RESUMEN
Hemorrhagic fever with renal syndrome (HFRS) and reversible splenial lesion syndrome are both considered uncommon conditions relatively rare. Fever, hemorrhage, and acute kidney injury are the prevailing symptoms frequently observed in cases of HFRS. We describe a case of a middle-aged man who had been hospitalized with fever and acute neurological symptoms. His main symptom was recurrent dizziness. Cranial computed tomography (CT) did not reveal any obvious lesions, such as encephalorrhagia or infarctions. The splenium of corpus callosum showed hyperintensity on brain magnetic resonance imaging (MRI), which is in line with the characteristic radiographic observations of reversible splenial lesion syndrome (RESLES). Further analyses revealed that the patient's platelet counts had decreased to 7×109/L while hemorrhagic fever antibodies were positive. Eventually, the patient was diagnosed with HFRS and exhibited clinical improvements after active treatment.
Asunto(s)
Encefalopatías , Fiebre Hemorrágica con Síndrome Renal , Masculino , Persona de Mediana Edad , Humanos , Encefalopatías/diagnóstico , Fiebre Hemorrágica con Síndrome Renal/complicaciones , Fiebre Hemorrágica con Síndrome Renal/diagnóstico por imagen , Fiebre Hemorrágica con Síndrome Renal/patología , Imagen por Resonancia Magnética , Encéfalo/patología , Cuerpo Calloso/diagnóstico por imagen , Cuerpo Calloso/patologíaRESUMEN
OBJECTIVE: This study aimed to explore the role of glomerular lesions in patients who suffered from acute kidney injury (AKI) during hemorrhagic fever with renal syndrome (HFRS). METHODS: The study comprised 66 patients with AKI during HFRS treated at the National Clinical Research Center of Kidney Diseases of China, Jinling Hospital, from January 2014 to December 2018. According to the kidney pathological findings, the 66 patients were divided into two groups: the tubulointerstitial injury group (HFRS-TI group, n = 43) and the tubulointerstitial injury with glomerular lesions group (HFRS-GL group, n = 23). The clinical and pathological characteristics of the 66 patients were analyzed. RESULTS: There were 9 cases of IgA nephropathy, 1 case of membranous nephropathy, 2 cases of diabetic nephropathy, and 11 cases of mesangial proliferative glomerulonephritis in the HFRS-GL group. There were more males in the HFRS-GL group than in the HFRS-TI group (92.3% vs. 69.8%, p < .05). A higher proportion of interstitial fibrosis (56.5% vs. 27.9%, p < .05) and more immunoglobulin and complement depositions (p < .001) were observed in the HFRS-GL group than in the HFRS-TI group. Rates of remission of AKI were lower in the HFRS-GL group than in the HFRS-TI group (73.9% vs. 95.3%, p < .05). The presence of glomerular lesions (HR = 5.636, 95% CI = 1.121-28.329, p = .036) and moderate tubulointerstitial injury (HR = 3.598, 95% CI = 1.278-10.125, p = .015) were found to be independent risk factors for kidney prognosis. CONCLUSIONS: Patients with AKI during HFRS can have glomerular lesions or glomerulonephritis. Patients with AKI during HFRS who have glomerular lesions or moderate renal tubulointerstitial injury proven by kidney biopsy have a relatively poor kidney prognosis. A kidney biopsy can help determine long-term prognosis in patients with AKI during HFRS.
