Globally Emerging Hantaviruses: An Overview

Hantaviruses are known to cause haemorrhagic fever with renal syndrome in Eurasia and hantavirus cardiopulmonary syndrome in the Americas. They are globally emerging pathogens as newer serotypes are routinely being reported. This review discusses hantavirus biology, clinical features and pathogenesis of hantavirus disease, its diagnostics, distribution and mammalian hosts. Hantavirus research in India is also summarised.     

Factors Influencing Microbe/Insecticide Interactions

Abstract

Hantaviruses comprise an emerging global threat for public health, affecting about 30?000 humans annually. Infection may lead to Hantavirus pulmonary syndrome (HPS) in the Americas and hemorrhagic fever with renal syndrome (HFRS) in the Europe and Asia. Humans are spillover hosts, acquiring infection primarily through the inhalation of aerosolized excreta from infected rodents and insectivores. Risk factors for infection include involvement in outdoor activities, such as rural- and forest-related activities, peridomestic rodent presence, exposure to potentially infected dust and outdoor military training; prolonged, intimate contact with infected individuals promotes transmission of Andes virus, the only Hantavirus known to be transmitted from human-to-human. The total number of Hantavirus case reports is generally on the rise, as is the number of affected countries. Knowledge of the geographical distribution, regional incidence and associated risk factors of the disease are crucial for clinicians to suspect and diagnose infected individuals early on. Climatic, ecological and environmental changes are related to fluctuations in rodent populations, and subsequently to human epidemics. Thus, prevention may be enhanced by host-reservoir control and human exposure prophylaxis interventions, which likely have led to a dramatic reduction of human cases in China over the past decades; vaccination may also play a role in the future.     

Time to revise the paradigm of hantavirus syndromes? Hantavirus pulmonary syndrome caused by European hantavirus

Hantaviruses have previously been recognised to cause two separate syndromes: hemorrhagic fever with renal syndrome in Eurasia, and hantavirus pulmonary syndrome (HPS) in the Americas. However, increasing evidence suggests that this dichotomy is no longer fruitful when recognising human hantavirus disease and understanding the pathogenesis. Herein are presented three cases of severe European Puumala hantavirus infection that meet the HPS case definition. The clinical and pathological findings were similar to those found in American hantavirus patients. Consequently, hantavirus infection should be considered as a cause of acute respiratory distress in all endemic areas worldwide.     

Increased permeability of human endothelial cell line EA.hy926 induced by hantavirus-specific cytotoxic T lymphocytes

Hantavirus infection causes two human diseases, hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. The typical feature of these diseases is increased permeability in microvascular beds in the kidneys and the lungs, respectively. The mechanism of capillary leakage, however, is not understood. Some evidence suggests that hantavirus disease pathogenesis is immunologically mediated by cytotoxic T lymphocytes and other immune cells in target organs producing inflammatory cytokines. In this study we examined the roles of virus-specific cytotoxic T lymphocytes in increased permeability of human endothelial cells infected with hantavirus. We used a human CD8(+) hantavirus-specific cytotoxic T lymphocyte line, 1A-E2, specific for the HLA-A24-restricted epitope in Sin Nombre and Puumala virus G2 protein, and the human endothelial cell line, EA.hy926 that expresses HLA-A24 molecule. The cytotoxic T lymphocyte line recognized and lysed target cells infected with Sin Nombre virus, and in transwell permeability assays increased permeability of EA.hy926 cell monolayer infected with Sin Nombre virus or recombinant adenovirus expressing the Sin Nombre virus G2 protein. These results suggest that cytotoxic T lymphocyte activity contribute to capillary leakage observed in patients with hantavirus pulmonary syndrome or hemorrhagic fever with renal syndrome.     

