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Hantavirus infection: an emerging infectious disease causing acute renal failure

2012; Elsevier BV; Volume: 83; Issue: 1 Linguagem: Inglês

10.1038/ki.2012.360

1523-1755

Ellen Krautkrämer, Martin Zeier, Alexander Plyusnin,

Viral Infections and Outbreaks Research

The function of the kidney with its highly differentiated and specialized cell types is affected by infection with several viruses. Viral infections of the kidney have a negative impact not only on patients undergoing renal transplantation and immunosuppression. Besides the increasing number of patients suffering from HIV-associated nephropathy, another group of viruses infects immunocompetent patients and induces renal failure. Hantaviruses belong nowadays to the emerging zoonoses that increase in number and geographic distribution. The viruses are distributed worldwide in endemic areas and distribution seems to expand. Together with the increase in the number of cases in the last few years, the understanding of epidemiology and pathology has deepened and some concepts had to be changed. Symptoms and mortality vary between species. The classification refers to geographical distribution: New World hantaviruses causing hantavirus cardiopulmonary syndrome (HCPS) and Old World hantaviruses causing hemorrhagic fever with renal syndrome (HFRS). Indeed, in most HFRS cases, the kidney is mainly affected and HCPS is characterized by cardiopulmonary involvement. But the picture of strict organ tropism is changing and reports of pulmonary findings and nonrenal manifestations in infections with Old World hantaviruses are increasing. However, the overall symptoms—vascular alterations and leakage—that are responsible for organ failure are characteristic for all diseases caused by hantaviruses. The function of the kidney with its highly differentiated and specialized cell types is affected by infection with several viruses. Viral infections of the kidney have a negative impact not only on patients undergoing renal transplantation and immunosuppression. Besides the increasing number of patients suffering from HIV-associated nephropathy, another group of viruses infects immunocompetent patients and induces renal failure. Hantaviruses belong nowadays to the emerging zoonoses that increase in number and geographic distribution. The viruses are distributed worldwide in endemic areas and distribution seems to expand. Together with the increase in the number of cases in the last few years, the understanding of epidemiology and pathology has deepened and some concepts had to be changed. Symptoms and mortality vary between species. The classification refers to geographical distribution: New World hantaviruses causing hantavirus cardiopulmonary syndrome (HCPS) and Old World hantaviruses causing hemorrhagic fever with renal syndrome (HFRS). Indeed, in most HFRS cases, the kidney is mainly affected and HCPS is characterized by cardiopulmonary involvement. But the picture of strict organ tropism is changing and reports of pulmonary findings and nonrenal manifestations in infections with Old World hantaviruses are increasing. However, the overall symptoms—vascular alterations and leakage—that are responsible for organ failure are characteristic for all diseases caused by hantaviruses. Hantaviruses mostly represent rodent-borne pathogens that infect different cell types and affect organ function.1.Plyusnin A. Elliott R. Bunyaviridae: Molecular and Cellular Biology. Caister Academic Press, Norfolk2011Google Scholar Infections comprise respiratory and renal illnesses ranging from subclinical, mild, and severe courses to fatal outcome. Moreover, some species are nonpathogenic to humans. Both virus- and patient-specific determinants are responsible for this heterogeneity in diseases caused by hantaviruses. Infection with pathogenic hantaviruses leads to the deterioration of the highly specialized and differentiated endothelial cell types, resulting in the loss of barrier function of the vasculature. Cellular damage can be induced by physical and chemical stress