Prevalence of Antibodies against Hantaviruses in Serum and Saliva of Adults Living or Working on Farms in Yorkshire,United Kingdom

Hantaviruses are an established cause of haemorrhagic fever with renal syndrome (HFRS) in Europe. Following a confirmed case of HFRS in the UK, in an individual residing on a farm in North Yorkshire and the Humber, a tidal estuary on the east coast of Northern England, and the subsequent isolation of a Seoul hantavirus from rats trapped on the patient’s farm, it was considered appropriate to further investigate the public health risk of this virus in the region. Of a total 119 individuals tested, nine (7.6%) were seropositive for hantavirus antibodies. Seven of the seropositive samples showed a stronger reaction to Seoul and Hantaan compared to other clinically relevant hantaviruses. Observation of rodents during the day, in particular mice, was associated with a reduced risk of seropositivity. In addition to one region known to be at risk following an acute case, five further potential risk areas have been identified. This study supports recently published evidence that hantaviruses are likely to be of public health interest in the region.     

汉坦病毒激发人胃上皮细胞病变和凋亡

目的证实人胃粘膜上皮细胞是否为汉坦病毒属(HV)汉滩病毒型(HTN)和汉城病毒型(SEO)病毒的靶细胞,病毒对其是否有致细胞病变效应(CPE)和促凋亡作用。方法建立人胃上皮细胞(HGEC)离体培养;用HVN8、76118、Z37、Seoul8039株感染HGEC,观察细胞CPE,用直接免疫荧光法(IFA)检测病毒感染细胞和感染灶;用AnnexinV FITCkit观察HV的致HGEC凋亡和坏死作用。结果HTNV和SEOV可以感染离体培养的HGEC,形成感染灶并出现CPE;与模拟感染细胞相比,N8、76118、Z37、Seoul8039株感染的HGEC凋亡和坏死细胞比例明显增高,HTNV较SEOV促凋亡和坏死作用更强。结论HGEC可作为HTNV和SEOV感染的靶细胞,致CPE并促进细胞凋亡和坏死,在急性肾综合征出血热病人胃粘膜损害机制中起重要作用。     

Emerging Zoonoses: Hantavirus-Infektionen

Among the emerging viruses, hantaviruses are being focused on more and more due to their increasing number and worldwide distribution. Transmission occurs via inhalation of aerosolized infected rodent excreta. The symptoms and course of disease vary with the infecting hantavirus species. The distribution of the different hantavirus species correlates with the geographical distribution of the virus-type-specific rodent host. Hantaviruses in Europe and Asia cause hemorrhagic fever with renal syndrome (HFRS). Infection with Puumala, the prevalent virus type in Germany, results in a more moderate form of HFRS, nephropathia epidemica. Infections with virus species on the American continents lead to a clinical picture with predominantly pulmonary pathology (hantaviral pulmonary syndrome). No specific antiviral therapy or approved vaccines are available for any hantavirus species. Controlling the rodent populations and avoiding contact with rodent excrement are the only measures that can be undertaken to contain and prevent infection.     

Innate and adaptive immune responses against human Puumala virus infection: immunopathogenesis and suggestions for novel treatment strategies for severe hantavirus‐associated syndromes

Two related hyperinflammatory syndromes are distinguished following infection of humans with hantaviruses: haemorrhagic fever with renal syndrome (HFRS) seen in Eurasia and hantavirus pulmonary syndrome (HPS) seen in the Americas. Fatality rates are high, up to 10% for HFRS and around 35%–40% for HPS. Puumala virus (PUUV) is the most common HFRS‐causing hantavirus in Europe. Here, we describe recent insights into the generation of innate and adaptive cell‐mediated immune responses following clinical infection with PUUV. First described are studies demonstrating a marked redistribution of peripheral blood mononuclear phagocytes (MNP) to the airways, a process that may underlie local immune activation at the site of primary infection. We then describe observations of an excessive natural killer (NK) cell activation and the persistence of highly elevated numbers of NK cells in peripheral blood following PUUV infection. A similar vigorous CD8 Tcell response is also described, though Tcell responses decline with viraemia. Like MNPs, many NK cells and CD8 T cells also localize to the lung upon acute PUUV infection. Following this, findings demonstrating the ability of hantaviruses, including PUUV, to cause apoptosis resistance in infected target cells, are described. These observations, and associated inflammatory cytokine responses, may provide new insights into HFRS and HPS disease pathogenesis. Based on similarities between inflammatory responses in severe hantavirus infections and other hyperinflammatory disease syndromes, we speculate whether some therapeutic interventions that have been successful in the latter conditions may also be applicable in severe hantavirus infections.     