How to diagnose hantavirus infections and detect them in rodents and insectivores

Hantaviruses are carried by rodents and insectivores in which they cause persistent and generally asymptomatic infections. Several hantaviruses can infect humans and many of them cause either haemorrhagic fever with renal syndrome (HFRS) in Eurasia or hantavirus cardiopulmonary syndrome (HCPS) in the Americas. In humans hantavirus infections are diagnosed using IgM-capture tests but also by RT-PCR detection of viral RNA. For detection of hantavirus infections in rodents and insectivores, serology followed by immunoblotting of, for example, lung tissue, and RT-PCR detection of viral RNA may be used, and if of interest followed by sequencing and virus isolation. For sero/genotyping of hantavirus infections in humans and carrier animals neutralisation tests/RNA sequencing are required. Hantaviruses are prime examples of emerging and re-emerging infections and it seems likely that many new hantaviruses will be detected in the near future.     

Hantavirus: recent data and review of the literature

Hantavirus (Bunyaviridae family) are present worldwide and are the causative agent of haemorrhagic fever with renal or pulmonary syndrome. These viruses are transmitted by rodents with asymptomatic infection which thus act as an excellent reservoir. Molecular epidemiology indicates that Hantavirus may have evolved in three ways: mutations within the genome, reassortment of the segmented genome between two closely related Hantavirus, and genomic recombination, a relatively rare phenomenon among negative stranded RNA viruses. Each virus is carried primarily by a specific rodent host. This observation is confirmed by phylogenetic analyses: the evolution tree of the different Hantavirus, based on viral genomic sequences has been shown to mirror the evolution tree of their specific rodents, based on sequences of mitochondrial DNA. Altogether these data suggest that an ancestral Hantavirus infected a specific rodent, early during evolution, and was subsequently submitted to the same evolutionary pressure as the rodent host.     

Hantavirus infection in Iranian patients suspected to viral hemorrhagic fever

Background: Hantaviruses are a group of emerging pathogens causing hemorrhagic fever with renal syndrome and Hantavirus cardiopulmonary syndrome in human. This study was conducted to investigate Hantavirus infection among Iranian viral hemorrhagic fever suspected patients. Methods: From April 2014 to June 2016, 113 cases from 25 different provinces of Iran were analyzed for Hantavirus infection by IgM/IgG ELISA and pan-Hantavirus RT-PCR tests. Results: Although, viral genome was detected in none of the subjects, IgM and IgG antibodies were detected in 19 and 4 cases, respectively. Differentiation of the anti-Hantavirus antibodies according to virus species by EUROLINE Anti-Hantavirus Profile Kit revealed three Puumala virus IgM positive, one Hantaan virus IgM positive, one Hantaan virus IgM borderline, and two Puumala virus IgG borderline cases. Conclusions: This study demonstrates the circulation of Hantaviruses in Iran and calls for further investigations of these life-threatening viruses in the country.     

Genetic characterization and phylogeny of a hantavirus from Western Mexico

Hantaviruses can cause two serious illnesses when transmitted from their rodent reservoirs to humans; hantavirus pulmonary syndrome (HPS) in the New World and hemorrhagic fever with renal syndrome in the Old World. Cases of HPS were first recognized in the Americas in small, focal outbreaks in rural populations in the Southwestern USA in 1993. Since that time, outbreaks as well as sporadic cases of HPS have been recognized throughout the Americas. Remarkably, HPS cases have not been reported in Mexico. Mexico is one of the most biodiverse regions in the world and this is reflected in the species diversity of the peromyscine, sigmodontine and oryzomyine rodents; all potential hosts of hantaviruses. Hence, we collected and surveyed several rodent species in Western Mexico and identified three previously unrecognized rodents with antibodies to hantaviral antigens: Oryzomys couesi, Sigmodon mascotensis and Baiomys musculus. The S and M segments cloned from O. couesi and S. mascotensis, referred to herein as Playa de Oro (ORO) virus, showed strongest similarity to Bayou and Catacamas viruses with 92/93% and 92/92% similarity based on S/M amino acid sequences, respectively. This and phylogenetic analysis of the M and S segments suggests that ORO virus is a unique genotype within Hantavirus.     

HANTAVIRUS SPECIES IN INDIA: A RETROSPECTIVE STUDY

Hantaviruses cause hemorrhagic fever with renal syndrome in Europe and Asia. There are about 20 documented hantavirus species and newer species are being described worldwide, especially in non-rodent reservoirs, i.e shrews. Focus reduction neutralization test is the classical serotyping technique for hantavirus. However, this study employs a previously established serotyping ELISA, to retrospectively analyze known hantavirus IgG reactive samples for infecting serotypes. The result suggests presence of Thailand virus-like and Hantaan virus-like strains in India.     

