Persistence and Sexual Transmission of Filoviruses.

There is an increasing frequency of reports regarding the persistence of the Ebola virus (EBOV) in Ebola virus disease (EVD) survivors. During the 2014⁻2016 West African EVD epidemic, sporadic transmission events resulted in the initiation of new chains of human-to-human transmission. Multiple reports strongly suggest that these re-emergences were linked to persistent EBOV infections and included sexual transmission from EVD survivors. Asymptomatic infection and long-term viral persistence in EVD survivors could result in incidental introductions of the Ebola virus in new geographic regions and raise important national and local public health concerns. Alarmingly, although the persistence of filoviruses and their potential for sexual transmission have been documented since the emergence of such viruses in 1967, there is limited knowledge regarding the events that result in filovirus transmission to, and persistence within, the male reproductive tract. Asymptomatic infection and long-term viral persistence in male EVD survivors could lead to incidental transfer of EBOV to new geographic regions, thereby generating widespread outbreaks that constitute a significant threat to national and global public health. Here, we review filovirus testicular persistence and discuss the current state of knowledge regarding the rates of persistence in male survivors, and mechanisms underlying reproductive tract localization and sexual transmission.

Filoviruses: Ecology, Molecular Biology, and Evolution.

The Filoviridae are a family of negative-strand RNA viruses that include several important human pathogens. Ebola virus (EBOV) and Marburg virus are well-known filoviruses which cause life-threatening viral hemorrhagic fever in human and nonhuman primates. In addition to severe pathogenesis, filoviruses also exhibit a propensity for human-to-human transmission by close contact, posing challenges to containment and crisis management. Past outbreaks, in particular the recent West African EBOV epidemic, have been responsible for thousands of deaths and vaulted the filoviruses into public consciousness. Both national and international health agencies continue to regard potential filovirus outbreaks as critical threats to global public health. To develop effective countermeasures, a basic understanding of filovirus biology is needed. This review encompasses the epidemiology, ecology, molecular biology, and evolution of the filoviruses.

Domesticated animals as hosts of henipaviruses and filoviruses: A systematic review.

Bat-borne viruses carry undeniable risks to the health of human beings and animals, and there is growing recognition of the need for a 'One Health' approach to understand their frequently complex spill-over routes. While domesticated animals can play central roles in major spill-over events of zoonotic bat-borne viruses, for example during the pig-amplified Malaysian Nipah virus outbreak of 1998-1999, the extent of their potential to act as bridging or amplifying species for these viruses has not been characterised systematically. This review aims to compile current knowledge on the role of domesticated animals as hosts of two types of bat-borne viruses, henipaviruses and filoviruses. A systematic literature search of these virus-host interactions in domesticated animals identified 72 relevant studies, which were categorised by year, location, design and type of evidence generated. The review then focusses on Africa as a case study, comparing research efforts in domesticated animals and bats with the distributions of documented human cases. Major gaps remain in our knowledge of the potential ability of domesticated animals to contract or spread these zoonoses. Closing these gaps will be necessary to fully evaluate and mitigate spill-over risks of these viruses, especially with global agricultural intensification.

Ecology of Filoviruses.

Filoviruses can cause severe and often fatal disease in humans. To date, there have been 47 outbreaks resulting in more than 31,500 cases of human illness and over 13,200 reported deaths. Since their discovery, researchers from many scientific disciplines have worked to better understand the natural history of these deadly viruses. Citing original research wherever possible, this chapter reviews laboratory and field-based studies on filovirus ecology and summarizes efforts to identify where filoviruses persist in nature, how virus is transmitted to other animals and ultimately, what drivers cause spillover to human beings. Furthermore, this chapter discusses concepts on what constitutes a reservoir host and highlights challenges encountered while conducting research on filovirus ecology, particularly field-based investigations.

Potential for introduction of bat-borne zoonotic viruses into the EU: a review.

Bat-borne viruses can pose a serious threat to human health, with examples including Nipah virus (NiV) in Bangladesh and Malaysia, and Marburg virus (MARV) in Africa. To date, significant human outbreaks of such viruses have not been reported in the European Union (EU). However, EU countries have strong historical links with many of the countries where NiV and MARV are present and a corresponding high volume of commercial trade and human travel, which poses a potential risk of introduction of these viruses into the EU. In assessing the risks of introduction of these bat-borne zoonotic viruses to the EU, it is important to consider the location and range of bat species known to be susceptible to infection, together with the virus prevalence, seasonality of viral pulses, duration of infection and titre of virus in different bat tissues. In this paper, we review the current scientific knowledge of all these factors, in relation to the introduction of NiV and MARV into the EU.

Filoviruses in bats: current knowledge and future directions.

Filoviruses, including Ebolavirus and Marburgvirus, pose significant threats to public health and species conservation by causing hemorrhagic fever outbreaks with high mortality rates. Since the first outbreak in 1967, their origins, natural history, and ecology remained elusive until recent studies linked them through molecular, serological, and virological studies to bats. We review the ecology, epidemiology, and natural history of these systems, drawing on examples from other bat-borne zoonoses, and highlight key areas for future research. We compare and contrast results from ecological and virological studies of bats and filoviruses with those of other systems. We also highlight how advanced methods, such as more recent serological assays, can be interlinked with flexible statistical methods and experimental studies to inform the field studies necessary to understand filovirus persistence in wildlife populations and cross-species transmission leading to outbreaks. We highlight the need for a more unified, global surveillance strategy for filoviruses in wildlife, and advocate for more integrated, multi-disciplinary approaches to understand dynamics in bat populations to ultimately mitigate or prevent potentially devastating disease outbreaks.