or infection. In hemorrhagic fever with renal syndrome (HFRS), the clinical picture is characterized by acute renal failure with often massive proteinuria caused by tubular and glomerular involvement. The mechanism of kidney injury during infection is not fully understood. In the last few years, interdisciplinary research aspects of epidemiology, virology, and nephrology provided useful insights in the pathology of diseases caused by these emerging viruses. Despite heterogeneous clinical pictures and different host reservoirs, hantaviruses have similar genomic organization, and RNA-encoded proteins share high levels of sequence homology.2.Londono A.F. Diaz F.J. Agudelo-Florez P. et al.Genetic evidence of hantavirus infections in wild rodents from northwestern Colombia.Vector Borne Zoonotic Dis. 2011; 11: 701-708Crossref PubMed Scopus (24) Google Scholar Hantaviruses constitute the genus Hantavirus in the family Bunyaviridae.3.Schmaljohn C. Hjelle B. Hantaviruses: a global disease problem.Emerg Infect Dis. 1997; 3: 95-104Crossref PubMed Scopus (828) Google Scholar Similar to other bunyaviruses, they are enveloped negative-stranded RNA viruses with a tripartite genome. Large (L), medium (M), and small (S) RNA segments encode, respectively, the viral RNA-dependent RNA-polymerase (the L protein), a precursor for two surface glycoproteins, Gn and Gc, and the nucleocapsid (N) protein. In some hantaviruses, the S segment encodes also a nonstructural protein NS, which acts as an interferon antagonist.4.Jääskeläinen K.M. Kaukinen P. Minskaya E.S. et al.Tula and Puumala hantavirus NSs ORFs are functional and the products inhibit activation of the interferon-beta promoter.J Med Virol. 2007; 79: 1527-1536Crossref PubMed Scopus (119) Google Scholar Genetic diversity in hantaviruses is generated by genetic drift, reassortment of genome RNA segments, and recombination.5.Sironen T. Vaheri A. Plyusnin A. Molecular evolution of Puumala hantavirus.J Virol. 2001; 75: 11803-11810Crossref PubMed Scopus (98) Google Scholar Genetic drift occurs through accumulation of point mutations (through the genome) and small insertions/deletions (in the noncoding regions). Reassortment of genome RNA segments seems to occur much more frequently than recombination.6.Razzauti M. Plyusnina A. Henttonen H. et al.Accumulation of point mutations and reassortment of genomic RNA segments are involved in the microevolution of Puumala hantavirus in a bank vole (Myodes glareolus) population.J Gen Virol. 2008; 89: 1649-1660Crossref PubMed Scopus (48) Google Scholar Peculiar distribution of rodent host species has led to specific geographical pattern of hantaviruses and associated diseases. In Eurasia, hantaviruses cause HFRS of various severity. In Asia, the list of hantavirus pathogens includes Hantaan, Seoul, and Amur-Soochong viruses, which affect mostly China, South Korea, and the far-eastern region of Russia.7.Bi Z. Formenty P.B. Roth C.E. Hantavirus infection: a review and global update.J Infect Dev Ctries. 2008; 2: 3-23Crossref PubMed Scopus (196) Google Scholar,8.Zhang Y.Z. Zou Y. Fu Z.F. et al.Hantavirus infections in humans and animals, China.Emerg Infect Dis. 2010; 16: 1195-1203Crossref PubMed Scopus (209) Google Scholar In Europe, in addition to the above-mentioned Seoul virus, Puumala, Dobrava-Belgrade, Saaremaa, and Tula viruses are found, often in co-circulation.7.Bi Z. Formenty P.B. Roth C.E. Hantavirus infection: a review and global update.J Infect Dev Ctries. 2008; 2: 3-23Crossref PubMed Scopus (196) Google Scholar,9.Vapalahti O. Mustonen J. Lundkvist A. et al.Hantavirus infections in Europe.Lancet Infect Dis. 2003; 3: 653-661Abstract Full Text Full Text PDF PubMed Scopus (495) Google Scholar Endemic area includes northern and central Europe (Denmark, Finland, Norway, Sweden, Belgium, Chech Republic, France, Germany, and Slovakia), Alpe-Adrian region (Austria, Croatia, Hungary, and Slovenia), the Balkans (Albania, Greece), and the European part of Russia. Sin Nombre, Andes, and related viruses such as New York, Bayou, Laguna Negra, Choclo, Rio Mamore, Araraquara, Castelo