Asunto(s)
Lesión Renal Aguda , Glomerulonefritis , Fiebre Hemorrágica con Síndrome Renal , Masculino , Humanos , Fiebre Hemorrágica con Síndrome Renal/complicaciones , Fiebre Hemorrágica con Síndrome Renal/patología , Estudios Retrospectivos , Riñón/patología , Lesión Renal Aguda/patología , Glomerulonefritis/complicaciones , Glomerulonefritis/patología , PronósticoRESUMEN
Hantaan orthohantavirus (HTNV) can cause hemorrhagic fever with renal syndrome (HFRS) characterized by acute kidney injury and hemorrhage. Neutrophils are the most abundant innate immune cell and the body's first line of defense against pathogens. Currently, an increasing number of studies have shown that neutrophils may be a mixed blessing in terms of viral infections. However, the role of neutrophils in HFRS patients with HTNV infection has not been fully declared. In this study, we analyzed plasma levels of both myeloperoxidase (MPO) and MPO-DNA in HFRS patients, together with the clinical parameters. Neutrophil-platelet aggregates (NPAs) during the acute and convalescent phases of HFRS were also assessed. The results showed that plasma MPO-DNA levels had no change in different disease phases or severities of HFRS patients. Whereas plasma MPO significantly increased in the acute phase and critical/severe groups of HFRS patients. Furthermore, plasma MPO was positively correlated with inflammatory clinical parameters, such as white blood cell counts, neutrophil counts, and renal injury-related parameters, such as blood urea nitrogen, blood uric acid, and serum creatinine, as well as negatively correlated with and platelet counts. In addition, NPAs increased both in acute and convalescent phase in HFRS patients compared with normal controls. These results suggested that elevated plasma MPO in HFRS patients correlated with disease severity, together with the increases of NPAs in HFRS patients, which may provide new insights into potential role of neutrophils in the pathogenesis of HFRS.
Asunto(s)
Virus Hantaan , Fiebre Hemorrágica con Síndrome Renal , Fiebre Hemorrágica con Síndrome Renal/patología , Humanos , Recuento de Leucocitos , Peroxidasa , Índice de Severidad de la EnfermedadRESUMEN
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.
Asunto(s)
Virus Hantaan/patogenicidad , Fiebre Hemorrágica con Síndrome Renal/virología , Péptidos y Proteínas de Señalización Intercelular/deficiencia , Riñón/virología , Animales , Citocinas/sangre , Modelos Animales de Enfermedad , Predisposición Genética a la Enfermedad , Virus Hantaan/inmunología , Fiebre Hemorrágica con Síndrome Renal/inmunología , Fiebre Hemorrágica con Síndrome Renal/metabolismo , Fiebre Hemorrágica con Síndrome Renal/patología , Interacciones Huésped-Patógeno , Péptidos y Proteínas de Señalización Intercelular/genética , Riñón/inmunología , Riñón/metabolismo , Riñón/patología , Leucocitos/inmunología , Leucocitos/metabolismo , Leucocitos/virología , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Carga ViralRESUMEN
Hantaan virus infection may cause severe lethal hemorrhagic fever with renal syndrome (HFRS) in humans. The chemokine fractalkine (CX3CL1) acts as a proinflammatory cytokine, and it is elevated in several infectious diseases. However, little is known about the contributions of CX3CL1 to HFRS pathogenesis. Present study detected plasma CX3CL1 levels and expression of the receptor CX3CR1 in HFRS patients and discussed the possible effects of CX3CL1 on pathogenesis of HFRS. Plasma CX3CL1 in acute phase and Critical/Severe groups of HFRS patients were significantly increased compared to that in normal controls (p < 0.001 and p < 0.01, respectively). High plasma CX3CL1 was negatively correlated with platelet count (r = -0.5844, p < 0.0001) and positively correlated with blood urea nitrogen (r = 0.3668, p = 0.0039), creatinine (r = 0.42, p = 0.0008), and white blood cells (r = 0.2646, p = 0.0411). Expression of CX3CR1 on nonclassical and intermediate monocytes was also increased in the acute phase (p < 0.01 for both the cells) and Critical/Severe groups (p < 0.05 and p < 0.01, respectively) of HFRS patients compared to that in normal controls. Taken together, elevation of plasma CX3CL1 in HFRS patients and expression of CX3CR1 on nonclassical and intermediate monocyte subsets might provide new insights into the potential role of CX3CL1/CX3CR1 in pathogenesis of HFRS.
