Assessing Pulmonary Epithelial Damage in Hantavirus Cardiopulmonary Syndrome: Challenging the Predominant Role of Vascular Endothelium through sRAGE as a Potential Biomarker.

Hantavirus cardiopulmonary syndrome (HCPS) is a severe respiratory illness primarily associated with microvascular endothelial changes, particularly in the lungs. However, the role of the pulmonary epithelium in HCPS pathogenesis remains unclear. This study explores the potential of soluble Receptors for Advanced Glycation End-products (sRAGE) as a biomarker for assessing pulmonary epithelial damage in severe HCPS, challenging the prevailing view that endothelial dysfunction is the sole driver of this syndrome. We conducted a cross-sectional study on critically ill HCPS patients, categorizing them into mild HCPS, severe HCPS, and negative control groups. Plasma sRAGE levels were measured, revealing significant differences between the severe HCPS group and controls. Our findings suggest that sRAGE holds promise as an indicator of pulmonary epithelial injury in HCPS and may aid in tracking disease progression and guiding therapeutic strategies. This study brings clarity on the importance of investigating the pulmonary epithelium's role in HCPS pathogenesis, offering potential avenues for enhanced diagnostic precision and support in this critical public health concern.

Infección por hantavirus en la Provincia de Buenos Aires-Argentina. Comportamiento de la serie temporal 1997-2021 / Hantavirus infection in the Province of Buenos Aires-Argentina. Characteristics of the time series 1997-2021

INTRODUCCIÓN: La infección por hantavirus es endémica en América del Sur, con un amplio espectro de gravedad y una letalidad que varía entre 17 y 40 por ciento. El presente estudio recoge información de 25 años de vigilancia epidemiológica en Buenos Aires, Argentina. OBJETIVO: Caracterizar el comportamiento de la serie temporal 1997-2021, observando tendencia y estacionalidad. MÉTODOS: La función de serie temporal utilizada empleó la media móvil centrada según periodos trimestrales, de forma que cada año se dividió en cuartiles. Se consideró un modelo multiplicativo. RESULTADOS: Con una tasa de mortalidad de la serie de 0,15 por 100 mil y de letalidad de 22,6, la razón varones : mujeres fue de 3,4:1. La distribución sindrómica mostró mayor compromiso renal, siendo la tasa de mortalidad prácticamente igual en ambos sexos. CONCLUSIÓN: Como enfermedad infecciosa, la infección por hantavirus reflejó en los últimos 25 años un comportamiento, recurrente y estacional, endémico y compartido en sus características clínicas con el resto de la región andina.

BACKGROUND: Hantavirus infection is endemic in South America, with a wide spectrum of severity and a fatality rate that varies between 17-40 percent. This study collects information from 25 years of epidemiological surveillance in Buenos Aires, Argentina. AIM: To characterize the behavior of the 1997-2021 time series, observing trends and seasonality. METHODS: The time series function used the moving average centered according to quarterly periods, so that each year was divided into quartiles. A multiplicative model is missed. RESULTS: With a mortality rate for the series of 0.15 per 100,000 and a fatality rate of 22.6, the male : female ratio was 3.4:1. The syndromic distribution showed greater renal involvement, with the mortality rate being practically the same in both sexes. CONCLUSION: As an infectious disease, hantavirus has reflected in the last 25 years a behavior, recurrent and seasonal, endemic and shared in its clinical characteristics with the rest of the Andean region.

Favorable course of leptospirosis and hantavirus-induced acute tubulointerstitial nephritis under corticosteroid treatment.

BACKGROUND: We present two children with acute tubulointerstitial nephritis (ATIN) caused by leptospirosis in a 12-year-old boy and hantavirus in a 10-year-old girl. The role of glucocorticoids in the management of ATIN triggered by infectious agents is unclear. CASE-DIAGNOSIS/TREATMENT: Both children were hospitalized with jaundice, elevated serum creatinine, and thrombocytopenia. There was no oliguria or hypertension. Urine analysis revealed tubular proteinuria. Kidney biopsy was performed on one patient and showed tubulointerstitial inflammation with mild mesangial proliferation. Both patients were treated with glucocorticoids in view of deteriorating kidney function with respective serum creatinine values of 5.2 and 4.1 mg/dl. Both children exhibited an excellent clinical and biochemical response to treatment. Neither of the patients required dialysis. Positive serology test results indicated a recent leptospirosis and hantavirus infection. CONCLUSIONS: Leptospirosis and hantavirus associated ATIN share common clinical and biochemical features. Due to the low incidence in Europe these infectious causes of kidney dysfunction may be overlooked. Glucocorticoids may be considered in the management of ATIN.

