 (DMP1) has been shown to degrade components of the basal membrane and interendothelial junctions via matrix metalloproteinase-9. To study the changes of serum DMP1 in HFRS, we determined the concentration of DMP1 using sandwich enzyme-linked immunosorbent assay. We found that serum DMP1 concentrations increased significantly, and reached peak value during the oliguric phase and in the critical group in HFRS patients. Moreover, serum DMP1 concentrations were closely related to blood urea nitrogen, creatinine, cystatin C, and vascular endothelial growth factor (VEGF). We further explored the role of DMP1 in HTNV-infected human umbilical vein endothelial cells (HUVECs) model. Data from immunocytochemistry showed that VEGF and tumor necrosis factor-α (TNF-α) promoted the expression of DMP1 on HTNV-infected HUVECs. Results from transwell assays demonstrated that the permeability of HUVECs increased significantly after HTNV infection with the addition of DMP1, VEGF, and TNF-α. This study suggests that elevated DMP1 concentrations may be associated with disease stage, severity, and the degree of acute kidney injury. DMP1 is involved in the regulation of capillary permeability in HFRS caused by hantavirus infection.

Self-association and subcellular localization of Puumala hantavirus envelope proteins.

Hantavirus assembly and budding are governed by the surface glycoproteins Gn and Gc. In this study, we investigated the glycoproteins of Puumala, the most abundant Hantavirus species in Europe, using fluorescently labeled wild-type constructs and cytoplasmic tail (CT) mutants. We analyzed their intracellular distribution, co-localization and oligomerization, applying comprehensive live, single-cell fluorescence techniques, including confocal microscopy, imaging flow cytometry, anisotropy imaging and Number&Brightness analysis. We demonstrate that Gc is significantly enriched in the Golgi apparatus in absence of other viral components, while Gn is mainly restricted to the endoplasmic reticulum (ER). Importantly, upon co-expression both glycoproteins were found in the Golgi apparatus. Furthermore, we show that an intact CT of Gc is necessary for efficient Golgi localization, while the CT of Gn influences protein stability. Finally, we found that Gn assembles into higher-order homo-oligomers, mainly dimers and tetramers, in the ER while Gc was present as mixture of monomers and dimers within the Golgi apparatus. Our findings suggest that PUUV Gc is the driving factor of the targeting of Gc and Gn to the Golgi region, while Gn possesses a significantly stronger self-association potential.

Expression of CD206 and CD163 on intermediate CD14++CD16+ monocytes are increased in hemorrhagic fever with renal syndrome and are correlated with disease severity.

BACKGROUND: Hantaan virus infection causes lethal hemorrhagic fever with renal syndrome (HFRS) in humans. Little is known about how monocytes contribute to HFRS pathogenesis. In this study, we aimed to investigate changes in various monocyte subsets in HFRS patients. METHODS: A total of 41 HFRS patients and 17 age-, sex-, and ethnicity-matched healthy control subjects were included in this study. Numbers/percentages of various monocyte subsets were quantitatively determined using flow cytometry. Serum levels of interleukin (IL)-10, IL-12, and tumor necrosis factor alpha (TNF-α) were detected using a cytometric bead array (CBA). RESULTS: CD14++CD16+ intermediate monocytes were significantly higher in HFRS patients compared to healthy controls (P < 0.01), especially during the acute phase. The expression of both CD163 and CD206 on CD14++CD16+ intermediate monocytes were increased during the acute phase of HFRS (P < 0.01 and P < 0.05, respectively) when comparing the convalescent phase and healthy controls. Furthermore, the numbers of CD14++CD16+ monocytes during the acute phase, and the percentages of CD14++CD16+CD163+ monocytes in patients with severe/critical HFRS were much higher compared to patients with mild/moderate HFRS. This also positively correlated with increased levels of white blood cells (WBC), blood urea nitrogen (BUN), and creatinine (Cr). However, the percentages of CD14++CD16+CD206+monocytes were higher in mild/moderate HFRS than in severe/critical HFRS, and they negatively correlated with platelets (PLT) and Cr. CONCLUSIONS: Higher frequency of the CD14++CD16+ intermediate monocytes and increased expression of CD163+ and CD206+ markers on CD14++CD16+ monocytes were detected in patients with HFRS. The changes in the frequency of CD14++CD16+ monocytes and expression of CD163 and CD206 markers on CD14++CD16+ monocytes positively correlated with the severity of HFRS.

