hantavirus infection cycle

  • 17 min read
  • Feb 04, 2020

The hantavirus life cycle. The basic steps include the attachment ...
The hantavirus life cycle. The basic steps include the attachment …

Hantavirus has attracted more and more attention as a pathogen that emerged in the last decade. This leads to two different human diseases. Hemorrhagic fever with renal syndrome (HFRS) and human pulmonary syndrome (HPS)

The report clinical entity may be caused by hantaviruses in Chinese and English backdate to the first millennium and the Middle ages, respectively (,). However, it lasted until 1951-1953 during the Korean War before hantaviruses found global attention. More than 3000 of the UN and US troops suffered acute renal failure acute fever and shock and death rate of 7% is close to a small river called Hantaan (,; G. Schreiner, personal communication, Washington, 1993). The causative agent, a virus Hantaan (HTNV), was identified in 1978 by Lee et al. (). Until now, 21 different species of hantavirus have been described, and more than 30 genotypes are marked and can be found all over the world (,).

Hantaviruses comprises one of the five genera of the family Bunyaviridae virus (). They replicate in the host cell cytoplasm and consists of a lipid envelope ball; four viral proteins; and three, negative-sense RNA segments of single-stranded designated S (small), M (medium), and L (large), which encodes the nucleocapsid protein (NP), the surface of the envelope glycoproteins G1 and G2, and RNA- dependent RNA polymerase, each (). minor additional open reading frames are present in the genome of hantaviruses, but to date, there is no corresponding protein is identified. NP, the major structural protein, a complex with viral genome RNA segments that form a helical nucleocapsid ().

Scheme hantavirus morphology. The (-) ssRNA segments S (small), M (medium), and L (large) encoded for the nucleocapsid protein, glycoprotein G1 and G2, and RNA-dependent RNA polymerase, respectively The main natural reservoir hantaviruses are rodent pupil (order Rodentia; family of mice; subfamilies Murinae, Arvicolinae, and Sigmodontinae). Virus and the host shares a long period of co-evolution is marked by the absence of hantavirus-caused disease on infected rodents (,). Initially, it was thought that one rodent species is the dominant host for one species of hantavirus, but recently more and more studies reveal that there may be some species of rodent hosts for individual viruses and some viruses in the host species (-). In addition, many studies have reported hantavirus infection to be present in animal species other than mice, for example, cattle, deer, cats, dogs, etc. However, the question of whether the animal is infected intentionally or represent a natural reservoir up had not been answered (). Sole distribution of hantavirus species is correlated with the geographical extension of their host (), and hantavirus genotypes from the same geographic region are phylogenetically related to (-).

Main reservoirs of natural and geographical distribution of pathogens hantavirusesa

Human beings do not belong to the host range of natural hantaviruses, and infections occur accidentally through virus-containing, excretion rodent aerosols such as urine, feces, or water saliva. People who live or work in close contact with infected rodents were at increased risk of infection, and studies usually show a higher percentage of seropositive individuals in groups as compared with control subjects (,).

The genus Hantavirus roughly consists of two main groups: Old World and New World hantaviruses. HFRS in humans are caused by pathogenic hantaviruses old world including viruses Amur, viruses Seoul, and HTNV, species epidemiologically most important, with lethal levels of up to 15% in Asia, as well as virus Dobrava (DOBV), virus Tula (TULV), and viruses Puumala (PUUV) in Europe; the latter is the main hantavirus species in Europe and induce Nephropathia epidemica (NE), a mild variant of HFRS, with a mortality rate of 0.1% (,). HFRS affects about 200,000 people each year, especially in Asia. In 2004, 235 cases were reported in Germany, according to a latest epidemiological bulletin of the Robert-Koch Institute.

First pathogenic New World hantavirus (Sin Nombre virus) was discovered in the early 1990s in the Four Corners region of the United States (). Starting today, many New World hantaviruses additional pathogens are identified and marked (). New World hantaviruses that is causative agent HPs around 300 cases each year in North and South America, with lethal levels of up to 50%.

Human hantavirus infection is assumed to occur by accident, and the man is a dead end for hantavirus life cycle. Transfer viral particles from infected to the uninfected person usually does not happen. One exception is the Andes hantavirus strain sou in Argentina, which sporadical person-to-person transmission is reported (,). These findings reveal an alarming potential risks to human health hantaviruses.