Puumala Hantavirus Infections Show Extensive Variation in Clinical Outcome.

The clinical outcome of Puumala hantavirus (PUUV) infection shows extensive variation, ranging from inapparent subclinical infection (70-80%) to severe hemorrhagic fever with renal syndrome (HFRS), with about 0.1% of cases being fatal. Most hospitalized patients experience acute kidney injury (AKI), histologically known as acute hemorrhagic tubulointerstitial nephritis. Why this variation? There is no evidence that there would be more virulent and less virulent variants infecting humans, although this has not been extensively studied. Individuals with the human leukocyte antigen (HLA) alleles B*08 and DRB1*0301 are likely to have a severe form of the PUUV infection, and those with B*27 are likely to have a benign clinical course. Other genetic factors, related to the tumor necrosis factor (TNF) gene and the C4A component of the complement system, may be involved. Various autoimmune phenomena and Epstein-Barr virus infection are associated with PUUV infection, but hantavirus-neutralizing antibodies are not associated with lower disease severity in PUUV HFRS. Wide individual differences occur in ocular and central nervous system (CNS) manifestations and in the long-term consequences of nephropathia epidemica (NE). Numerous biomarkers have been detected, and some are clinically used to assess and predict the severity of PUUV infection. A new addition is the plasma glucose concentration associated with the severity of both capillary leakage, thrombocytopenia, inflammation, and AKI in PUUV infection. Our question, "Why this variation?" remains largely unanswered.

Risk of lymphoid malignancies increased after Puumala virus infection in Finland, 2009-2019: A retrospective register-based cohort study.

OBJECTIVES: The Puumala virus (PUUV) is a hantavirus that causes hemorrhagic fever with renal syndrome. Studies showing an increased risk of lymphoid malignancies after hantavirus infection, together with the observation that PUUV infects B cells, motivated us to study the risk of lymphoid malignancies after PUUV infection. METHODS: We linked data from the Finnish Cancer Registry and National Infectious Diseases Register for 2009-2019. We used a time-dependent Cox regression model to evaluate the hazard of the lymphoid malignancies grouped according to the HAEMACARE classification. RESULTS: We identified 68 cases of lymphoid malignancies after PUUV infection among 16,075 PUUV-infected individuals during 61,114,826 person-years of observation. A total of 10 cases occurred within 3-<12 months and 38 within 1-<5 years after PUUV infection, and the risk of lymphoid malignancies increased with hazard ratios (HRs) of 2.0 (95% confidence interval [CI], 1.1-3.7) and 1.6 (95% CI, 1.2-2.3), respectively. The group of mature B cell neoplasms showed an increased risk 3-<12 months and 1-<5 years after PUUV infection, HR 2.2 (95% CI, 1.2-4.3) and HR 1.8 (95% CI, 1.3-2.5), respectively. CONCLUSION: PUUV infection is associated with lymphoid malignancies in the Finnish population, supporting the earlier studies. Further research is required to understand the pathophysiological mechanisms behind this association.

Características e diagnóstico laboratorial das infecções causadas pelo hantavírus: revisão integrativa / Characteristics and laboratory diagnosis of infections caused by hantavirus: integrative review