Hemorrhagic fever with renal syndrome accompanied by panhypopituitarism and central diabetes insipidus: a case report.

Central diabetes insipidus (DI) was detected in a patient with hemorrhagic fever with renal syndrome (HFRS) who had been molecularly and serologically diagnosed with Hantaan virus infection. We recommend that clinicians differentiate central DI in HFRS patients with a persistent diuretic phase even when pituitary MRI findings are normal.

Identifying Restriction Factors for Hemorrhagic Fever Viruses: Dengue and Junín.

Host restriction factors are cellular components that interfere with viral multiplication. They are up-regulated and expressed upon viral infection and in consequence their activity is specific. So far several important restriction factors have been described against diverse viruses. The cellular antiviral mechanisms defined include proteins with the ability to interfere with early steps of viral replication and others that have been shown to block viral morphogenesis. However, other strategies by which the antiviral action is exerted still remain elusive. An additional interesting matter is how viruses also developed ways to by-pass these host-specific obstacles. Thus, unusual cell localization or re-localization represents a frequent virus choice to evade the cellular surveillance. In the present chapter, we summarize methods to identify cell restriction factors, their antiviral activity, and possible subcellular locations where their activity can take place.

Protocols to Assess Coagulation Following In Vitro Infection with Hemorrhagic Fever Viruses.

During the course of infection with a hemorrhagic fever virus (HFV), the checks and balances associated with normal coagulation are perturbed resulting in hemorrhage in severe cases and, in some patients, disseminated intravascular coagulopathy (DIC). While many HFVs have animal models that permit the analyses of systemic coagulopathy, animal infection models do not exist for all HFVs and moreover do not always recapitulate the pathology observed in human tissues. Furthermore, molecular analyses of how coagulation is affected are not always straightforward or practical when using ex-vivo animal-derived samples, thus reinforcing the importance of cell culture studies. This chapter highlights procedures utilizing human umbilical vein endothelial cells (HUVECs) as a model system to evaluate components of the intrinsic (prekallikrein (PK), factor XII (FXII), kininogen, and bradykinin (BK)) and extrinsic (Tissue Factor (TF)) systems. Specifically, protocols are included for the generation of a coculture blood vessel model, plating and infection of HUVEC monolayers and assays designed to measure activation of PK and FXII, cleavage of kininogen, and to measure the expression of TF mRNA and protein.

Deregulation of levels of angiopoietin-1 and angiopoietin-2 is associated with severe courses of hantavirus infection.

BACKGROUND: Hantavirus disease is characterized by endothelial dysfunction. Angiopoietin-1 (Ang-1) and its antagonist angiopoietin-2 (Ang-2) play a key role in the control of capillary permeability. Ang-1 is responsible for maintenance of cell-to-cell contacts whereas Ang-2 destabilizes monolayers. An imbalance of Ang-1 and Ang-2 levels results in enhanced permeability and capillary leakage. OBJECTIVES: To analyze the involvement of angiopoietins in hantavirus-induced disruption of endothelia, we measured the levels of Ang-1 and Ang-2 in hantavirus infection. STUDY DESIGN: Levels of angiopoietins of 31 patients with acute Puumala virus (PUUV) infection and a patient infected with Dobrava-Belgrade virus genotype Sochi (DOBV-Sochi) were analyzed. An age-matched group of 16 healthy volunteers served as control. The ratios of Ang-2 to Ang-1 levels were calculated and correlated with laboratory parameters. RESULTS: Patients with PUUV and DOBV-Sochi infection exhibited elevated ratios of Ang-2/Ang-1 compared to the control group. The imbalance of Ang-2 to Ang-1 levels was observed early after onset of symptoms and lasted for the acute phase of infection. The deregulation in DOBV-Sochi infection was more prominent than in PUUV infection. Analysis of Ang-2/Ang-1 ratio and laboratory parameters in the PUUV cohort revealed a positive correlation with serum creatinine and a negative correlation with serum albumin and thrombocyte levels. CONCLUSIONS: We observed an imbalance between levels of Ang-1 and Ang-2 in patients infected with PUUV and DOBV-Sochi. Elevated Ang-2/Ang-1 ratios correlate with disease severity. The virus-induced deregulation of angiopoietin levels may enhance capillary permeability and contribute to the pathogenesis of hantavirus disease.