Asunto(s)
Quimiocina CX3CL1 , Fiebre Hemorrágica con Síndrome Renal , Quimiocina CX3CL1/sangre , Quimiocina CX3CL1/metabolismo , Fiebre Hemorrágica con Síndrome Renal/sangre , Fiebre Hemorrágica con Síndrome Renal/patología , Humanos , Riñón/patología , Recuento de Leucocitos , Monocitos/metabolismoRESUMEN
BACKGROUND: Hemorrhagic fever with renal syndrome (HFRS) caused by Hantaan virus is characterized by systemic immunopathological injury. Pentraxin-3 is an acute-phase reactant involved in the processes of inflammation and infection. This study aimed to investigate the levels of plasma pentraxin-3 and evaluate its predictive value on disease severity and mortality risk in patients with HFRS. METHODS: This was a prospective real-world observational study. The concentrations of plasma pentraxin-3 were measured by enzyme linked immunosorbent assay (ELISA) in 105 HFRS patients and 27 healthy controls. We analyzed the clinical relevance between pentraxin-3 and clinical subtyping, hospital stay and conventional laboratory parameters of HFRS patients. Considering the prognosis (death) as the primary endpoint, the levels of pentraxin-3 between survivors and non-survivors were compared, and its association with mortality was assessed by Kaplan-Meier survival analysis. The predictive potency of pentraxin-3 for mortality risk in HFRS patients was evaluated by receiver operating characteristic (ROC) curve analysis. RESULTS: The levels of pentraxin-3 during the acute phase were increased with the aggravation of the disease, and showed the highest expression in critical-type patients (P < 0.05). Pentraxin-3 demonstrated significant correlations with conventional laboratory parameters (WBC, PLT, AST, ALB, APTT, Fib) and the length of hospital stay. Compared with the survivors, non-survivors showed higher levels of pentraxin-3 and worse expressions of conventional laboratory parameters during the acute phase. The Kaplan-Meier survival curves showed that high levels of pentraxin-3 during the acute phase were significantly associated with the death in HFRS patients. Pentraxin-3 demonstrated significant predictive value for the mortality risk of HFRS patients, with the area under ROC curve (AUC) of 0.753 (95%CI: 0.593 ~ 0.914, P = 0.003). CONCLUSIONS: The detection of plasma pentraxin-3 might be beneficial to the evaluation of disease severity and to the prediction of mortality risk in HFRS patients.
Asunto(s)
Proteína C-Reactiva/análisis , Fiebre Hemorrágica con Síndrome Renal/patología , Componente Amiloide P Sérico/análisis , Enfermedad Aguda , Adulto , Área Bajo la Curva , Femenino , Virus Hantaan/aislamiento & purificación , Fiebre Hemorrágica con Síndrome Renal/mortalidad , Fiebre Hemorrágica con Síndrome Renal/virología , Humanos , Estimación de Kaplan-Meier , Tiempo de Internación , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Curva ROC , Índice de Severidad de la EnfermedadRESUMEN
Hantaviruses are zoonotic RNA viruses that cause severe acute disease in humans. Infected individuals have strong inflammatory responses that likely cause immunopathology. Here, we studied the response of mucosal-associated invariant T (MAIT) cells in peripheral blood of individuals with hemorrhagic fever with renal syndrome (HFRS) caused by Puumala orthohantavirus, a hantavirus endemic in Europe. We show that MAIT cell levels decrease in the blood during HFRS and that residual MAIT cells are highly activated. This activation correlates with HFRS severity markers. In vitro activation of MAIT cells by hantavirus-exposed antigen-presenting cells is dependent on type I interferons (IFNs) and independent of interleukin-18 (IL-18). These findings highlight the role of type I IFNs in virus-driven MAIT cell activation and suggest a potential role of MAIT cells in the disease pathogenesis of viral infections.