A hantavirose é uma zoonose de distribuição mundial que utiliza como vetores roedores, musaranhos, toupeiras e morcegos. Os sintomas da infecção pelo hantavírus assemelham-se aos de diversas doenças, por isso o diagnóstico laboratorial é crucial para o tratamento precoce. Objetivo: Realizar uma revisão da literatura sobre as características e diagnóstico laboratorial da hantavirose. Métodos: Trata-se de uma revisão integrativa da literatura com base no modelo PRISMA, com seleção de estudos nas bases de dados Portal de Periódicos da Capes, PubMed/Medline, SciELO, ScienceDirect e Biblioteca Virtual em Saúde (BVS). Foram empregados os descritores: hantavírus, diagnóstico laboratorial, exames e zoonose, em português e inglês, no período de 2015 a 2022, sendo selecionados 19 artigos científicos em atendimento aos critérios de inclusão. Resultados e Discussão: Diversas técnicas diagnósticas podem ser empregadas em casos de hantavirose, sendo a biologia molecular a mais empregada, conjuntamente com a imunologia. Há outros recursos utilizados para monitoramento e evolução da doença, como a bioquímica, a hematologia e a imagenologia. Para a ocorrência de hantavirose é necessário um ambiente propício, clima específico e contato com hospedeiro suscetível, podendo evoluir para quadros assintomáticos ou sintomáticos com complicações graves. Conclusão: O diagnóstico dessa doença é desafiador e requer investigação detalhada que inclua a sintomatologia do paciente, o histórico de exposição a animais reservatórios e os resultados de exames laboratoriais. Como desfechos negativos da hantavirose incluem-se a febre hemorrágica com síndrome renal, a síndrome pulmonar por hantavírus e o óbito

Hantavirus is a worldwide distributed zoonosis that uses rodents, shrews, moles and bats as vectors. The symptoms of hantavirus infection resemble those of many diseases, so laboratory diagnosis is crucial for early treatment. Objective: The present study aimed to conduct a literature review on the characteristics and laboratory diagnosis of hantavirus. Methods: This is an integrative literature review based on the PRISMA model, with a selection of studies in the Capes Portal de Periódicos, PubMed/Medline, SciELO, ScienceDirect and Virtual Health Library databases, using the descriptors: hantavirus, laboratory diagnosis, exams, and zoonosis, in portuguese and english, from 2015 to 2022, and nineteen scientific articles that met the inclusion criteria were selected. Results and Discussion: Several techniques can be used in cases of hantavirus, with molecular biology being the most evidenced along with immunology. There are other parameters that are used for monitoring and evolution of the disease, such as biochemistry, hematology, and imaging. For the hantavirus disease, an adequate environment, specific climate and contact with a susceptible host are necessary, which may lead to asymptomatic conditions or symptoms with more serious complications. Conclusion: The diagnosis of this disease is challenging and requires detailed investigation that includes the patient's symptoms, the history of exposure to reservoir animals and the results of laboratory tests. Negative outcomes of hantavirus infection include hemorrhagic fever with renal syndrome, hantavirus pulmonary syndrome, and death

A rare case of acute acalculous cholecystitis secondary to hantavirus infection with renal syndrome.

Hantaviruses are single-stranded RNA viruses. They are transmitted to humans by rodents and insectivore hosts. Some Hantavirus subtypes are the causative agents of haemorrhagic fever with renal syndrome (HFRS), which is characterized by fever, thrombocytopenia, and acute kidney injury. Hantavirus infection is difficult to diagnose due to its non-specific clinical symptoms. Causes of acalculous cholecystitis are severe trauma or burn, surgery, long-term starvation and some viral infections. It is very rare for Hantavirus to cause acute acalculous cholecystitis. The treatment of acute acalculous cholecystitis is usually directed towards its symptoms. A 22-year-old male forest worker was admitted to our emergency outpatient clinic with the complaints of fatigue, oliguria, fever, abdominal pain and vomiting. After the clinical and laboratory examinations, HFRS and acute cholecystitis secondary to Hantavirus infection were diagnosed. The patient's condition and clinical findings improved after supportive treatment. Hantavirus infection should be considered in patients with acute kidney injury, cholecystitis and thrombocytopenia (Fig. 2, Ref. 10). Keywords: Hantavirus, acute kidney injury, acalculous cholecystitis, thrombocytopeni.

Central nervous system infection with Seoul Orthohantavirus in a child after hematopoietic stem cell transplantation: a case report.