dos Sonhos viruses cause hantavirus cardiopulmonary syndrome (HCPS) in the Americas (Argentina, Bolivia, Brazil, Canada, Chile, Panama, Paraguay, Uruguay, and USA). Naturally, both lists—for the viruses and for the countries—are incomplete and it is safe to assume that they will get longer in the nearest future. Currently, 23 distinct hantaviruses species have been recognized; the list of provisional species includes 30 viruses.10.Plyusnin A. Beaty B. Elliott R. et al.Bunyaviridae.in: King A. Lefkowitz E. Adams J. Carstens E. Virus Taxonomy: Classification And Nomenclature Of Viruses. Ninth Report of the International Committee on Taxonomy of Viruses. Elsevier, San Diego2011: 693-709Google Scholar Recently, we have been witnessing an ‘explosion’ in a number of newly discovered hantaviruses that was started by publication of Klempa et al.,11.Klempa B. Fichet-Calvet E. Lecompte E. et al.Hantavirus in African wood mouse, Guinea.Emerg Infect Dis. 2006; 12: 838-840Crossref PubMed Scopus (235) Google Scholar who designed remarkably efficient, generic PCR primers for the recovery of partial hantaviral L segment sequences. Recently, the first indigenous African hantavirus (Sangassou virus) was isolated, and a retrospective seroepidemiological analysis revealed the presence of Sangassou virus-specific neutralizing antibodies in the sera of patients suffering from fever of unknown origin.12.Klempa B. Koivogui L. Sylla O. et al.Serological evidence of human hantavirus infections in Guinea, West Africa.J Infect Dis. 2010; 201: 1031-1034Crossref PubMed Scopus (53) Google Scholar Besides the detection of new hantaviruses in rodents, other small mammals such as shrews, moles, and bats were captured and identified as reservoir hosts of hantaviruses. The epidemiological importance of these hantaviruses remains to be evaluated. The knowledge of hantaviruses as viruses of broader host range and identification of possible new human pathogens increase the number of populations that may be affected by hantavirus infection. Epidemiological studies also try to identify risk factors for severe courses. The male-to-female ratio for hantavirus disease varies from 2 to 5:1. Interestingly, though the prevalence of HCPS and HFRS is higher among males than females, the case fatality ratio is higher for women in HCPS, HFRS, and nephropathia epidemica (NE).13.Martinez V.P. Bellomo C.M. Cacace M.L. et al.Hantavirus pulmonary syndrome in Argentina, 1995-2008.Emerg Infect Dis. 2010; 16: 1853-1860Crossref PubMed Scopus (71) Google Scholar, 14.Klein S.L. Marks M.A. Li W. et al.Sex differences in the incidence and case fatality rates from hemorrhagic fever with renal syndrome in China, 2004-2008.Clin Infect Dis. 2011; 52: 1414-1421Crossref PubMed Scopus (55) Google Scholar, 15.Hjertqvist M. Klein S.L. Ahlm C. et al.Mortality rate patterns for hemorrhagic fever with renal syndrome caused by Puumala virus.Emerg Infect Dis. 2010; 16: 1584-1586Crossref PubMed Scopus (89) Google Scholar Besides gender, several clinical parameters have been analyzed as predictors for the clinical course. The study of Rasche et al. and our own observations (Figure 1) in cohorts of patients with NE demonstrate that a low platelet count ( 620μmol/l).16.Rasche F.M. Uhel B. Kruger D.H. et al.Thrombocytopenia and acute renal failure in Puumala hantavirus infections.Emerg Infect Dis. 2004; 10: 1420-1425Crossref PubMed Scopus (72) Google Scholar As the first description of New World hantaviruses, the differences in the clinical pictures were emphasized.17.Nichol S.T. Spiropoulou C.F. Morzunov S. et al.Genetic identification of a hantavirus associated with an outbreak of acute respiratory illness.Science. 