Pathogenesis of puumala and other hantavirus infections

Hantaviruses are rodent/insectivore-borne negative-stranded RNA viruses which belong to the Bunyaviridae family. They do not cause any symptomatic disease in their adult carrier rodents, but in humans they are aetiologic agents of haemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), both associated with a significant mortality. In cell culture hantaviruses do not cause cytopathic effects and the mechanisms of disease in man are not well understood. Increased capillary permeability is a central phenomenon in the pathogenesis of hantavirus infections. Although the viruses have in vivo a predilection for endothelial cells, it is presumed that inflammatory mediators of the host immune response play a significant role in the capillary leak that may produce abrupt hypotension and shock in severely ill patients. Mediators released by activated macrophages including NO and TNF-α are considered important. The pathogenesis of renal failure in HFRS also awaits to be resolved. This review summarises what is known about these phenomena and discusses also the molecular basis of the putative virulence factors of hantaviruses. Finally, the genetic predisposition and HLA association with severe Puumala virus infection will be discussed. © 1998 John Wiley & Sons, Ltd.     

Hantavirus pulmonary syndrome

Hantavirus pulmonary syndrome (HPS) is a severe disease characterized by a rapid onset of pulmonary edema followed by respiratory failure and cardiogenic shock. The HPS associated viruses are members of the genus Hantavirus, family Bunyaviridae. Hantaviruses have a worldwide distribution and are broadly split into the New World hantaviruses, which includes those causing HPS, and the Old World hantaviruses [including the prototype Hantaan virus (HTNV)], which are associated with a different disease, hemorrhagic fever with renal syndrome (HFRS). Sin Nombre virus (SNV) and Andes virus (ANDV) are the most common causes of HPS in North and South America, respectively. Case fatality of HPS is approximately 40%. Pathogenic New World hantaviruses infect the lung microvascular endothelium without causing any virus induced cytopathic effect. However, virus infection results in microvascular leakage, which is the hallmark of HPS. This article briefly reviews the knowledge on HPS-associated hantaviruses accumulated since their discovery, less than 20 years ago.     

Hantaviruses and hantavirus infections

Hemorrhagic fever with renal syndrome (HVRS) has been for decades a topical problem for healthcare systems of many countries in the Eurasian continent. Viruses triggering HVRS alongside with other related viruses (but not pathogenic to man) were discovered in 70-80-ies and formed a new genus Hantavirus of the Bunyaviridae family. The study results of a severe outbreak of the respiratory disease with the mortality rate of 60% (South-West of the USA, 1933) showed that hantaviruses were also among the causative agents. Later, the disease was designated as hantavirus cardio-pulmonary syndrome. By now, it has been established that hantaviruses are wide spread with different rodents being their carriers. The discussed viruses cause, in rodents, a chronic asymptomatic infection and are transferred, later, to man by the aerogenic path through excretions of infected animals. Studies of hantaviruses have been restricted for a long time due to their high pathogenicity (protection equipment not below than the P-3 level is needed), because of a lack of a laboratory model of infected animals and because of a low growth in cell cultures. With the rapid development and application of molecular biological techniques of the recent years, substantial progress has been made in studies of hantaviruses. Different aspects of hantavirus ecology, molecular biology, morphology, pathogenesis and diagnostics are discussed in the offered survey.     