BACKGROUND: Patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT) are prone to complicate viral infection. Central nervous system (CNS) involvement caused by the viruses is rare but with poor prognosis. Hantavirus, which usually cause hemorrhagic fever with renal syndrome (HFRS), and none case has been reported about these infection in allo-HSCT patients. CASE PRESENTATION: In August 2021, a 13-year-old male child developed intermittent fever and refractory hypotension after allo-HSCT. Magnetic resonance imaging of the head revealed abnormal signal foci in the left midbrain cerebral peduncle and bilateral thalamus. His family reported traces of mouse activity in the patient's home kitchen. HFRS was suspected, but with no significant kidney damage. The specific immunoglobulin (Ig) G and M of hantavirus were negative. The metagenomic next-generation sequencing (mNGS) detected Seoul Orthohantavirus (SEOV) sequences directly in cerebrospinal fluid and blood. CONCLUSIONS: Allo-HSCT patients are a high-risk group for infection. Usually the causative agent of infection is difficult to determine, and sometimes the site of infection is concealed. This report highlights the importance of suspecting hantavirus infection in allo-HSCT patients with CNS symptoms despite the absence of renal syndromes. The mNGS is a powerful tool for detecting pathogens. CNS infection with Seoul orthohantavirus in transplant patients is rare but possible as demonstrated in this case. To the best of our knowledge, this is the first reported case employing mNGS to diagnose SEOV caused CNS infection in an allo-HSCT patient.

Modelamiento del síndrome cardiopulmonar por hantavirus / Modeling of hantavirus cardiopulmonary syndrome

INTRODUCCIÓN: El síndrome cardiopulmonar por hantavirus es una enfermedad causada por un virus perteneciente al orden bunyanvirales, y transmitida hacia los humanos a través de roedores. Esta enfermedad en Chile es considerada endémica, la cual tiene una alta tasa de letalidad. En la actualidad existen estudios que evidencian el contagio entre personas del virus Andes, cuya localidad se concentra en los países de Argentina y Chile. OBJETIVOS: Analizar la posibilidad de transmisión de hantavirus entre humanos, mediante un modelo matemático tipo SEIR. MÉTODOS: Se plantea un modelo matemático tipo SEIR (susceptible, expuesto, infeccioso y recuperado) para expresar la dinámica de la enfermedad por hantavirus, incluyendo la posibilidad de transmisión entre humanos y la percepción del riesgo. Resultados: El máximo de contagio entre humanos disminuye cerca de 25% tras aumentar la percepción de riesgo de las personas, mediante la reducción de la tasa de resistencia al cambio y aumento la velocidad de reaccionar de las personas. CONCLUSIONES: Es urgente revisar las estrategias de comunicación de riesgo y medidas de prevención ante esta posibilidad de contagios masivos entre humanos, además de fortalecer la investigación y proyectar el desarrollo de una vacuna para proteger las poblaciones expuestas a esta enfermedad con alta tasa de letalidad.

INTRODUCTION: Hantavirus cardiopulmonary syndrome is an infection caused by rodents of the Bunyanvirales family towards humans. This disease in Chile is considered endemic, which has a high fatality rate. At present, some studies show the contagion between people of the Andes virus, whose locality is concentrated in Argentina and Chile. OBJECTIVES: Analyze the possibility of hantavirus transmission between humans using an SEIR-type mathematical model. METHODS: An SEIR (Susceptible, Exposed, Infectious and Recovered) mathematical model to express the dynamics of hantavirus disease is proposed, including the possibility of human-to-human transmission and the perception of risk. RESULTS: The peak of human-to-human contagion decreases by about 25% after increasing people's perception of risk by reducing the rate of resistance to changeand increasing the speed of people's reaction. CONCLUSIONS: It is urgent to review risk communication strategies and prevention measures in the face of this possibility of massive human-tohuman infections, in addition to strengthening research and planning the development of a vaccine to protect populations exposed to this disease with a high fatality rate.

Alcohol Consumption and Its Influence on the Clinical Picture of Puumala Hantavirus Infection.

Puumala hantavirus (PUUV) causes hemorrhagic fever with renal syndrome. Characteristic clinical findings include acute kidney injury (AKI), thrombocytopenia, and capillary leakage. Smoking increases the risk of severe AKI, but it is not known whether alcohol consumption predisposes patients to a more severe infection. Liver and pancreatic enzymes, as well as biomarkers of alcohol consumption (gamma-glutamyl transferase, GGT; carbohydrate-deficient transferrin, CDT; GGT-CDT combination; and ethyl glucuronide, EtG), were measured from 66 patients with acute PUUV infection during hospitalization and at the convalescence phase. Alcohol consumption was present in 41% of the study population, 15% showing signs of heavy drinking. Alcohol use did not affect the severity of PUUV induced AKI nor the overall clinical picture of the infection. Liver enzyme levels (GGT or alanine aminotransferase, ALT) were elevated in 64% of the patients, but the levels did not associate with the markers reflecting the severity of the disease. Serum amylase activities at the convalescent stage were higher than those at the acute phase (p < 0.001). No cases with acute pancreatitis were found. In conclusion, our findings indicate that alcohol consumption does not seem to affect the clinical course of an acute PUUV infection.