1993; 262: 914-917Crossref PubMed Scopus (935) Google Scholar It was a clear-cut picture of New World hantaviruses causing HCPS and Old World hantaviruses causing HFRS. Indeed, most European and Asian cases of hantavirus infection fit well in this scheme and are characterized by acute renal failure. However, in the last few years, reports of hantavirus cases with divergent symptomatology increased in quantity. Cases of hantavirus infection with pulmonary involvement were observed in Europe, and acute renal failure occurs in patients infected with New World hantaviruses.18.Rasmuson J. Andersson C. Norrman E. et al.Time to revise the paradigm of hantavirus syndromes? Hantavirus pulmonary syndrome caused by European hantavirus.Eur J Clin Microbiol Infect Dis. 2011; 30: 685-690Crossref PubMed Scopus (90) Google Scholar,19.MacNeil A. Ksiazek T.G. Rollin P.E. Hantavirus pulmonary syndrome, United States, 1993-2009.Emerg Infect Dis. 2011; 17: 1195-1201Crossref PubMed Scopus (84) Google Scholar Today we are dealing with hantavirus infection as an intriguing event with a unique range of symptoms and the intensity of presenting symptoms for each individual is also unique. Hantavirus infections, HCPS and HFRS, are characterized by sudden onset with flu-like symptoms, such as fever, headache, abdominal pain, and nausea, followed by a hypotensive phase with often severe thrombocytopenia and increased vascular permeability, leukocytosis, elevated levels of lactate dehydrogenase, and C-reactive protein. After this phase, the infection manifests in different organs. HCPS is a predominantly cardiopulmonary disease in which renal symptoms may be observed as well. In contrast, in most cases, HFRS affects predominantly kidney function. Laboratory findings in HFRS and NE demonstrate high-serum creatinine and low-serum albumin, and urinalysis shows hematuria and albuminuria. This oliguric phase with acute renal failure is followed by the diuretic phase in which renal function improves and the convalescent phase during which patients recover completely. Acute renal failure is observed in 90–95% of infections with Old World hantaviruses. The long-term prognosis of NE caused by Puumala virus is favorable and most patients fully recover renal function. However, hypertension is discussed to be a long-term consequence of Puumala virus infection.20.Miettinen M.H. Makela S.M. Ala-Houhala I.O. et al.Ten-year prognosis of Puumala hantavirus-induced acute interstitial nephritis.Kidney Int. 2006; 69: 2043-2048Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar Although mortality rate for NE is <1%, case fatality rate for HFRS ranges from 5 to 15% and up to 50% for HCPS. Severity is mainly determined by the hantavirus species that causes the disease, but it also varies individually from subclinical presentation to fatality. Cardiogenic shock due to respiratory failure is responsible for the often fatal outcome of HCPS. Death due to HFRS maybe because of several complications: renal insufficiency, edema and hemorrhages, encephalopathy, or shock. Signs and symptoms of hantavirus infection may present differently and can affect different organs.21.Hautala T. Mahonen S.M. Sironen T. et al.Central nervous system-related symptoms and findings are common in acute Puumala hantavirus infection.Ann Med. 2010; 42: 344-351Crossref PubMed Scopus (36) Google Scholar,22.Dzagurova T.K. Witkowski P.T. Tkachenko E.A. et al.Isolation of sochi virus from a fatal case of hantavirus disease with fulminant clinical course.Clin Infect Dis. 2012; 54: e1-e4Crossref PubMed Scopus (20) Google Scholar Serological tests for the detection of IgM and IgG antibodies based on indirect immunofluorescence assays, strip immunoblot, or enzyme-linked immunosorbent assays are commercially available and are commonly used for diagnosis. IgM response starts with the onset of symptoms, is early detectable, and indicates acute infection. Patients develop antibodies that recognize hantaviral structural proteins: the envelope glycoproteins (Gn, Gc) and the nucleocapsid proteins (N protein). Serological tests detect antibodies specific for the N protein. Identification of the infecting hantavirus species by these methods is often not reliable because of cross-reactivity of antihantavirus antibodies. Reverse transcription PCR with specific primers detects viral genomes in blood or tissue specimens and allows the differentiation between hantaviruses species. Viral RNA in blood samples is detectable only after the onset of symptoms. In this phase, viral RNA may be detected before IgM antibodies are present.23.Evander M. Eriksson I. Pettersson L. et al.Puumala hantavirus viremia diagnosed by real-time reverse transcriptase PCR using samples from patients with hemorrhagic fever and renal syndrome.J Clin Microbiol. 