深圳市HFRS疫源地鼠携带汉坦病毒与人感染汉坦病毒的基因特征对应性研究

目的 了解深圳市肾综合征出血热(HFRS)疫源地鼠携带汉坦病毒与人感染汉坦病毒二者的病原学特征及联系,为HFRS的防控提供科学依据.方法 收集疑似HFRS病人急性期血清标本,并在相同区域开展笼日法捕鼠,无菌取鼠肺.分别采用ELISA和直接免疫荧光法筛选阳性标本,选择代表性血清标本以及鼠肺标本进行逆转录-套式聚合酶链反应(RT-nested PCR)扩增部分M和S片段及核苷酸序列测定,与国内外的汉坦病毒毒株一起进行同源性比对和系统进化树分析.结果 472份鼠肺经直接免疫荧光检测共获得阳性鼠肺47份,带毒率为9.96%.对60份IgM抗体阳性的血液标本进行RT-nested PCR扩增,检出12份阳性,阳性率为20%.从代表性的8份鼠肺和8份病人血清中提取的标本二者之间M片段核苷酸序列的同源性高达95%以上,S片段之间的同源性高达96.5%以上.其推导的氨基酸序列同源性分别为98.0%～100%、98.4%～100%.深圳市HFRS疫源地鼠携带的汉坦病毒和人感染汉坦病毒均为汉城型S2亚型.结论 深圳市流行的汉坦病毒为SEO型S2亚型.无论是同一地区的鼠和人之间,还是不同地区的鼠和人之间,汉坦病毒都是具有较高的同源性.     

A lethal disease model for hantavirus pulmonary syndrome

Hantaviruses are associated with two human diseases, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Development of vaccines and therapies to prevent and treat HFRS and HPS have been hampered by the absence of a practical animal model. Here we report that Andes virus (ANDV), a South American hantavirus, is highly lethal in adult Syrian hamsters. The characteristics of the disease in hamsters, including the incubation period, symptoms of rapidly progressing respiratory distress, and pathologic findings of pulmonary edema and pleural effusion, closely resemble HPS in humans. This is the first report of a lethal disease model for hantaviruses that causes HPS.     

Hantaviruses: immunology, treatment, and prevention

Hantaviruses are rodent-borne bunyaviruses that are associated with two main clinical diseases in humans: hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. It has been suggested that host-related immune mechanisms rather than direct viral cytopathology may be responsible for the principal abnormality (vascular dysfunction) in these syndromes. This review summarizes the current knowledge on hantaviral host immune responses, immune abnormalities, laboratory diagnosis, and antiviral therapy as well as the current approaches in vaccine development.     

Antiviral effect of human saliva against hantavirus

Hemorrhagic fever with renal syndrome (HFRS) and Hantavirus pulmonary syndrome are zoonotic diseases caused by rodent borne hantaviruses. Transmission to humans occurs usually by inhalation of aerozolized virus‐contaminated rodent excreta. Although human‐to‐human transmission of Andes hantavirus has been observed, the mode of transmission is currently not known. Saliva from Puumala hantavirus (PUUV)‐infected patients was shown recently to contain viral RNA. To test if human saliva interferes with hantavirus replication, the effect of saliva and salivary proteins on hantavirus replication was studied. It was observed that saliva from healthy individuals reduced Hantaan hantavirus (HTNV) infectivity, although not completely. Furthermore, HTNV was resistant against the antiviral capacity of histatin 5, lysozyme, lactoferrin, and SLPI, but was inhibited by mucin. Inoculation of bank voles (Myodes glareolus) with HFRS‐patient saliva, positive for PUUV‐RNA, did not induce sero‐conversion. In conclusion, no evidence of infectious virus in patient saliva was found. However, the in vitro experiments showed that HTNV, the prototype hantavirus, is insensitive to several antiviral salivary proteins, and is partly resistant to the antiviral effect of saliva. It therefore remains to be shown if human saliva might contain infectious virions early during infection, that is, before seroconversion. J. Med. Virol. 80:2122–2126, 2008. © 2008 Wiley‐Liss, Inc.     

Hanta hemorrhagic fever with renal syndrome: a case report and review.

Hantavirus infection is seldom reported in Taiwan. The spectrum of clinical severity ranges from mild to severe and may cover Hantavirus pulmonary syndrome and hemorrhagic fever with renal syndrome (HFRS). We report a case of HFRS in a 24-year-old soldier presenting with fever, chills, abdominal pain and generalized myalgia. His clinical course progressed through febrile, hypotensive, oliguria and polyuria phases. Hantavirus infection was proven by serology at the second hospital week. The patient was successfully treated with supportive management. Clinicians should be alert to the possibility of HFRS when examining patients with symptoms of fever, renal function impairment, hemorrhagic tendency and with rural exposure in Taiwan.     