Seoul virus in patients and rodents from Beijing, China

Hemorrhagic fever with renal syndrome (HFRS) is a significant public health problem with an increasing incidence in Beijing, China (report of disease surveillance from the Center for Disease Control and Prevention of Beijing, China). Hantaviruses were detected using RT-PCR method in blood samples of HFRS patients and lung tissues of rodents captured in Beijing. Phylogenetic analyses of 724bp partial S segment of the hantavirus gene showed that the detected Seoul virus (SEOV) fell into three different lineages, two of which circulated in Beijing. A nucleotide sequence identity of 99.7% for one of the cases of HFRS--the human- and Rattus norvegicus-originated SEOV sequences--had only two silent substitutions, suggesting genetic analysis is an essential tool for "case-investigation."     

Comment on Jameson et al.: Prevalence of Antibodies against Hantaviruses in Serum and Saliva of Adults Living or Working on Farms in Yorkshire,United Kingdom

This British hantavirus IgG prevalence study, aimed at 119 asymptomatic farmers in England, and using indirect immunofluorescence assay (IFA) as screening technique, concluded that rat-transmitted Seoul virus (SEOV) might be the main suspect as hantaviral pathogen in the UK. Exactly the same conclusion, using the same IFA screening technique, resulted from a 1994 serosurvey in the same country, and in 627 clinical cases plus 100 healthy controls. SEOV-positive study subjects were also mainly farmers with heavy rat-exposure, but residing in Northern-Ireland, a region where all other known rodent reservoirs for pathogenic hantaviruses are known to be absent, except the wild rat. A rodent capture action in and around the farms of eight seropositives confirmed SEOV seropositivity in 21.6% of 51 rats. All SEOV seropositives were patients, hospitalized with an acute feverish condition, a majority of which having the clinical picture of hantavirus-induced nephropathy, known as hemorrhagic fever with renal syndrome (HFRS). Leptospirosis, often mimicking perfectly HFRS, was serologically excluded. Thus, SEOV was established as a human hantaviral pathogen in the UK and in Europe 20 years ago.     

肾综合征出血热流行过程及其影响因素研究进展

肾综合征出血热（hemorrhagic fever with renal syndrome, HFRS）是由汉坦病毒（hantavirus）感染引起的一种乙类传染病,可引发急性肾损伤,病死率较高。汉坦病毒型别与选择性宿主转换和地区适应密切相关,并由此不断以基因重组等方式进化,不同型别汉坦病毒所致疾病严重程度不同。全球环境变化及宿主动物习性改变加速了汉坦病毒基因组变异;同时,我国大规模土地改造、基础设施建设也使人群与病毒宿主和疾病传播媒介的接触机会增加,一定程度上增大了人群患病风险。本文综述了肾综合征出血热流行过程的主要特征及其相关影响因素,为有效防控该疾病的发生和流行提供参考依据。     

Severity Biomarkers in Puumala Hantavirus Infection

Annually, over 10,000 cases of hemorrhagic fever with renal syndrome (HFRS) are diagnosed in Europe. Puumala hantavirus (PUUV) causes most of the European HFRS cases. PUUV causes usually a relatively mild disease, which is rarely fatal. However, the severity of the infection varies greatly, and factors affecting the severity are mostly unrevealed. Host genes are known to have an effect. The typical clinical features in PUUV infection include acute kidney injury, thrombocytopenia, and increased vascular permeability. The primary target of hantavirus is the endothelium of the vessels of different organs. Although PUUV does not cause direct cytopathology of the endothelial cells, remarkable changes in both the barrier function of the endothelium and the function of the infected endothelial cells occur. Host immune or inflammatory mechanisms are probably important in the development of the capillary leakage. Several immunoinflammatory biomarkers have been studied in the context of assessing the severity of HFRS caused by PUUV. Most of them are not used in clinical practice, but the increasing knowledge about the biomarkers has elucidated the pathogenesis of PUUV infection.     

Serological and genetic evidence for the presence of Seoul hantavirus in Rattus norvegicus in Flanders, Belgium

Seoul hantavirus (SEOV), carried by Rattus rattus (black rat) and R. norvegicus (Norway, brown rat), was reported to circulate as well as cause HFRS cases in Asia. As Rattus sp. are present worldwide, SEOV has the potential to cause human disease worldwide. In Europe however, only SEOV prevalence in rats from France was reported and no confirmed cases of SEOV infection were published. We here report genetic and serological evidence for the presence of SEOV virus in brown rat populations in Belgium. We also serologically screened an at-risk group that was in contact with R. norvegicus on a daily basis and found no evidence for SEOV infection.     