HFRS and HPS are partly overlapping clinical syndrome. In Europe, the serotype Puumala hantavirus lead to the NE, the lighter variant of HFRS. Viremia occurred after the initial infection of alveolar macrophages and acute-phase symptoms of life-threatening infections caused mainly by vascular endothelial cells of the lungs and kidneys with a concomitant loss of barrier function of endothelial permeability resulting in increased weight.

NE characterized by sudden high fever, headache, back pain, and abdominal pain. Transient thrombocytopenia is a typical finding in the early phase of the disease. Conjunctival bleeding, petechiae palatine, and truncal petechial rash after 3 or 4 d is possible. Approximately 1% of patients experienced severe neurological manifestations, for example, bladder spasm or paralysis. The bleeding is accompanied by oliguria, azotemia, proteinuria and hematuria. Within 3 d, the rash disappeared and the patients develop polyuria. A recovery phase extends for several weeks, and its sequelae are rare. NE severe course with acute kidney failure and a variety of lethal outcomes between 0.1 and 1% ().

The incubation period is 7-36 d HFRS. Only 10 to 15% of cases have a severe program with lethal levels of between 6 and 15%. HFRS characterized by systemic involvement capillaries and venules. It induces various manifestations of bleeding and circulatory disorders. Renal involvement is characterized by acute renal failure due to interstitial hemorrhage and interstitial infiltrates (,)

The clinical course is divided into five phases :. fever, hypotension, oliguria, diuretic, and cured. The emergence of HFRS resembles NE with a high fever, back pain, abdominal pain, chills, myalgia, malaise, and bradycardia over 3 to 4 d. Photophobia, pharynx enanthema, and spread flushed face was also observed. In the third to fifth day, petechia develop initially on the ceiling. At the same time, conjunctival bleeding may appear and temporary disruption of visual function were reported. Urine sediment revealed atypical gross hematuria and proteinuria (in some cases> 3 g / 24 h). Phase hypotension ranged from 3 to 6 days after the onset of fever. Shock or hypotension may occur. laboratory findings in this phase is leukocytosis and thrombocytopenia. Patients show various kidney conditions, including acute tubulointerstitial nephritis, necrotizing glomerulonephritis, and IgA nephropathy. Oliguria phase begins at about day 8, and hemorrhagic manifestations become more prominent. Phase begins diuretic on day around 11, and the healing phase lasts about 3 weeks to 6 mo.

sequelae are rare but include chronic renal failure and hypertension. In a series of 46 patients in Tampere (Finland), which has a NE 3 to 7 y ago, the patient has a high GFR and filtration fraction, more proteinuria and systolic ambulatory BP higher than healthy control subjects (). In addition, we studied 42 patients after NE of some regions in Germany and found hypertension or elevated serum creatinine (1.5 mg / dl) ().

extrarenal manifestations include acute visual function disorder, acute myopia, CNS complications with seizures, sometimes myocarditis and severe gastrointestinal bleeding. In addition, thyroid, liver, and pancreas may be affected. The involvement of the lungs but at a lower level than in HPS also observed during HFRS (, -).

The occurrence of HPS is characterized by flu-like symptoms such as high fever, myalgia, and headache. The patients develop acute pulmonary edema and hypotension noncardiac within 2 to 15 d. bilateral infiltrates develop rapidly, sometimes associated with pleural effusion. neutrophilic leukocytosis, hemoconcentration, thrombocytopenia, and circulating immunoblasts observed. HPS severe course associated with increased lactatee level. The mortality rate of approximately 50% HPS. Patients who survive the acute phase of the disease typically recover within 5-7 d without any residual symptoms (). Acute renal failure is secondary to shock and respiratory failure.

medical knowledge about HFRS and HPS has increased substantially in recent years, resulting in the conclusion that the two syndromes which partially overlap. The number of reported cases of HFRS with lung involvement and HPS cases with renal involvement continues to grow, and it is conceivable that the description of the clinical course of the syndrome will meet up in the near future.

Immunohistochemistry analysis hantavirus-infected kidney tissue revealed interstitial infiltrates with immune cells and interstitial hemorrhage. Histopathological lesions are the most common acute nephritis tubulointerstitial. Tubular epithelial and luminal changes are present. Intertubular dense capillary and interstitium was expanded by edema, an indication of the general capillary damage. Sometimes, glomerular pathology, for example, hypercellularity and expansion of the mesangium was observed, and this is probably the cause of the gross proteinuria. Tubular, interstitial, and glomerular histological damage associated with the clinical severity of renal failure (). It is noted that the urine sediment containing tubular cells with greatly enlarged nucleoli. These cells resemble cells uroepithelial and spontaneous tumor disappeared after the illness subsides (,). Recent work has demonstrated that tubular cells containing antigen Hantavirus ().