Caracterización y evolución temporal de la mortalidad por zoonosis bajo declaración obligatoria, entre los años 1997 y 2018 / Characterization and temporal evolution of mortality due to zoonoses under mandatory declaration, between the years 1997 and 2018

INTRODUCCIÓN: Las zoonosis son enfermedades transmitidas desde un hospedador animal al ser humano o viceversa. En Chile, las zoonosis de Notificación Obligatoria (NO) son: brucelosis, carbunco, triquinosis, hidatidosis, leptospirosis, dengue, enfermedad de Chagas, hantavirosis y rabia. OBJETIVO: Evaluar la tendencia y caracterizar la mortalidad por zoonosis de NO en Chile entre 1997-2018. METODOLOGÍA: Estudio ecológico de la mortalidad por zoonosis de NO. Se utilizaron bases de mortalidad y población oficiales. Se describió la mortalidad relativa, general y específica, según variables sociodemográficas. Se calcularon tasas de mortalidad anuales brutas (TMb) y ajustadas (TMa, método directo). Se evaluó la tendencia temporal con modelos de regresión de Prais-Winsten. Resultados: Entre 1997 y 2018 la mortalidad por zoonosis de NO correspondió al 0,12% (2.359 muertes) de la mortalidad total, siendo las principales causas la enfermedad de Chagas (59,8%), hidatidosis (23,9%) y hantavirosis (13,8%). La TMa general disminuyó significativamente (B: -0,017; IC95%: -0,024; -0,009) al igual que hidatidosis (B: -0,011; IC95%: -0,013; -0,008), sólo hantavirosis mostró un aumento (no significativo). CONCLUSIÓN: La mortalidad por zoonosis de NO disminuyó durante el período estudiado; solo la hantavirosis mostró un aumento en su tendencia. Se sugiere enfocar estrategias para prevenir la transmisibilidad y mortalidad por hanta, así como mejorar el acceso a tratamiento para las otras zoonosis.

BACKGROUND: Zoonoses are diseases transmitted from an animal host to humans or vice versa. In Chile, the zoonoses of mandatory notification are brucellosis, anthrax, trichinosis, hydatidosis, leptospirosis, dengue, Chagas disease, hantavirosis and rabies. AIM: To assess the trend and characterize the mortality from zoonoses of mandatory notification in Chile between 1997-2018. METHODS: An official mortality and population data were used. Relative, general and specific mortality rates were described according to sociodemographic variables. Crude and adjusted annual mortality rates (direct method) were calculated. Temporal trend was evaluated with the Prais-Winsten regression model. RESULTS: Between 1997 and 2018, the mortality rate due to zoonosis of mandatory notification corresponded to 0.13% (2152 deaths) of the total mortality, being Chagas disease (59.2%), hydatidosis (24.6%) and hantavirosis (13.5%) the main causes. The general adjusted mortality rate decreased significantly (B: -0.017; IC95%: -0.024; -0.009) as did hydatidosis (B: -0.011; IC95%: -0.013; -0.008), and only hantavirosis showed an increase trend (not significant). CONCLUSION: Mortality due to zoonoses decreased during the period; only hantavirosis showed an increasing trend. It is suggested to focus on strategies to prevent contagion and mortality by hantavirosis, as well as to improve access to treatment for the other zoonoses.

Hantavirus Research in Finland: Highlights and Perspectives.

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

Prediction model to discriminate leptospirosis from hantavirus

SUMMARY OBJECTIVE: The aim of this study was to build a prediction model to discriminate precociously hantavirus infection from leptospirosis, identifying the conditions and risk factors associated with these diseases. METHODS: A logistic regression model in which the response variable was the presence of hantavirus or leptospirosis was adjusted. RESULTS: As a result, the method selected the following variables that influenced the prediction formula: sociodemographic variables, clinical manifestations, and exposure to environmental risks. All variables considered in the model presented statistical significance with a p<0.05 value. The accuracy of the model to differentiate hantavirus from leptospirosis was 88.7%. CONCLUSIONS: Concluding that the development of statistical tools with high potential to predict the disease, and thus differentiate them precociously, can reduce hospital costs, speed up the patient's care, reduce morbidity and mortality, and assist health professionals and public managers in decision-making.