肾综合征出血热抗病毒治疗及疫苗研发进展

肾综合征出血热(hemorrhagic fever with renal syndrome, HFRS)是由汉坦病毒感染引起的一种自然疫源性疾病,在世界范围内广泛流行,我国一直是流行高发区,患者占所有HFRS患者一半以上,其主要临床特征为发热、出血、低血压休克和肾脏损害,严重危害人类健康。尽管抗病毒治疗和疫苗免疫接种可以防治汉坦病毒感染,但目前尚无特效抗病毒药物。近年来,随着医学科技进步,汉坦病毒的抗病毒治疗和疫苗研发有了新的进展。本文基于近年体内外研究及临床试验结果,对HFRS抗病毒治疗和疫苗研发进展作一综述。     

2007年云南省汉坦病毒宿主动物及其基因分型研究

目的掌握云南省肾综合征出血热（HFRS）流行病学特点、汉坦病毒（HV）宿主动物及基因型分布,为防治提供科学依据。方法收集2007年全省HFRS疫情资料;居民区采用笼夜法捕鼠,野外采用夹夜法捕鼠;鼠肺组织标本用直接免疫荧光法检测HV抗原,用RT-PCR法检测HV核酸及分型。结果2007年全省共报告HFRS病例14例,死亡1例,年发病率为0.02/10万,病死率为7.14%。主要发病地区为大理和楚雄州。2007年在泸西、五华、祥云、玉龙、古城、河口、麻栗坡、泸水和隆阳区（县）捕获鼠类21种1 390只,其中居民区以黄胸鼠和褐家鼠为优势鼠种,野外以大绒鼠、中华姬鼠为优势鼠种。鼠间HV总带病毒率为4.17%,阳性鼠种为大林姬鼠、褐家鼠、大绒鼠、高山姬鼠、黄胸鼠、中华姬鼠和卡氏小鼠,带病毒率依次为9.09%（1/11）,7.52%（10/133）,7.35%（23/313）,5.71%（2/35）,2.57%（13/505）,2.38%（2/84）,2.22%（2/9）;用RT-PCR法检测HV抗原阳性鼠肺标本58份,阳性29份,其中汉城型阳性16份,汉滩型阳性13份;汉城型主要带毒鼠种为褐家鼠和黄胸鼠,汉滩型带毒鼠种主要为大绒鼠、高山姬鼠和中华姬鼠。结论调查地区广泛存在以褐家鼠为主要传染源的家鼠型HFRS疫源地,也存在以大绒鼠为主要传染源的野鼠型HFRS疫源地;存在汉城型和汉滩型病毒的流行,汉滩型病毒具有多种宿主动物的特点,在国内具有特殊性。     

肾综合征出血热发病机制的研究进展

肾综合征出血热(hemorrhagic fever with renal syndrome, HFRS)是由汉坦病毒感染引起的以发热、休克、出血和肾脏损害为主要特征的急性自然疫源性疾病。汉坦病毒主要感染人血管内皮细胞,引起小血管和毛细血管广泛损伤。血管通透性增加是HFRS临床表现的病理基础。国内外学者尽管在汉坦病毒致病机制方面开展了诸多研究,如病毒诱导的免疫病理反应、宿主遗传与细胞凋亡、血小板减少与功能障碍、血管内皮损伤等,但HFRS发病机制仍未完全阐明,也无特效治疗药物,深入探讨汉坦病毒致病的分子机制,寻找有效治疗药物仍是汉坦病毒/HFRS领域的研究热点。本文结合近年来国内外相关研究,阐述HFRS发病机制的研究进展。     

Hantavirus infection in bank voles in the natural reservoir. Part 1. Characteristics of an infection process in bank voles]

The specific features of hantavirus infection in naturally infected bank voles (Clethrionomys glareolus), the principal host of hantavirus of the serotype Puumala, were studied during long-term observation of individually marked animals in the active focus of hemorrhagic fever with renal syndrome (HFRS) in the south of Udmurtia. The infection time in the bank voles was defined by paired serum seroconversion tests. In the natural focus, hantavirus was shown to cause asymptomatic persistent infection in the bank voles with the body's peak accumulation of the virus and its environmental discharge within the first month of infection. In this period the animals present the greatest epidemic and epizootic hazards. Hantavirus infection has no negative impact on the viability of bank voles.     

云南省恙虫病与肾综合征出血热混合感染的诊断及分析

目的 调查云南省不明原因发热患者中是否存在恙虫病与肾综合征出血热混合感染病例.方法 采用间接免疫荧光法和胶体金法检测不明原因发热患者血清中的恙虫病东方体(OT)抗体及肾综合征出血热(HFRS)病毒抗体,用巢式PCR扩增患者血液中的OT 基因sta56片断与汉坦病毒(HV)基因L片断.结果 79例患者中,实验室确诊HFRS 5例,恙虫病3例,HFRS与恙虫病混合感染4例;巢式PCR检测到HV L片断核酸2例(DLR2和DLR6), 序列分析两者间的同源性100%,DLR2与老挝汉城病毒L0199株核苷酸序列同源性最高为94.6%, 与中国汉城病毒L99株的同源性80.5%, 与云南汉坦病毒YN06-256的同源性69.8%.结论 首次证实云南省存在恙虫病与肾综合征出血热混合感染病例,其HFRS病原体遗传进化关系与老挝汉城病毒L0199株密切相关.     