Asunto(s)
Células Presentadoras de Antígenos/inmunología , Infecciones por Hantavirus/inmunología , Fiebre Hemorrágica con Síndrome Renal/inmunología , Activación de Linfocitos , Células T Invariantes Asociadas a Mucosa/inmunología , Virus Puumala/patogenicidad , Adulto , Anticuerpos Antivirales/sangre , Células Presentadoras de Antígenos/virología , Biomarcadores/metabolismo , Estudios de Casos y Controles , Progresión de la Enfermedad , Células Endoteliales/inmunología , Células Endoteliales/virología , Femenino , Regulación de la Expresión Génica , Infecciones por Hantavirus/genética , Infecciones por Hantavirus/patología , Infecciones por Hantavirus/virología , Fiebre Hemorrágica con Síndrome Renal/genética , Fiebre Hemorrágica con Síndrome Renal/patología , Fiebre Hemorrágica con Síndrome Renal/virología , Humanos , Inmunofenotipificación , Interferón Tipo I/genética , Interferón Tipo I/inmunología , Interferón gamma/genética , Interferón gamma/inmunología , Interleucina-10/genética , Interleucina-10/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Masculino , Persona de Mediana Edad , Monocitos/inmunología , Monocitos/virología , Células T Invariantes Asociadas a Mucosa/virología , Virus Puumala/inmunología , Índice de Severidad de la EnfermedadRESUMEN
Endoplasmic reticulum stress (ER stress) can be induced by virus infection. In this part, we explored whether Hantaan virus (HTNV) infection could induce ER stress in differentiated THP-1 (dTHP-1) cells. It showed that the mRNA and protein levels of ER stress-related 78 kDa glucose-regulated protein (GRP78, HSPA5) and mRNA levels of X box-binding protein 1 (XBP-1), activating transcription factor 6(ATF6) and PKR-like ER kinase (PERK) after HTNV infection, were significantly higher than that in uninfected control group. However, the mRNA levels of C/EBP homologous protein (CHOP), glucose-regulated protein 94 (GRP94, HSPC4), and inositol-requiring enzyme1 (IRE1) were not significantly different between the infected group and the untreated group in 2 h after virus infection. It is unusual in activating GRP78 but not GRP94. Meanwhile, dTHP-1 cells infected with HTNV at 12 h did not show obvious apoptosis. These results indicated that the HTNV infection could induce the unfolded protein response (UPR) in dTHP-1 cells, without directly leading to cell apoptosis during 12 h after virus infection.
Asunto(s)
Estrés del Retículo Endoplásmico , Virus Hantaan/fisiología , Fiebre Hemorrágica con Síndrome Renal/patología , Interacciones Huésped-Patógeno , Humanos , Células THP-1RESUMEN
Podocyte injury has recently been described as unifying feature in idiopathic nephrotic syndromes (INS). Puumala hantavirus (PUUV) infection represents a unique RNA virus-induced renal disease with significant proteinuria. The underlying pathomechanism is unclear. We hypothesized that PUUV infection results in podocyte injury, similar to findings in INS. We therefore analyzed standard markers of glomerular proteinuria (e.g. immunoglobulin G [IgG]), urinary nephrin excretion (podocyte injury) and serum levels of the soluble urokinase plasminogen activator receptor (suPAR), a proposed pathomechanically involved molecule in INS, in PUUV-infected patients. Hantavirus patients showed significantly increased urinary nephrin, IgG and serum suPAR concentrations compared to healthy controls. Nephrin and IgG levels were significantly higher in patients with severe proteinuria than with mild proteinuria, and nephrin correlated strongly with biomarkers of glomerular proteinuria over time. Congruently, electron microcopy analyses showed a focal podocyte foot process effacement. suPAR correlated significantly with urinary nephrin, IgG and albumin levels, suggesting suPAR as a pathophysiological mediator in podocyte dysfunction. In contrast to INS, proteinuria recovered autonomously in hantavirus patients. This study reveals podocyte injury as main cause of proteinuria in hantavirus patients. A better understanding of the regenerative nature of hantavirus-induced glomerulopathy may generate new therapeutic approaches for INS.
Asunto(s)
Barrera de Filtración Glomerular/patología , Fiebre Hemorrágica con Síndrome Renal/patología , Glomérulos Renales/patología , Síndrome Nefrótico/patología , Virus Puumala , Adolescente , Adulto , Femenino , Fiebre Hemorrágica con Síndrome Renal/sangre , Fiebre Hemorrágica con Síndrome Renal/orina , Humanos , Masculino , Proteínas de la Membrana/orina , Persona de Mediana Edad , Síndrome Nefrótico/sangre , Síndrome Nefrótico/orina , Podocitos/patología , Receptores del Activador de Plasminógeno Tipo Uroquinasa/sangre , Adulto JovenRESUMEN
Type I interferon receptor knockout mice (strain A129) were assessed as a disease model of hantavirus infection. A range of infection routes (intramuscular, intraperitoneal and intranasal) were assessed using minimally passaged Seoul virus (strain Humber). Dissemination of virus to the spleen, kidney and lung was observed at 5 days after intramuscular and intraperitoneal challenge, which was resolved by day 14. In contrast, intranasal challenge of A129 mice demonstrated virus tropism to the lung, which was maintained to day 14 post-challenge. These data support the use of the A129 mouse model for future infection studies and the in vivo evaluation of interventions.