New Ecological Aspects of Hantavirus Infection: A Change of A Paradigm and a Challenge of Prevention- A Review

In the last decades a significant number of so far unknown or underestimated pathogens have emerged as fundamental health hazards of the human population despite intensive research and exceptional efforts of modern medicine to embank and eradicate infectious diseases. Almost all incidents caused by such emerging pathogens could be ascribed to agents that are zoonotic or expanded their host range and crossed species barriers. Many different factors influence the status of a pathogen to remain unnoticed or evolves into a worldwide threat. The ability of an infectious agent to adapt to changing environmental conditions and variations in human behavior, population development, nutrition, education, social, and health status are relevant factors affecting the correlation between pathogen and host. Hantaviruses belong to the emerging pathogens having gained more and more attention in the last decades. These viruses are members of the family Bunyaviridae and are grouped into a separate genus known as Hantavirus. The serotypes Hantaan (HTN), Seoul (SEO), Puumala (PUU), and Dobrava (DOB) virus predominantly cause hemorrhagic fever with renal syndrome (HFRS), a disease characterized by renal failure, hemorrhages, and shock. In the recent past, many hantavirus isolates have been identified and classified in hitherto unaffected geographic regions in the New World (North, Middle, and South America) with characteristic features affecting the lungs of infected individuals and causing an acute pulmonary syndrome. Hantavirus outbreaks in the United States of America at the beginning of the 10th decade of the last century fundamentally changed our knowledge about the appearance of the hantavirus specific clinical picture, mortality, origin, and transmission route in human beings. The hantavirus pulmonary syndrome (HPS) was first recognized in 1993 in the Four Corners Region of the United States and had a lethality of more than 50%. Although the causative virus was first termed in connection with the geographic name of its outbreak region the analysis of the individual viruses indicate that the causing virus of HPS was a genetically distinct hantavirus and consequently termed as Sin Nombre virus. Hantaviruses are distributed worldwide and are assumed to share a long time period of co-evolution with specific rodent species as their natural reservoir. The degree of relatedness between virus serotypes normally coincides with the relatedness between their respective hosts. There are no known diseases that are associated with hantavirus infections in rodents underlining the amicable relationship between virus and host developed by mutual interaction in hundreds of thousands of years. Although rodents are the major reservoir, antibodies against hantaviruses are also present in domestic and wild animals like cats, dogs, pigs, cattle, and deer. Domestic animals and rodents live jointly in a similar habitat. Therefore the transmission of hantaviruses from rodents to domestic animals seems to be possible, if the target organs, tissues, and cell parenchyma of the co-habitat domestic animals possess adequate virus receptors and are suitable for hantavirus entry and replication. The most likely incidental infection of species other than rodents as for example humans turns hantaviruses from harmless to life-threatening pathogenic agents focusing the attention on this virus group, their ecology and evolution in order to prevent the human population from a serious health risk. Much more studies on the influence of non-natural hosts on the ecology of hantaviruses are needed to understand the directions that the hantavirus evolution could pursue. At least, domestic animals that share their environmental habitat with rodents and humans particularly in areas known as high endemic hantavirus regions have to be copiously screened. Each transfer of hantaviruses from their original natural hosts to other often incidental hosts is accompanied by a change of ecology, a change of environment, a modulation of numerous factors probably influencing the pathogenicity and virulence of the virus. The new environment exerts a modified evolutionary pressure on the virus forcing it to adapt and probably to adopt a form that is much more dangerous for other host species compared to the original one.     

Fatal illness associated with a new hantavirus in Louisiana

A fatal case of hantaviral illness occurred in Louisiana, outside of the range of P. maniculatus, the rodent reservoir for Sin Nombre virus. Hantavirus RNA and antigens were detected in patient autopsy tissues, and nucleotide sequence analysis of amplified polymerase chain reaction (PCR) products identified a newly recognized unique hantavirus, provisionally named Bayou virus. Prominent features of the clinical illness are compatible with hantavirus pulmonary syndrome (HPS), but several features such as renal insufficiency and intraalveolar hemorrhage are more compatible with hemorrhagic fever with renal syndrome (HFRS), a disease associated with Eurasian hantaviruses. © 1995 Wiley-Liss, Inc.