Mechanisms of shock in hantavirus pulmonary syndrome

PURPOSE OF REVIEW: Despite abundant literature on hantavirus, few reports have focused on the shock in hantavirus pulmonary syndrome. This review approaches recent advances that allow us to better understand the pathogenesis of hantavirus pulmonary syndrome shock. RECENT FINDINGS: Hantavirus pulmonary syndrome has been studied in a hamster model that mimics human shock and respiratory failure. In-vitro experiments show that pathogenic hantaviruses are able to inhibit antiviral responses, and that cytotoxicity of hantavirus-specific T cells enhances the permeability of infected endothelial cells. The idea that the primary cardiac lesion of shock is mostly functional has been shaken by the report of a typical myocarditis in hearts from human hantavirus pulmonary syndrome fatal cases. The involvement of regulatory T cells on hantavirus persistence in its rodent reservoir suggests that these cells could protect from severe hantavirus pulmonary syndrome and shock. SUMMARY: Hantavirus pulmonary syndrome shock is probably related to an exacerbated immune response of CD8+ T cells producing cytotoxicity on infected endothelial cells, presence of myocarditis and myocardial depression induced by nitric oxide. The virulence elements in G1 glycoprotein could also contribute to shock. Active suppression of immune T regulatory cells is probably involved in hantavirus pulmonary syndrome pathogenesis. These are all new aspects of hantavirus pulmonary syndrome pathogenesis that stimulate further studies to elucidate mechanisms of shock and to develop effective treatment strategies.     

Seoul virus infection in a Wisconsin patient with recent travel to China, March 2009: first documented case in the Midwestern United States

Diagnosis of Seoul virus-associated hemorrhagic fever with renal syndrome (HFRS) cases among United States residents is rare. We describe confirmation of a Seoul virus infection in a 36-year-old scientist who worked with laboratory rats in Milwaukee, Wisconsin, but most likely acquired the infection during a trip to Shenyang, China.     

High prevalence of hantavirus infection in a group of Chinese patients with acute hepatitis of unknown aetiology

In southwestern China, small but substantial numbers of patients with acute hepatitis were found without known hepatropic viral infections (hepatitisA, B, C, D or E, cytomegalovirus, Epstein–Barr virus) and were receiving no hepatotoxic drugs. Prevalence of antibodies, both neutralizing and specific immunoglobulin (Ig)M and IgG, to Hantaan virus were evaluated in a cohort of 136 such patients: 83 were of unknown aetiology, 53 had known viral hepatitis and 59 healthy subjects acted as controls. The results showed that the incidence of neutralizing antibody to Hantaan virus in acute hepatitis patients with non-hepatitisA–E virus infections (13 of 83) was significantly higher than in those with A–E infections (0 of 53, P <0.01). Furthermore, the incidence of specific IgM antibody to Hantaan virus in acute hepatitis patients with non-hepatitisA–E virus infections (6 of 83) was significantly higher than in those with A–E infections (0 of 53, P <0.05) and in healthy subjects (0 of 59, P <0.05). These findings suggest that Hantaan virus may be an important agent, contributing, at least in southwestern China, to a significant number of the cases of acute hepatitis of unknown aetiology. This hantavirus infection resulted in an acute hepatitis, differing from the typical diseases: haemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS).     

Belgrade virus: a new hantavirus causing severe hemorrhagic fever with renal syndrome in Yugoslavia.

Two biologically and genetically distinct hantaviruses were isolated from blood and urine specimens collected from four Yugoslavian patients with clinically severe hemorrhagic fever with renal syndrome (HFRS). Viral isolates from three patients, designated strains Belgrade 1-3, were distinct from Hantaan, Seoul, Puumala, and Prospect Hill viruses as determined by plaque-reduction neutralization tests and restriction analysis of enzymatically amplified M-segment fragments. The fourth isolate, called Kraljevo, was indistinguishable from Hantaan virus. Strains Belgrade 1 and 2, like the Kraljevo strain, caused a fatal meningoencephalitis in newborn mice inoculated with 100 pfu of virus intracerebrally and intraperitoneally. Strain Belgrade 3 was much less neurovirulent, requiring 30,000 pfu of virus to cause fatal disease in mice. These data indicate that two distinct hantaviruses, one of which constitutes a new serotype, cause clinically severe HFRS in Yugoslavia.