Asunto(s)
Modelos Animales de Enfermedad , Infecciones por Hantavirus , Orthohantavirus/fisiología , Animales , Orthohantavirus/aislamiento & purificación , Orthohantavirus/patogenicidad , Infecciones por Hantavirus/patología , Infecciones por Hantavirus/virología , Fiebre Hemorrágica con Síndrome Renal/patología , Fiebre Hemorrágica con Síndrome Renal/virología , Riñón/virología , Hígado/patología , Pulmón/patología , Pulmón/virología , Masculino , Ratones , Ratones Noqueados , ARN Viral/análisis , ARN Viral/sangre , Receptor de Interferón alfa y beta/genética , Bazo/patología , Bazo/virología , Tropismo ViralRESUMEN
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.
Asunto(s)
Clatrina/metabolismo , Fiebre Hemorrágica con Síndrome Renal/metabolismo , Pinocitosis , Virus Puumala/metabolismo , Internalización del Virus , Animales , Chlorocebus aethiops , Fiebre Hemorrágica con Síndrome Renal/patología , Células VeroRESUMEN
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.
Asunto(s)
Apoptosis , Fiebre Hemorrágica con Síndrome Renal/metabolismo , Potencial de la Membrana Mitocondrial , Membranas Mitocondriales/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesis , Regulación hacia Arriba , Células A549 , Caspasas/genética , Caspasas/metabolismo , Citocromos c/genética , Citocromos c/metabolismo , Fiebre Hemorrágica con Síndrome Renal/patología , Humanos , Membranas Mitocondriales/patología , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Most cases of hemorrhagic fever with renal syndrome (HFRS) in Europe are caused by the Puumala hantavirus (PUUV). Typical features of the disease are increased vascular permeability, acute kidney injury (AKI), and thrombocytopenia. YKL-40 is an inflammatory glycoprotein involved in various forms of acute and chronic inflammation. In the present study, we examined plasma YKL-40 levels and the associations of YKL-40 with disease severity in acute PUUV infection. A total of 79 patients treated in Tampere University Hospital during 2005-2014 were studied. Plasma YKL-40 was measured in the acute phase, the recovery phase, and one year after hospitalization. Plasma YKL-40 levels were higher during the acute phase compared to the recovery phase and one year after hospitalization (median YKL-40 142 ng/mL, range 11-3320, vs. 45 ng/mL, range 15-529, vs. 32 ng/mL, range 3-213, p < 0.001). YKL-40 level was correlated with the length of hospital stay (r = 0.229, p = 0.042), the levels of inflammatory markers-that is, blood leukocytes (r = 0.234, p = 0.040), plasma C-reactive protein (r = 0.332, p = 0.003), and interleukin-6 (r = 0.544, p < 0.001), and maximum plasma creatinine level (r = 0.370, p = 0.001). In conclusion, plasma YKL-40 levels were found to be elevated during acute PUUV infection and correlated with the overall severity of the disease, as well as with the degree of inflammation and the severity of AKI.