Structural Basis for a Neutralizing Antibody Response Elicited by a Recombinant Hantaan Virus Gn Immunogen.

Hantaviruses are a group of emerging pathogens capable of causing severe disease upon zoonotic transmission to humans. The mature hantavirus surface presents higher-order tetrameric assemblies of two glycoproteins, Gn and Gc, which are responsible for negotiating host cell entry and constitute key therapeutic targets. Here, we demonstrate that recombinantly derived Gn from Hantaan virus (HTNV) elicits a neutralizing antibody response (serum dilution that inhibits 50% infection [ID50], 1:200 to 1:850) in an animal model. Using antigen-specific B cell sorting, we isolated monoclonal antibodies (mAbs) exhibiting neutralizing and non-neutralizing activity, termed mAb HTN-Gn1 and mAb nnHTN-Gn2, respectively. Crystallographic analysis reveals that these mAbs target spatially distinct epitopes at disparate sites of the N-terminal region of the HTNV Gn ectodomain. Epitope mapping onto a model of the higher order (Gn-Gc)4 spike supports the immune accessibility of the mAb HTN-Gn1 epitope, a hypothesis confirmed by electron cryo-tomography of the antibody with virus-like particles. These data define natively exposed regions of the hantaviral Gn that can be targeted in immunogen design. IMPORTANCE The spillover of pathogenic hantaviruses from rodent reservoirs into the human population poses a continued threat to human health. Here, we show that a recombinant form of the Hantaan virus (HTNV) surface-displayed glycoprotein, Gn, elicits a neutralizing antibody response in rabbits. We isolated a neutralizing (HTN-Gn1) and a non-neutralizing (nnHTN-Gn2) monoclonal antibody and provide the first molecular-level insights into how the Gn glycoprotein may be targeted by the antibody-mediated immune response. These findings may guide rational vaccine design approaches focused on targeting the hantavirus glycoprotein envelope.

MAIT cell activation is associated with disease severity markers in acute hantavirus infection.

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.

Interactions of Viral Proteins from Pathogenic and Low or Non-Pathogenic Orthohantaviruses with Human Type I Interferon Signaling.

Rodent-borne orthohantaviruses are asymptomatic in their natural reservoir, but they can cause severe diseases in humans. Although an exacerbated immune response relates to hantaviral pathologies, orthohantaviruses have to antagonize the antiviral interferon (IFN) response to successfully propagate in infected cells. We studied interactions of structural and nonstructural (NSs) proteins of pathogenic Puumala (PUUV), low-pathogenic Tula (TULV), and non-pathogenic Prospect Hill (PHV) viruses, with human type I and III IFN (IFN-I and IFN-III) pathways. The NSs proteins of all three viruses inhibited the RIG-I-activated IFNß promoter, while only the glycoprotein precursor (GPC) of PUUV, or its cleavage product Gn/Gc, and the nucleocapsid (N) of TULV inhibited it. Moreover, the GPC of both PUUV and TULV antagonized the promoter of IFN-stimulated responsive elements (ISRE). Different viral proteins could thus contribute to inhibition of IFNß response in a viral context. While PUUV and TULV strains replicated similarly, whether expressing entire or truncated NSs proteins, only PUUV encoding a wild type NSs protein led to late IFN expression and activation of IFN-stimulated genes (ISG). This, together with the identification of particular domains of NSs proteins and different biological processes that are associated with cellular proteins in complex with NSs proteins, suggested that the activation of IFN-I is probably not the only antiviral pathway to be counteracted by orthohantaviruses and that NSs proteins could have multiple inhibitory functions.

Small animal jet injection technique results in enhanced immunogenicity of hantavirus DNA vaccines.