(A) Focal interstitial mononuclear infiltration, capillary congestion, and interstitial hemorrhage at the intersection corticomedullary. (B) normal glomeruli. focus interstitial edema with mild mononuclear infiltrates and endothelial cells protruding from peritubular capillaries. Magnification, × 100 A, Masson trichrome stain; × 160 in B, PAS stain.

Immunohistochemistry analysis document distribution HPS virus antigen in capillary endothelium throughout the various networks. Endothelial cells infected shortage morphological changes and showed no visible cytopathic effect (CPE). Hantaviral antigen accumulation is observed in pulmonary microvasculature and dendritic cells in lymphoid follicles of the spleen and lymph nodes. In some cases the autopsy, the endothelial cells in the capillaries of the myocardium and endocardium antigen bears hantavirus, contributed substantially to the severe HPS program.

Gross pathological findings showed that the lungs of patients with HPS dense, chewy, and heavy, usually weighing twice as much as the lungs of the average. Especially vascular pathological lesions with variable degrees of public capillary dilation and edema. Often, the lungs revealed mild to moderate interstitial pneumonitis with variable degrees of congestion, edema, and infiltration of mononuclear cells ().

The main factor that determines the course and severity of HFRS and HPS is the title of the infected endothelial permeability enhancement that shows no signs of histological damage and no visible CPE. Currently, it is less understood how pathogenic hantaviruses induce capillary leak during the acute phase of the two syndromes and why some species are pathogenic hantavirus.

Patients with certain HLA antigens seem to have a genetic predisposition to severe course of HFRS and HPS. Patients who bear HLA-B8, DRB1 * 0301, C4a * Q0, or alleles DQ2 seems to have a higher risk for severe course NE (-), and HLA-B35 allele is associated with severe HPS program (). The mechanisms involved in this genetic predisposition is unknown.

hantavirus replication takes place in macrophages and vascular endothelial cells, particularly in the lungs and kidneys (,). For pathogenic hantaviruses, the entry into the host cell attachment occurred with αVβ3 integrins on the cell surface and subsequent endocytosis (,). Virion envelope fuses with the endosome membrane with pH-dependent manner, and the nucleocapsid is released into the cytoplasm. After that, the virus RNA-dependent RNA polymerase directs transcription of viral genes and replication of the viral genomic RNA segments. NP and viral RNA polymerase mRNAs are translated at the ribosome-free, while the mRNA is translated into reticu glycoprotein endoplasmiclum. G1 and G2 glycoprotein complex transported to the Golgi for glycosylation end. Large intracellular inclusion bodies, may consist of NP, formed in the cytoplasm. It is assumed that hantavirions formed on the membrane Golgi complex, followed by budding into the Golgi cisternae, migration in secretory vesicles to the plasma membrane and release by exocytosis. Several in vitro studies have shown that the life cycle of this hantaviral not cause any CPE seen in endothelial cells. host cells are not lysed by infection with pathogenic hantaviruses, and no increased permeability induced in cultured endothelial cells (,). Apoptosis and expression of genes related to apoptosis in cells infected with pathogenic hantaviruses VeroE6 reported for cultured cells and human embryonic kidney; However, in vivo, there is no evidence to program cell death in infected endothelial cells (-). These data suggest that an increase in endothelial permeability for HFRS and HPS may result from infection with pathogenic hantaviruses in combination with the additional factors that are specific to the situation in vivo and which are not present in the cell cultures in vitro. In this context, it is assumed that the antivirus processes within infected cells and immune mechanisms may play a key role in the development of vascular dysfunction (,).

Infection hantaviruses induce innate immune response in the host cell, while the pathogenic hantaviruses seem to be able to avoid this response to a certain degree. Various types of interferon are presented, and IFN-inducible genes activated. The expression of IFN-induced protein MxA delayed in cells infected with pathogenic hantaviruses compared with pathogenic hantaviruses. Similarly, the level of antigen molecules, for example, HLA class I, increased; However, upregulation which is slower after the infection with the pathogen compared with pathogenic hantaviruses (-). Other innate antiviral mechanisms induced during hantavirus infections, including activation of the complement system of the classical and alternative service, for example, with increasing titer of soluble complex SC5b-9 terminal and the ratio of C4D / C4 higher during the NE caused by PUUV (). natural killer cells, known as effector and regulatory cells in innate and adaptive immunity in the case of the production of cytotoxic molecules and the secretion of cytokines and chemokines (), assumed to migrate to hantavirus infected tissue (,).