2007; 45: 2491-2497Crossref PubMed Scopus (71) Google Scholar However, later after onset, reverse transcription PCR is not applicable for diagnosis because of short or low-level viremic status of patients. Therefore, the diagnosis should occur on the basis of clinical symptoms together with a serological confirmation.24.Vaheri A. Vapalahti O. Plyusnin A. How to diagnose hantavirus infections and detect them in rodents and insectivores.Rev Med Virol. 2008; 18: 277-288Crossref PubMed Scopus (84) Google Scholar As no specific antiviral medication is available, the treatment of infection is limited to supportive therapy. The nucleoside analog, ribavirin, reduces mortality in HFRS, but the usefulness in HCPS patients is still controversial. New strategies for vaccination and treatment are currently under investigation. The effects of vaccines based on recombinant hantaviral antigens, virus-like particles, or transfer of adenoviral vectors expressing hantaviral proteins were studied in animal models and clinical trials. Furthermore, steps of the viral replication cycle were explored as potential therapeutic targets: peptides and small molecules, which block viral receptors or drugs that inhibit the increase of endothelial permeability.25.Krüger D.H. Schonrich G. Klempa B. Human pathogenic hantaviruses and prevention of infection.Hum Vaccin. 2011; 7: 685-693Crossref PubMed Scopus (139) Google Scholar The understanding of hantaviral pathogenesis is a prerequisite for the development of such specific antiviral strategies. In addition to the observation that gender may influence the risk for specific symptoms and fatal outcome, certain human leukocyte antigen (HLA) haplotypes were identified to be associated with milder or severe courses.26.Mustonen J. Partanen J. Kanerva M. et al.Genetic susceptibility to severe course of nephropathia epidemica caused by Puumala hantavirus.Kidney Int. 1996; 49: 217-221Abstract Full Text PDF PubMed Scopus (178) Google Scholar, 27.Makela S. Mustonen J. Ala-Houhala I. et al.Human leukocyte antigen-B8-DR3 is a more important risk factor for severe Puumala hantavirus infection than the tumor necrosis factor-alpha(-308) G/A polymorphism.J Infect Dis. 2002; 186: 843-846Crossref PubMed Scopus (95) Google Scholar, 28.Wang M.L. Lai J.H. Zhu Y. et al.Genetic susceptibility to haemorrhagic fever with renal syndrome caused by Hantaan virus in Chinese Han population.Int J Immunogenet. 2009; 36: 227-229Crossref PubMed Scopus (24) Google Scholar Therefore, the frequency of severe courses in endemic areas may be dependent on the genetic susceptibility by the prevalence of certain HLA genes in the population. Furthermore, the association between HLA alleles and severity implies an involvement of T-cell-mediated effects in hantavirus pathogenesis. High counts of specific CD8+ cells were observed in severe cases of HPS and in HFRS patients.29.Kilpatrick E.D. Terajima M. Koster F.T. et al.Role of specific CD8+ T cells in the severity of a fulminant zoonotic viral hemorrhagic fever, hantavirus pulmonary syndrome.J Immunol. 2004; 172: 3297-3304Crossref PubMed Scopus (148) Google Scholar,30.Markotic A. Dasic G. Gagro A. et al.Role of peripheral blood mononuclear cell (PBMC) phenotype changes in the pathogenesis of haemorrhagic fever with renal syndrome (HFRS).Clin Exp Immunol. 