Asunto(s)
Biomarcadores/sangre , Proteína 1 Similar a Quitinasa-3 , Fiebre Hemorrágica con Síndrome Renal , Virus Puumala/patogenicidad , Lesión Renal Aguda/patología , Lesión Renal Aguda/virología , Adulto , Anciano , Autoantígenos/análisis , Autoantígenos/sangre , Proteína 1 Similar a Quitinasa-3/análisis , Proteína 1 Similar a Quitinasa-3/sangre , Creatinina/sangre , Femenino , Fiebre Hemorrágica con Síndrome Renal/patología , Fiebre Hemorrágica con Síndrome Renal/virología , Humanos , Inflamación/virología , Interleucina-6/sangre , Masculino , Persona de Mediana Edad , Índice de Severidad de la EnfermedadRESUMEN
Hemorrhagic fever with renal syndrome (HFRS) and Crimean-Congo hemorrhagic fever (CCHF) are important viral hemorrhagic fevers (VHF), especially in the Balkan region. Infections with Dobrava or Puumala orthohantavirus and Crimean-Congo hemorrhagic fever orthonairovirus can vary from a mild, nonspecific febrile illness, to a severe disease with a fatal outcome. The pathogenesis of both diseases is poorly understood, but it has been suggested that a host's immune mechanism might influence the pathogenesis of the diseases and survival. The aim of our study is to characterize cytokine response in patients with VHF in association with the disease progression and viral load. Forty soluble mediators of the immune response, coagulation, and endothelial dysfunction were measured in acute serum samples in 100 HFRS patients and 70 CCHF patients. HFRS and CCHF patients had significantly increased levels of IL-6, IL-12p70, IP-10, INF-γ, TNF-α, GM-CSF, MCP-3, and MIP-1b in comparison to the control group. Interestingly, HFRS patients had higher concentrations of serum MIP-1α, MIP-1ß, which promote activation of macrophages and NK cells. HFRS patients had increased concentrations of IFN-γ and TNF-α, while CCHF patients had significantly higher concentrations of IFN-α and IL-8. In both, CCHF and HFRS patients' viral load significantly correlated with IP-10. Patients with fatal outcome had significantly elevated concentrations of IL-6, IFN-α2 and MIP-1α, while GRO-α, chemokine related to activation of neutrophils and basophils, was downregulated. Our study provided a comprehensive characterization of biomarkers released in the acute stages of CCHF and HFRS.
Asunto(s)
Citocinas/sangre , Fiebre Hemorrágica con Síndrome Renal/inmunología , Fiebre Hemorrágica de Crimea/inmunología , Anticuerpos Antivirales/sangre , Biomarcadores/sangre , Quimiocina CXCL10/sangre , Progresión de la Enfermedad , Femenino , Orthohantavirus/inmunología , Virus de la Fiebre Hemorrágica de Crimea-Congo/inmunología , Fiebre Hemorrágica con Síndrome Renal/patología , Fiebre Hemorrágica con Síndrome Renal/virología , Fiebre Hemorrágica de Crimea/patología , Fiebre Hemorrágica de Crimea/virología , Humanos , Masculino , Eslovenia , Carga ViralRESUMEN
Hemorrhagic fever with renal syndrome (HFRS) is endemic in Tatarstan, where thousands of cases are registered annually. Puumalaorthohantavirus is commonly detected in human case samples as well as in captured bank voles, the rodent hosts. The pathogenesis of HFRS is still not well described, although the cytokine storm hypothesis is largely accepted. In this study, we present a comprehensive analysis of a fatal HFRS case compared with twenty four non-fatal cases where activation of the humoral and cellular immune responses, pro-inflammatory cytokines and disturbed blood coagulation were detected using immunological, histological, genetic and clinical approaches. Multiple organ failure combined with disseminated intravascular coagulation syndrome and acute renal failure was the cause of death. Decreased Interleukin (IL)-7 and increased IL-18, chemokine (C-C motif) ligand (CCL)-5, stem cell growth factor (SCGF)-b and tumor necrosis factor-beta (TNF-ß) serum levels were found, supporting the cytokine storm hypothesis of hantavirus pathogenesis.