The adaptive immune system counters hantavirus infection through humoral and cellular responses. In the course of the humoral immune response, all kinds of Ig expressed during HFRS and HPS. The increase in total serum titers and virus-specific IgA, a major component of mucosal immunology, detected during the acute phase of the syndrome (,). Total and virus-specific IgE titers found to be increased before and during the acute phase of HFRS. It is conceivable that the IgE participate in the pathophysiology hantavirus by activation of IL-1β and TNF-α secretion which can affect endothelial permeability infected; However, it was not possible to find a correlation between IgE levels and severity of HFRS (,,). high titers of virus-specific IgM against the virus NP, G1, and G2 are produced during and after the acute phase of HFRS and HPS, whereas NP hantavirus considered a primary viral antigen (,,,,). Virus-specific IgG, the most abundant antibodies against hantaviruses total Ig, also predominantly directed against NP and emerging virus during the acute phase of HFRS and HPS, while further increasing titer can be observed during the initial healing phase (,,).

CD8 + cytotoxic T cells (CTL) is dominant in the process of lymphocyte cellular immune response against hantavirus infection and is assumed to play an important role in clearing virus and HFRS / HPS pathogenicity. Increasing the number of CTL was observed at the beginning of HFRS and HPS and is also found in the lungs of patients who died of HPS. The severity of disease is generally correlated with the number of CTL (,,). CTL epitopes identified in the three viral structural proteins, whereas NP appears to again be a dominant immunogenic proteins (,).

Different types of chemokines and cytokines are secreted in varying amounts to regulate the immune response during infection hantavirus. It is assumed that the cytokines / chemokines playimportant role in vascular dysfunction during HFRS and HPS. Many cytokines / chemokines, such as TNF-α, which is known to increase endothelial permeability in the course of a natural immune response mechanisms, for example, during the migration of lymphocytes through the blood vessel wall. significantly increased plasma levels of IFN-γ, TNF-α, IL-2, and IL-6 was detected in the early acute phase of HFRS and HPS (,,). Increased TNF-α titer appears to correlate with severe course NE (). Increased expression of cytokines, particularly TNF-α in the peritubular of the distal nephron, reported during HFRS (,), and in the lungs of patients with HPS, an increase in the amount of IFN-γ-, IL-1α-, IL -1β-, IL- 2-, IL-4, IL-6, and TNF-α / β-cells that produce the observed (). Hantaviruses also able to infect dendritic cells, resulting in the secretion of proinflammatory cytokines, for example, IFN-α and TNF-α which can also contribute to an increase in endothelial permeability (,). In vitro infection of lung microvascular endothelial cells or human HTNV Sin Nombre virus produced an increase in the number of RANTES and the 10-kD protein IFN-induced (). Recent in vitro studies by Niikura et al. () Indicates that the TNF-α-induced increase in permeability of the endothelial cells was significantly prolonged in HTNV infected cells compared to uninfected cells.

The cumulative data on the pathophysiology hantavirus so far show that hantavirus infection interfere in the way so far unknown to the regulation of vascular permeability during inflammation, resulting in endothelial dysfunction. It is conceivable that these disorders mediated by interactions between viral proteins and cells that participate in the regulation of permeability. Several studies have identified an association Hantavirus NP with a small ubiquitin-like modifier-1, with a small ubiquitin-like modifier protein-1-interacting and Fas-mediated apoptosis enhancer Daxx (-); However, none of these proteins are involved in the regulation of endothelial cell permeability.