1999; 115: 329-334Crossref PubMed Scopus (34) Google Scholar The absence of obvious endothelial damage in biopsies suggests that barrier breakdown is caused by the release of cytokines rather than by endothelial cell death. Endothelial function is regulated by a complex interplay between endothelial cells with platelets and immune cells. In noninflamed state, endothelial cells regulate permeability, quiesce leukocytes, and inhibit activation of platelets. Infection of endothelial cells leads to activation of signaling pathways, induction of proinflammatory chemokines, and recruitment of immune cells at the site of inflammation. The inflammatory response leads to the activation of the complement system and the secretion of multiple proinflammatory cytokines that interfere with endothelial function and induce leakage of proteins. Cytokines in humans during hantavirus infection include tumor necrosis factors, interleukins, interferons, colony-stimulating factors, and transforming growth factors (summarized in Safronetz et al.31.Safronetz D. Zivcec M. Lacasse R. et al.Pathogenesis and host response in Syrian hamsters following intranasal infection with Andes virus.PLoS Pathog. 2011; 7: e1002426Crossref PubMed Scopus (55) Google Scholar). It is still unclear which cytokines have a critical role in the capillary leakage in hantavirus diseases. Another subset of T cells—regulatory T cells (Treg)—is downregulated in hantavirus infection in humans and upregulated in rodents.32.Lindgren T. Ahlm C. Mohamed N. et al.Longitudinal analysis of the human T cell response during acute hantavirus infection.J Virol. 2011; 85: 10252-10260Crossref PubMed Scopus (71) Google Scholar, 33.Zhu L.Y. Chi L.J. Wang X. et al.Reduced circulating CD4+CD25+ cell populations in haemorrhagic fever with renal syndrome.Clin Exp Immunol. 2009; 156: 88-96Crossref PubMed Scopus (24) Google Scholar, 34.Chen L.B. Yang W.S. Abnormalities of T cell immunoregulation in hemorrhagic fever with renal syndrome.J Infect Dis. 1990; 161: 1016-1019Crossref PubMed Scopus (39) Google Scholar, 35.Easterbrook J.D. Zink M.C. Klein S.L. Regulatory T cells enhance persistence of the zoonotic pathogen Seoul virus in its reservoir host.Proc Natl Acad Sci USA. 2007; 104: 15502-15507Crossref PubMed Scopus (77) Google Scholar Treg cells mediate suppression of immune response and may therefore be beneficial in infection by limiting the immunopathogenesis. The downregulation of Treg cells in hantavirus infection of humans may result in enhanced immune-mediated tissue damage. In contrast, the upregulation of Treg cells contributes to the manifestation of hantaviral persistence in rodents. Neither viral pathogenicity factor(s) nor determinants for organ manifestation responsible for the clinical picture have been identified so far. The clinical symptoms were elicited by vascular leakage. The control of endothelial barrier function is complex and makes the understanding of the molecular pathogenesis difficult, and research is hampered by the lack of an adequate small animal model. Data from human blood samples and biopsies, infected rodent reservoir species, cell culture, and monkey models suggest pathomechanisms, which are based on direct effects by viral replication and indirect damage caused by the overreacting immune system. Different cell types have been identified to be permissive for hantavirus infection: endothelial, epithelial cells of different organs, and several immune cells (monocytes, macrophages, dendritic cells).36.Temonen M. Vapalahti O. Holthofer H. et al.Susceptibility of human cells to Puumala virus infection.J Gen Virol. 1993; 74: 515-518Crossref PubMed Scopus (88) Google Scholar,37.Raftery M.J. Kraus A.A. Ulrich R. et al.Hantavirus infection of dendritic cells.J Virol. 2002; 76: 10724-10733Crossref PubMed Scopus (107) Google Scholar Dendritic cells residing in the respiratory tract become infected and may facilitate hantaviral spread to endothelial cells of distant organs. Hantaviral entry in target cells is mediated by integrins and CD55.38.Gavrilovskaya I.N. Shepley M. Shaw R. et al.beta3 Integrins mediate the cellular entry of hantaviruses that cause respiratory failure.Proc Natl Acad Sci USA. 1998; 95: 7074-7079Crossref PubMed Scopus (335) Google Scholar,39.Krautkrämer E. Grouls S. Stein N. et al.Pathogenic old world hantaviruses infect renal glomerular and tubular cells and induce disassembling of cell-to-cell contacts.J Virol. 