[Alterations and clinical signifecance of exosome-containing innate immunity related lncRNAs in patients of hemorrhagic fever with renal syndrome].

Objective To observe the alterations of innate immunity related long non-coding RNAs (lncRNAs) in exosomes extracted from the plasma of hemorrhagic fever with renal syndrome (HFRS) patients, and analyze their relationship with the disease stage and severity. Methods Exosomes were extracted from the plasma samples of HFRS patients, healthy controls and recovered HFRS patients. Transmission electronic microscopy and Western blotting were performed to confirm the efficiency of the extraction. lncRNA profiles in the different groups were determined by high-throughput sequencing. The contents of several innate immunity related lncRNAs were detected by quantitative real-time PCR, and their relationship with the disease stage and severity was analyzed. Results Exosomes from the plasma were accurately extracted. Innate immunity related lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1), negative regulator of interferon response (NRIR), negative regulator of antiviral response (NRAV) were found in exosomes. NEAT1 content was significantly reduced in the exosomes from HFRS patients compared with healthy controls and it was significantly restored in recovered HFRS patients. The exosome NEAT1 content was correlated with the epidemic of HFRS but had no relationship with the stage and severity of the disease. Conclusion Several innate immunity related lncRNAs exist in the exosome from HFRS patients, among which NEAT1 content significantly decreases in HFRS patients compared with healthy controls and recovered HFRS patients. The reduced NEAT1 level is correlated with the epidemic of HFRS.

Interferons Induce STAT1-Dependent Expression of Tissue Plasminogen Activator, a Pathogenicity Factor in Puumala Hantavirus Disease.

Hantaviruses are zoonotic viruses that show various degrees of vasculopathy in humans. In this study, we analyzed the regulation of 2 fibrinolytic parameters, tissue plasminogen activator (tPA) and its physiological inhibitor, plasminogen activator inhibitor 1 (PAI-1), in Puumala hantavirus (PUUV)-infected patients and in human microvascular endothelial cells. We detected strong upregulation of tPA in the acute phase of illness and in PUUV-infected macaques and found the tPA level to positively correlate with disease severity. The median levels of PAI-1 during the acute stage did not differ from those during the recovery phase. In concordance, hantaviruses induced tPA but not PAI-1 in microvascular endothelial cells, and the induction was demonstrated to be dependent on type I interferon. Importantly, type I and II interferons directly upregulated tPA through signal transducer and activator of transcription 1 (STAT1), which regulated tPA gene expression via a STAT1-responsive enhancer element. These results suggest that tPA may be a general factor in the immunological response to viruses.

Puumala Hantavirus-Induced Hemorrhagic Fever with Renal Syndrome Must Be Considered across the Borders of Nephrology to Avoid Unnecessary Diagnostic Procedures.

BACKGROUND: Nephropathia epidemica (NE), a milder form of hemorrhagic fever with renal syndrome, is caused by Puumala virus and is characterized by acute kidney injury and thrombocytopenia. METHODS: A cross-sectional prospective survey of 456 adult patients with serologically confirmed NE was performed. RESULTS: Of the 456 investigated patients, 335 had received inpatient treatment. At time of admission to hospital, 72% of the patients had still an AKI and thrombocytopenia was present in 64% of the patients. The 335 patients were treated in 29 different hospitals and 6 of which had nephrology departments. 10 out of 335 patients received treatment in university hospitals and 63% of patients admitted themselves to hospital. Initially, the patients were admitted to 12 different clinical departments (29% of the patients were referred to a nephrology department) and during the course of the disease, 8% of the patients were transferred to another department in the same hospital and 3% were transferred to a nephrology department at another hospital. Regarding diagnostic procedures, in 28% of the inpatients computed tomography to exclude pulmonary embolism or due to severe gastrointestinal symptoms, lumbar puncture to exclude meningitis, magnetic resonance tomography of the brain owing to suspected stroke because of visual disorders, gastroscopy, or colonoscopy due to gastrointestinal symptoms was performed at time of admission to hospital. CONCLUSIONS: NE must be considered by physicians across the borders of nephrology to avoid unnecessary diagnostic procedures especially in areas where NE is endemic.