A much more promising candidate is αVβ3-integrin, cellular surface receptor for pathogenic hantaviruses. integrin αVβ3 participates in the regulation of cell-cell adhesion, platelet aggregation, and maintenance of vascular barrier function. Hantaviruses binding to αVβ3 integrin β3 inhibit endothelial cell migration by integrin-directed. In addition, it shows that the so-called hantaviruses bind plexin-semaphorin-integrin domains are present on the surface of the molecule integrin αVβ3 dormant. This interaction is assumed to inhibit the function of integrin αVβ3 usual and may interfere with the regulation of endothelial permeability (,, -). A further study identified immunoreceptor tyrosine-based activation motif in the cytoplasmic tail G1 of all HPS hantaviruses cause. G1 immunoreceptor tyrosine-based activation motif bind key cellular kinase that regulates immune function and endothelial cells. The implications of this interaction is unclear, but the influence on permeability regulation is possible ().

hantaviruses Diagnosis is usually made on the basis of clinical and serological findings. Hantavirus should be performed in patients with fever, back pain, kidney failure, and outdoor activities recently. In the course of the disease early, thrombocytopenia detected. ELISA-based detection is an NP-specific IgM antibodies are usually done for the laboratory diagnosis of acute infection hantavirus (). Highest titers were demonstrated between 8 and 25 d after the onset of illness. It is important to note for the differential diagnosis of Puumala and Hantaan virus infection that PUUV NP-specific ELISA HTNV cross-react with the NP, while HTNV NP-specific ELISA showed virtually no cross-reaction with PUUV NP (). In addition, the immunochromatographic test () and reverse transcriptase-PCR has been used increasingly in recent years, but they have not become widely accepted as a standard clinical laboratory tests (,).

Currently, there are no antiviral drugs that apply for hantavirus infection cure. Treatment of patients with HFRS or HPS limited to supporting procedures to keep under control the symptoms, which may be life-threatening. Patients are typically monitored in the emergency room or intensive care unit for close monitoring and treatment until a patient’s immune system has cleared the virus and begin the healing phase.

Ribavirin (1-β-D-ribofuranosyl-1, 2,4-triazole-3-carboxamide), a guanosine analog, shown to have anti-hantaviral activity. controlled trials in the early 1990s reported a decreased viral titers, the survival rate is higher, and decreased morbidity in both the murine models and in patients with HFRS (,). However, the new trial of ribavirin in patients with HPS does not confirm the promising results (,,). More recently, it was shown that inhibiting the production of hantavirus descent ribavirin in vitro. Antiviral activity is due to the incorporation of ribavirin into RNA newborn, so that a high frequency of mutation (9.5 / 1,000 nucleotides) and, hence, in a transcriptionally defective viral RNA synthesis (). The results show that hantavirus RNA-dependent RNA polymerase vulnerable to drugs that cause catastrophic errors during the replication cycle of the virus. This insight enables a new strategy for the development of therapeutic procedures, including incorporation of a lethal mutation during replication hantavirus ()

Typically, virus infection induces certain antivirus processes in target cells .; among them is the expression of interferon and IFN-inducible genes. In VeroE6 cells, it was demonstrated that early treatment with human IFN-α, -β, and -γ leads to inhibition of HTNV, PUUV, and replication TULV (). The human IFN-induced protein MxA, an intracytoplasmic from Dynamin GTPase superfamily, showed antiviral activity against a variety of RNA viruses, including hantaviruses. induces viral replication MxA protein expression were shown to interfere with the replication cycle of hantaviruses (,,). However, until now, no study has shown how interferon and IFN-inducible protein could serve as a therapeutic agent for hantavirus infection.

Recently, Klingstrom et al. () Passive cynomolgus macaques immunized with neutralizing mAb and then challenged them with the wild-type PUUV. A delayed onset of viremia and seroconversion was observed, and one of the immunized monkeys showed no symptoms or increased levels of IL-6, IL-10, and TNF-α. The efficiency of passive immunization was also confirmed in a previous study in Syrian hamster models for HPS off using antibodies against Andes virus glycoprotein induced by DNA vaccine (). Future clinical trials should indicate whether passive immunization could represent a therapeutic instrument for the treatment of acute HFRS or HPS in humans.

In a study in China recently, it was reported that the intracellular applied to a single-chain Fv of mAb against NP HTNV capable of binding to hantavirus nucleocapsid protein in the cytoplasm of infected cells. This method could represent a new therapeutic approach in the future ().

Unusual approaches such as assessment of therapeutic compounds targeted against phleboviruses plant (a plant virus of the family Bunyaviridae) () or an integrated application of traditional Chinese medicine () pursued to identify treatment for hantavirus infection; However, until now, none of these studies have provided important breakthrough in therapy HFRS or HPS. It is conceivable that the explanation of the molecular mechanism of hantavirus pathophysiology or, more precisely, clarification of cellular processes that participate in endothelial dysfunction during HFRS and HPS in the future will provide new targets for effective therapeutic strategy.