2011; 85: 9811-9823Crossref PubMed Scopus (50) Google Scholar Interestingly, pathogenic and nonpathogenic hantaviruses differ in the use of integrin receptors: pathogenic hantaviruses enter through beta 3 integrins, whereas nonpathogenic hantaviruses utilize beta 1 integrin. As beta 3 integrins function in angiogenesis and regulation of vascular permeability, the use as entry receptor may contribute to the disease.40.Brooks P.C. Clark R.A. Cheresh D.A. Requirement of vascular integrin alpha v beta 3 for angiogenesis.Science. 1994; 264: 569-571Crossref PubMed Scopus (2732) Google Scholar Upon entry, viral replication and spread take place. Pathogenic hantaviruses exert a delayed induction of interferon response, facilitating initial viral spread that leads afterward to enhanced damage due to a stronger immune response. High viral RNA copy numbers correlate with low platelet counts, and the mean viral load in fatal cases is higher than in survivors.41.Terajima M. Hendershot J.D. Kariwa H. et al.High levels of viremia in patients with the Hantavirus pulmonary syndrome.J Infect Dis. 1999; 180: 2030-2034Crossref PubMed Scopus (96) Google Scholar However, viral replication does not result in any gross cytopathic effects causing cell death, but changes of subcellular structures leading to cellular dysfunction were observed. Tight and adherens junctions are specialized multiprotein complexes that are crucial for the endothelial and epithelial barrier function. Studies in vitro and in biopsy samples of hantavirus-infected patients demonstrate the disruption of cell-to-cell contacts and its correlation with the severity of clinical picture (Figure 2).39.Krautkrämer E. Grouls S. Stein N. et al.Pathogenic old world hantaviruses infect renal glomerular and tubular cells and induce disassembling of cell-to-cell contacts.J Virol. 2011; 85: 9811-9823Crossref PubMed Scopus (50) Google Scholar The mechanism of disruption of cell-to-cell contacts is not known. Barrier breakdown may be mediated directly by infection and/or by secretion of cytokines involved in the regulation of permeability. In vitro studies demonstrate, that hantavirus-infected endothelial cells are sensitized to the induction of permeability by vascular endothelial growth factor and demonstrate enhanced internalization of E-cadherin.42.Gorbunova E. Gavrilovskaya I.N. Mackow E.R. Pathogenic hantaviruses Andes virus and Hantaan virus induce adherens junction disassembly by directing vascular endothelial cadherin internalization in human endothelial cells.J Virol. 2010; 84: 7405-7411Crossref PubMed Scopus (66) Google Scholar Identification of the signaling pathways that are disturbed by hantavirus infection provides possible options for antiviral therapeutic strategies. To draw a comprehensive picture of molecular pathogenesis is still difficult. Severe hantavirus infections are multifactorial diseases involving both patient- and virus-specific determinants. Several factors have been identified so far that influence the clinical course, such as gender, HLA haplotype, viral load, cytokine levels, and T-cell response. Analysis of the underlying molecular pathomechanisms revealed that hantavirus infection impairs the integrity of cell-to-cell contacts. This loss of endothelial barrier function may be mediated by altered signaling pathways involving integrin, vascular endothelial growth factor, and E-cadherin. Increasing case numbers that are associated with host reservoirs and influenced by climatic conditions and the broad range and variance of symptoms, whose molecular mechanisms are not yet completely understood, make the hantavirus one of the emerging zoonoses that will require the attention of a multidisciplinary research. At present, the lack of vaccines and a specific antiviral therapy render the prevention of infection as the only way to decrease the emergence of hantavirus cases. Closer attention in endemic areas is needed for the control of mice in and outside houses and for the prevention of contact with contaminated aerosols. Furthermore, increased awareness of hantavirus infection should be given by a medical practitioner early in the diagnosis of flu-like symptoms with acute renal failure and thrombocytopenia.