DNA vaccine evaluation in small animals is hampered by low immunogenicity when the vaccines are delivered using a needle and syringe. To overcome this technical hurdle we tested the possibility that a device developed for human intradermal medicine delivery might be adapted to successfully deliver a DNA vaccine to small animals. Disposable syringe jet injection (DSJI) does not currently exist for small animals. However, a commercialized, human intradermal device used to to administer medicines to the human dermis in a 0.1 mL volume was evaluated in Syrian hamsters. Here, we found that hantavirus DNA vaccines administered to hamsters using DSJI were substantially more immunogenic than the same vaccines delivered by needle/syringe or particle mediated epidermal delivery (gene gun) vaccination. By adjusting how the device was used we could deliver vaccine to either subcutaneous tissues, or through the skin into the muscle. RNA and/or antigen expression was detected in epidermal, subepidermal and fibroblast cells. We directly compared six optimized and non-optimized hantavirus DNA vaccines in hamsters. Optimization, including codon-usage and mRNA stability, did not necessarily result in increased immunogenicity for all vaccines tested; however, optimization of the Andes virus (ANDV) DNA vaccine protected vaccinated hamsters from lethal disease. This is the first time active vaccination with an ANDV DNA vaccine has shown protective efficacy in the hamster model. The adaptation of a human intradermal jet injection device for use as a method of subcutaneous and intramuscular jet injection of DNA vaccines will advance the development of nucleic acid based medical countermeasures for diseases modeled in hamsters.

3D-printed electrode as a new platform for electrochemical immunosensors for virus detection.

Simple, low-cost, and sensitive new platforms for electrochemical immunosensors for virus detection have been attracted attention due to the recent pandemic caused by a new type of coronavirus (SARS-CoV-2). In the present work, we report for the first time the construction of an immunosensor using a commercial 3D conductive filament of carbon black and polylactic acid (PLA) to detect Hantavirus Araucaria nucleoprotein (Np) as a proof-of-concept. The recognition biomolecule was anchored directly at the filament surface by using N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and N-Hydroxysuccinimide (EDC/NHS). Conductive and non-conductive composites of PLA were characterized using thermal gravimetric analysis (TGA), revealing around 30% w/w of carbon in the filament. Morphological features of composites were obtained from SEM and TEM measurements. FTIR measurement revealed that crosslinking agents were covalently bonded at the filament surface. Electrochemical techniques such as cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) were used for the evaluation of each step involved in the construction of the proposed immunosensor. The results showed the potentiality of the device for the quantitative detection of Hantavirus Araucaria nucleoprotein (Np) from 30 µg mL-1 to 240 µg mL-1 with a limit of detection of 22 µg mL-1. Also, the proposed immunosensor was applied with success for virus detection in 100x diluted human serum samples. Therefore, the PLA conductive filament with carbon black is a simple and excellent platform for immunosensing, which offers naturally carboxylic groups able to anchor covalently biomolecules.

Two patients, two viruses and multiple sites of injury in the kidney.

Viral nephropathy is a term defines glomerular, tubular and/or vascular injury in kidney caused by viruses itself or virus-induced immune mechanisms. It is difficult to prove causality between the renal disease and the viral infection, however, renal biopsy findings can help in this regard. Several viruses such as hepatitis B and C, Human immun deficiciency virus (HIV), Hantavirus, Cytomegalovirus (CMV), an recently Coronavirus are shown to affect the kidney. Treatment of viral nephropathies are unique regarding the diagnosis which can be made only with renal biopsy in most of the situations. We present two patients presented with acute kidney injury and thrombocytopenia caused by different viruses (Hantavirus and HIV) that affect multiple areas in kidney that revealed with kidney biopsy. Supportive treatment in the patient with Hantavirus nephropathy and HIV treatment along with eculizumab and supportive treatment in the patient with HIVAN were successfully implemented.

Síndrome febril asociado a síntomas gastrointestinales: Hantavirus. Caso Clínico pediátrico / Febrile syndrome associated with gastrointestinal symptoms: Hantavirus. Pediatric Clinical Case

Reportamos el caso de un niño con diagnóstico de Sepsis a foco gastrointestinal que evoluciona de manera desfavorable con compromiso respiratorio. Ya instaurados tratamientos de sostén, se evalúa cuadro clínico en contexto de epidemiología positiva para contacto con roedores, presentando serología Virus Andes reactiva.

We report the case of a child with Sepsis and gastrointestinal focus that evolves unfavorably with respiratory compromise. Once supportive treatments have been established, the clinical picture is evaluated in the context of positive epidemiology for contact with rodents, presenting reactive Andes Virus serology.