Because infection with hantavirus some species results in morbidity and mortality, and in view of the present situation of effective antiviral drugs is lost, it is very important to prevent infection. On the one hand, this is indicated to avoid places where rodents students live in large numbers to contact ignorant with rodent excretions containing virus. This includes keeping the house and nearby surrounding areas-free mice, for example, by removing the crawl space and debris and remove food sources to make it home and work areas unattractive to rodents. On the other hand, many research efforts have been made in recent years to develop an effective and safe vaccine against the hantaviruses implement vaccination technique varies from killed virus by recombinant DNA technology. In Korea, the vaccine HTNV formalin-inactive, Hantavax (Korea Green Cross, Seoul, Korea), resulting from a virus derived from mouse brain, are commercially available. Hantavax shown to induce high titers of specific IgG antibodies in nearly 100% of human volunteers after three vaccination accompanied by the production of antibodies in approximately 80% of the individual test; However, antibody titers declined very rapidly within a few months, and booster do not produce a satisfactory level of protection (-). Further research confirms that Hantavax raises the level of protection is only between 30 and 50% for a longer period of time (). In another study, a vaccine HTNV VeroE6 cell-culture-derived formaldehyde inactive showed significantly higher antibody titers and protection levels in Balb / c mice compared to Hantavax; However, the level of protection in humans is very low (). To this day, no hantavirus vaccine based on a virus is not active and that a satisfactory level of protection of human Potential (,,).

In addition to inactive particles of the whole virus, viral components alone (viral structural proteins NP, G1, and G2) obtained by recombinant DNA technology, is expressed in several cell culture systems and organisms, and tested for immunogenicity and potential protector , For example, recombinant NP PUUV expressed in yeast induced protective immunity in mice bank (), and recombinant NP of DOBV expressed in yeast induced a high antibody titers in Balb / c and C57BL / 6 mice (). PUUV NP successfully expressed in transgenic tobacco and potato plants by our group but failed to induce antibody responses in mice when administered as an oral vaccine (,). More recently, recombinant NP of DOBV tested in combination with various adjuvants on the immunogenicity and protective efficacy in C57 / BL6 mice. The study identifies the adjuvant Freund as an additive of choice because the mice vaccinated with the adjuvant is in combination with NP DOBV indicates the level of protection from challenge by 75%, while the use of adjuvants such as Alum, which induces a strong Th2-type immune response, do not give rise to protective immunity ( ).

In addition, known immunogenic epitope of PUUV, DOBV, and HTNV NP incorporated into the virus particle chimeric hepatitis B core and cause high antibody titers and protective immunity in mice bank (,). Additionally, a live recombinant viruses that express and carry hantavirus structural proteins are built. For example, HTNV NP, G1, and G2 Baculovirus expressed with the vaccinia virus vector and shown to induce protection after challenge Hantaan virus in hamster and rat models (-). A Hantaan virus vaccine vaccinia vectors tested in Phase II, double-blind, placebo-controlled clinical trial among 142 volunteers. Antibodies to Hantaan virus was detected in 72% of the individual test ().

Finally, plasmid-based DNA vaccine, which revealed hantavirus structural protein, immunogenic and protective potential tested them. Many groups introduce structural protein coding sequences from a variety of hantaviruses pathogens into a eukaryotic expression vector and tested CMV usually based immunogenic potential of this DNA vaccine in a mouse, hamster, and Rhesus monkey models. DNA vaccines have always induced a high antibody titers are often of the type of neutralizing (,, -). Despite the extensive work of many research groups in the field of vaccine development hantavirus and the presence of promising data in animal models, there is still no worldwide approved and vaccine commercially available against hantaviruses, and it seems unlikely that this situation will change in the near future period front.

Since the discovery of HFRS HTNV as the causative agent, a lot of knowledge about a variety of hantaviruses and their manifestations in animals and humans have accumulated. NE, HFRS and HPS is a human disease, caused by hantaviruses, which may be faced by clinical nephrologists. The diagnosis rests on serological evidence. Supportive therapy depends on the strain of hantavirus and clinical symptoms, especially important in HFRS and HPS, the correction of the bleeding, BP maintenance, and treatment of renal or respiratory insufficiency may be indicated. Expected better understand virus biology and pathophysiology will lead to more effective therapeutic modalities and specific in the future.

We are very grateful to Prof. Andrassy and Prof. Konrad Gholamreza Darai for the generous support and aid critical comments.

Published online before print. The date of publication is available at

© 2020 American Society of Nephrology

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