NLRP3 inflammasome is responsible for Hantavirus inducing interleukin-1ß in THP-1 cells.

Persistent high fever is one typical clinical symptom of hemorrhagic fever with renal syndrome (HFRS) and circulating interleukin-1ß (IL-1ß) is elevated throughout HFRS. The mechanisms responsible for viral induction of IL-1ß secretion are unknown. In the present study, Hantaan virus (HTNV) induced the secretion of IL-1ß in the human monocytic cell line THP-1. Induction of IL-1ß by HTNV relies on the activation of caspase-1. Small hairpin RNA knockdown in HTNV-infected THP-1 cells indicated that nucleotide-binding domain, leucine-rich repeat containing protein 3 (NLRP3) recruits the adaptor apoptosis-associated speck-like protein and caspase-1 to form an NLRP3 inflammasome complex, crucial for the induction of IL-1ß. In HTNV-infected THP-1 cells, reactive oxygen species release, but not extracellular adenosine triphosphate, was crucial for IL-1ß production. In conclusion, Hantavirus induces the formation of the NLRP3 inflammasome in THP-1 cells and this may be responsible for the elevated IL-1ß levels in HFRS patients.

Acute kidney injury and tools for risk-stratification in 456 patients with hantavirus-induced nephropathia epidemica.

BACKGROUND: Puumala virus (PUUV) is the most common species of hantavirus in Central Europe. Nephropathia epidemica (NE), caused by PUUV, is characterized by acute kidney injury (AKI) and thrombocytopenia. The major goals of this study were to provide a clear clinical phenotyping of AKI in patients with NE and to develop an easy prediction rule to identify patients, who are at lower risk to develop severe AKI. METHODS: A cross-sectional prospective survey of 456 adult patients with serologically confirmed NE was performed. Data were collected from medical records and prospectively at follow-up visit. Severe AKI was defined by standard criteria according to the RIFLE (Risk, Injury, Failure, Loss, End-stage kidney disease) classification. Fuller statistical models were developed and validated to estimate the probability for severe AKI. RESULTS: During acute NE, 88% of the patients had AKI according to the RILFE criteria during acute NE. A risk index score for severe AKI was derived by using three independent risk factors in patients with normal kidney function at time of diagnosis: thrombocytopenia [two points; odds ratios (OR): 3.77; 95% confidence intervals (CI): 1.82, 8.03], elevated C-reactive protein levels (one point; OR: 3.02; 95% CI: 1.42, 6.58) and proteinuria (one point; OR: 3.92; 95% CI: 1.33, 13.35). On the basis of a point score of one or two, the probability of severe AKI was 0.18 and 0.28 with an area under the curve of 0.71. CONCLUSION: This clinical prediction rule provides a novel and diagnostically accurate strategy for the potential prevention and improved management of kidney complications in patients with NE and, ultimately, for a possible decrease in unnecessary hospitalization in a high number of patients.

Pathophysiology of a severe case of Puumala hantavirus infection successfully treated with bradykinin receptor antagonist icatibant.

We recently described a patient with very severe Puumala hantavirus infection manifested by capillary leakage syndrome and shock. He was successfully treated with the bradykinin receptor antagonist, icatibant (Antonen et al., 2013). Here we report analysis of the pathophysiology which indicated pronounced complement activation, prolonged leukocytosis, extensive fibrinolysis, circulating histones, and defects in liver function. The patient had an uncommon HLA-phenotype, which may have contributed to the severe course of the disease.

Acute hantavirus infection induces galectin-3-binding protein.

Hantaviruses are zoonotic viruses that cause life-threatening diseases when transmitted to humans. Severe hantavirus infection is manifested by impairment of renal function, pulmonary oedema and capillary leakage. Both innate and adaptive immune responses contribute to the pathogenesis, but the underlying mechanisms are not fully understood. Here, we showed that galectin-3-binding protein (Gal-3BP) was upregulated as a result of hantavirus infection both in vitro and in vivo. Gal-3BP is a secreted glycoprotein found in human serum, and increased Gal-3BP levels have been reported in chronic viral infections and in several types of cancer. Our in vitro experiments showed that, whilst Vero E6 cells (an African green monkey kidney cell line) constitutively expressed and secreted Gal-3BP, this protein was detected in primary human cells only as a result of hantavirus infection. Analysis of Gal-3BP levels in serum samples of cynomolgus macaques infected experimentally with hantavirus indicated that hantavirus infection induced Gal-3BP also in vivo. Finally, analysis of plasma samples collected from patients hospitalized because of acute hantavirus infection showed higher Gal-3BP levels during the acute than the convalescent phase. Furthermore, the Gal-3BP levels in patients with haemorrhagic fever with renal syndrome correlated with increased complement activation and with clinical variables reflecting the severity of acute hantavirus infection.