Asunto(s)
Citocinas/inmunología , Fiebre Hemorrágica con Síndrome Renal/inmunología , Inmunidad Humoral/inmunología , Adulto , Animales , Chlorocebus aethiops , Femenino , Células HEK293 , Orthohantavirus/inmunología , Fiebre Hemorrágica con Síndrome Renal/patología , Fiebre Hemorrágica con Síndrome Renal/virología , Humanos , Interleucina-17/metabolismo , Interleucina-18/metabolismo , Riñón/inmunología , Riñón/patología , Pulmón/diagnóstico por imagen , Pulmón/patología , Masculino , Persona de Mediana Edad , Filogenia , Virus Puumala/clasificación , Virus Puumala/genética , Roedores , Tatarstán , Células VeroRESUMEN
Seoul virus (SEOV) is a zoonotic orthohantavirus carried by black and brown rats, and can cause hemorrhagic fever with renal syndrome in humans. Human cases of SEOV virus infection have most recently been reported in the USA, United Kingdom, France and the Netherlands and were primarily associated with contact with pet rats and feeder rats. Infection of rats results in an asymptomatic but persistent infection. Little is known about the cell tropism of SEOV in its reservoir and most available data is based on experimental infection studies in which rats were inoculated via a route which does not recapitulate virus transmission in nature. Here we report the histopathological analysis of SEOV cell tropism in key target organs following natural infection of a cohort of feeder rats, comprising 19 adults and 11 juveniles. All adult rats in this study were positive for SEOV specific antibodies and viral RNA in their tissues. One juvenile rat was seropositive, but negative in the rRT-PCR. Of the 19 adult rats of which subsequently additional organs were tested, SEOV RNA was detected in all lungs, followed by kidney (79%) and liver (74%). Histopathologic changes associated with SEOV infection were primarily found in the liver, consistent with a pathological diagnosis of a mild hepatitis. In conclusion, natural SEOV infection results in mild inflammation of the liver in the absence of clinical disease.
Asunto(s)
Fiebre Hemorrágica con Síndrome Renal/patología , Fiebre Hemorrágica con Síndrome Renal/virología , Virus Seoul/patogenicidad , Tropismo , Animales , Francia , Fiebre Hemorrágica con Síndrome Renal/diagnóstico , Humanos , Inflamación , Riñón/patología , Riñón/virología , Hígado/patología , Hígado/virología , Pulmón/patología , Pulmón/virología , Reacción en Cadena de la Polimerasa , ARN Viral/genética , Ratas , Virus Seoul/genética , Reino Unido , Estados UnidosRESUMEN
Several case reports have described hypopituitarism following orthohantavirus infection, mostly following Puumala virus. The pathogenesis of this seemingly rare complication of orthohantavirus infection remains unknown. This review explores the possible pathophysiological mechanisms of pituitary damage due to orthohantavirus infection. In only three out of the 28 reported cases, hypopituitarism was detected during active infection. In the remaining cases, detection of pituitary damage was delayed, varying from two months up to thirteen months post-infection. In these cases, hypopituitarism remained undetected during the acute phase of infection or only occurred weeks to months post infection. Both ischemic and hemorrhagic damage of the pituitary gland have been detected in radiographic imaging and post-mortem studies in the studied case reports series. Ischemic damage could be caused by hypotension and/or vasospasms during the acute phase of hemorrhagic fever with renal syndrome (HFRS) while hemorrhage could be caused by thrombocytopenia, thrombopathy, and other known causes of coagulation disorders during orthohantavirus infection. Also, hypophysitis due to the presence of auto-antibodies have been suggested in the literature. In conclusion, a significant number of case reports and series describe hypopituitarism after orthohantavirus infection. In most cases hypopituitarism was diagnosed with a delay and therefore could very well be underreported. Clinicians should be aware of this potential endocrine complication, with substantial morbidity, and if unrecognized, significant mortality.
Asunto(s)
Fiebre Hemorrágica con Síndrome Renal/complicaciones , Hipopituitarismo/etiología , Orthohantavirus/patogenicidad , Fiebre Hemorrágica con Síndrome Renal/diagnóstico , Fiebre Hemorrágica con Síndrome Renal/patología , Fiebre Hemorrágica con Síndrome Renal/fisiopatología , Humanos , Hipopituitarismo/diagnóstico , Hipopituitarismo/patología , Hipopituitarismo/fisiopatología , Hipófisis/patología , Hipófisis/fisiopatología , Virus Puumala/patogenicidadRESUMEN
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.
Asunto(s)
Proteínas de la Matriz Extracelular/metabolismo , Fiebre Hemorrágica con Síndrome Renal/patología , Células Endoteliales de la Vena Umbilical Humana/patología , Células Endoteliales de la Vena Umbilical Humana/virología , Orthohantavirus/fisiología , Fosfoproteínas/metabolismo , Biomarcadores/sangre , Permeabilidad Capilar/efectos de los fármacos , Células Cultivadas , Proteínas de la Matriz Extracelular/sangre , Proteínas de la Matriz Extracelular/farmacología , Fiebre Hemorrágica con Síndrome Renal/sangre , Fiebre Hemorrágica con Síndrome Renal/metabolismo , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Fosfoproteínas/sangre , Fosfoproteínas/farmacología , Factor de Necrosis Tumoral alfa/farmacología , Factores de Crecimiento Endotelial Vascular/sangre , Factores de Crecimiento Endotelial Vascular/farmacologíaRESUMEN
Orthohantaviruses, previously known as hantaviruses, are zoonotic viruses that can cause hantavirus pulmonary syndrome (HPS) and hemorrhagic fever with renal syndrome (HFRS) in humans. The HPS-causing Andes virus (ANDV) and the HFRS-causing Hantaan virus (HTNV) have anti-apoptotic effects. To investigate if this represents a general feature of orthohantaviruses, we analysed the capacity of six different orthohantaviruses - belonging to three distinct phylogroups and representing both pathogenic and non-pathogenic viruses - to inhibit apoptosis in infected cells. Primary human endothelial cells were infected with ANDV, HTNV, the HFRS-causing Puumala virus (PUUV) and Seoul virus, as well as the putative non-pathogenic Prospect Hill virus and Tula virus. Infected cells were then exposed to the apoptosis-inducing chemical staurosporine or to activated human NK cells exhibiting a high cytotoxic potential. Strikingly, all orthohantaviruses inhibited apoptosis in both settings. Moreover, we show that the nucleocapsid (N) protein from all examined orthohantaviruses are potential targets for caspase-3 and granzyme B. Recombinant N protein from ANDV, PUUV and the HFRS-causing Dobrava virus strongly inhibited granzyme B activity and also, to certain extent, caspase-3 activity. Taken together, this study demonstrates that six different orthohantaviruses inhibit apoptosis, suggesting this to be a general feature of orthohantaviruses likely serving as a mechanism of viral immune evasion.
Asunto(s)
Apoptosis/inmunología , Virus Hantaan/inmunología , Evasión Inmune/inmunología , Orthohepadnavirus/inmunología , Virus Puumala/inmunología , Virus Seoul/inmunología , Células A549 , Caspasa 3/inmunología , Línea Celular Tumoral , Células Endoteliales/virología , Granzimas/inmunología , Orthohantavirus/inmunología , Síndrome Pulmonar por Hantavirus/patología , Síndrome Pulmonar por Hantavirus/virología , Fiebre Hemorrágica con Síndrome Renal/patología , Fiebre Hemorrágica con Síndrome Renal/virología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Células K562 , Células Asesinas Naturales/virología , Nucleocápside/genética , Nucleocápside/inmunología , Orthohepadnavirus/clasificación , Orthohepadnavirus/genéticaRESUMEN
Over the past few decades understanding and recognition of hantavirus infection has greatly improved worldwide, but both the amplitude and the magnitude of hantavirus outbreaks have been increasing. Several novel hantaviruses with unknown pathogenic potential have been identified in a variety of insectivore hosts. With the new hosts, new geographical distributions of hantaviruses have also been discovered and several new species were found in Africa. Hantavirus infection in humans can result in two clinical syndromes: haemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS) caused by Old World and New World hantaviruses, respectively. The clinical presentation of HFRS varies from subclinical, mild, and moderate to severe, depending in part on the causative agent of the disease. In general, HFRS caused by Hantaan virus, Amur virus and Dobrava virus are more severe with mortality rates from 5 to 15%, whereas Seoul virus causes moderate and Puumala virus and Saaremaa virus cause mild forms of disease with mortality rates <1%. The central phenomena behind the pathogenesis of both HFRS and HCPS are increased vascular permeability and acute thrombocytopenia. The pathogenesis is likely to be a complex multifactorial process that includes contributions from immune responses, platelet dysfunction and the deregulation of endothelial cell barrier functions. Also a genetic predisposition, related to HLA type, seems to be important for the severity of the disease. As there is no effective treatment or vaccine approved for use in the USA and Europe, public awareness and precautionary measures are the only ways to minimize the risk of hantavirus disease.