Hantaan virus infection induces CXCL10 expression through TLR3, RIG-I, and MDA-5 pathways correlated with the disease severity.

Hantaan virus (HTNV) is a major agent causing hemorrhagic fever with renal syndrome (HFRS). Although the pathogenesis of HFRS is unclear, some reports have suggested that the abundant production of proinflammatory cytokines and uncontrolled inflammatory responses may contribute to the development of HFRS. CXCL10 is one of these cytokines and is found to be involved in the pathogenesis of many virus infectious diseases. However, the role of CXCL10 in the pathogenesis of HFRS and the molecular regulation mechanism of CXCL10 in HTNV infection remain unknown. In this study, we report that CXCL10 expresses highly in the HFRS patients' sera and the elevated CXCL10 is positively correlated with the severity of HFRS. We find that HTNV, a single-strand RNA virus, can act as a double-strand RNA to activate the TLR3, RIG-I, and MDA-5 signaling pathways. Through the downstream transcription factors of these pathways, NF-κB and IRF7, which bind directly to the CXCL10's promoter, the expression of CXCL10 is increased. Our results may help to better understand the role of CXCL10 in the development of HFRS and may provide some novel insights into the immune response of HTNV infection.

Proliferation and local manifestations of oxidative stress in mucous membrane of the ileum in patients at early stages of hemorrhagic fever with renal syndrome.

Activation of proliferative processes (Ki-67 proliferation index) and local oxidative stress was found in biopsy material from the mucosa of the large intestine of patients at the early stages of hemorrhagic fever with renal syndrome on days 5-10 after disease onset. Analysis of data of rectosigmoidoscopy and clinical examination refl ected the presence of colitis. It can be suggested that activation of proliferation is typically associated with local oxidative stress during various pathological processes.

Elevated plasma soluble Sema4D/CD100 levels are associated with disease severity in patients of hemorrhagic fever with renal syndrome.

BACKGROUND: Hantaan virus (HTNV) could cause a severe lethal hemorrhagic fever with renal syndrome (HFRS) in humans. Despite a limited understanding of the pathogenesis of HFRS, the importance of host-related immune responses in the pathogenesis of HFRS has been widely recognized. CD100/Sema4D has been demonstrated to play an important role in physiological and pathological immune responses, but the functional role of CD100 in infectious diseases has only been inadequately reported. The aim of this study was to investigate the pathological significance of CD100 in patients after HTNV infection. METHODOLOGY/PRINCIPAL FINDINGS: Blood samples were collected from 99 hospitalized patients in Tangdu Hospital and 27 health controls. The level of soluble CD100 (sCD100) in plasma were quantified by ELISA and the relationship between sCD100 and the disease course or severity were analyzed. The expressions of membrane CD100 on various subpopulations of peripheral blood mononuclear cell (PBMC) were analyzed by flow cytometry. The results showed that sCD100 level in acute phase of HFRS was significantly higher in patients than that in healthy controls (P<0.0001) and the sCD100 level declined in convalescent phase. Multivariate model analysis showed that platelet count, white blood cell count, serum creatinine level and blood urea nitrogen level were associated with sCD100 levels and contributed independently to the elevated sCD100 levels. The expression of membrane CD100 on PBMCs decreased in the acute phase of HFRS patients compared with that of the normal controls and recovered in the convalescent phase. CONCLUSIONS: We reported the elevated level of plasma sCD100 in HFRS patients and the elevated level might be a result from the shedding of membrane CD100 on PBMC. The elevated level of sCD100 was associated with disease severity, suggesting that sCD100 might be a cause or a consequence of progression of HFRS. The underlying mechanisms should be explored further.