[Filoviruses].

Filoviruses (Ebola and Marburg viruses) cause severe hemorrhagic fever in humans and nonhuman primates. No effective prophylaxis or treatment for filovirus diseases is yet commercially available. Recent studies have advanced our knowledge of filovirus protein functions and interaction between viral and host factors in the replication cycle. Current findings on the ecology of filoviruses (i.e., natural infection of nonprimate animals and discovery of a new member of filoviruses in Europe) have also provided new insights into the epidemiology of Ebola and Marburg hemorrhagic fever. This article reviews the fundamental aspects of filovirus biology and the latest topics on filovirus research.

Current perspectives on the phylogeny of Filoviridae.

Sporadic fatal outbreaks of disease in humans and non-human primates caused by Ebola or Marburg viruses have driven research into the characterization of these viruses with the hopes of identifying host tropisms and potential reservoirs. Such an understanding of the relatedness of newly discovered filoviruses may help to predict risk factors for outbreaks of hemorrhagic disease in humans and/or non-human primates. Recent discoveries such as three distinct genotypes of Reston ebolavirus, unexpectedly discovered in domestic swine in the Philippines; as well as a new species, Bundibugyo ebolavirus; the recent discovery of Lloviu virus as a potential new genus, Cuevavirus, within Filoviridae; and germline integrations of filovirus-like sequences in some animal species bring new insights into the relatedness of filoviruses, their prevalence and potential for transmission to humans. These new findings reveal that filoviruses are more diverse and may have had a greater influence on the evolution of animals than previously thought. Herein we review these findings with regard to the implications for understanding the host range, prevalence and transmission of Filoviridae.

An alternative method of measuring aerosol survival using spiders' webs and its use for the filoviruses.

Understanding the ability to survive in an aerosol leads to better understanding of the hazard posed by pathogenic organisms and can inform decisions related to the control and management of disease outbreaks. This basic survival information is sometimes lacking for high priority select agents such as the filoviruses which cause severe disease with high case fatality rates and can be acquired through the aerosol route. Microthreads in the form of spiders' webs were used to capture aerosolised filoviruses, and the decay rates of Zaire ebolavirus and Marburgvirus were determined. Results were compared to data obtained using a Goldberg drum to measure survival as a dynamic aerosol. The two methods of obtaining aerostability information are compared.

Diagnostics and discovery in viral hemorrhagic fevers.

The rate of discovery of new microbes and of new associations of microbes with health and disease is accelerating. Many factors contribute to this phenomenon including those that favor the true emergence of new pathogens as well as new technologies and paradigms that enable their detection and characterization. This chapter reviews recent progress in the field of pathogen surveillance and discovery with a focus on viral hemorrhagic fevers.

"Filoviruses": a real pandemic threat?

Filoviruses are zoonotic and among the deadliest viruses known to mankind, with mortality rates in outbreaks reaching up to 90%. Despite numerous efforts to identify the host reservoir(s), the transmission cycle of filoviruses between the animal host(s) and humans remains unclear. The last decade has witnessed an increase in filovirus outbreaks with a changing epidemiology. The high mortality rates and lack of effective antiviral drugs or preventive vaccines has propagated the fear that filoviruses may become a real pandemic threat. This article discusses the factors that could influence the possible pandemic potential of filoviruses and elaborates on the prerequisites for the containment of future outbreaks, which would help prevent the evolution of filovirus into more virulent and more transmissible viruses.

Filoviruses: Interactions with the host cell.

The highly pathogenic filoviruses, Marburg and Ebola virus, are difficult to handle and knowledge of the interactions between filoviruses and their host cells remained enigmatic for many years. Two developments were crucial for the presented advances in our understanding of the cell biology of filoviruses, which is still fragmentary. On the one hand, the number of high containment laboratories increased where handling of the highly pathogenic filoviruses is possible. On the other hand, molecular biological tools have been developed that allow investigation of certain aspects of filoviral replication under normal laboratory conditions which considerably accelerated research on filoviruses. This review describes advances in understanding the interactions between host cells and filoviruses during viral attachment, entry, transcription, assembly and budding.

Outbreaks of filovirus hemorrhagic fever: time to refocus on the patient.

In the 40 years since the recognition of filoviruses as agents of lethal human disease, there have been no specific advances in antiviral therapies or vaccines and few clinical studies on the efficacy of supportive care. On 20 September 2006, experts from 14 countries representing 68 institutions integrally involved in the response to outbreaks of filovirus hemorrhagic fever gathered at the National Microbiology Laboratory of the Public Health Agency of Canada in Winnipeg to discuss possible remedies for this grim situation, in a unique workshop entitled "Marburg and Ebola Hemorrhagic Fever: Feasibility of Prophylaxis and Therapy." A summary of the opportunities for and challenges to improving treatment of filovirus hemorrhagic fevers is presented here.

Ebolavirus and other filoviruses.

Since Ebola fever emerged in Central Africa in 1976, a number of studies have been undertaken to investigate its natural history and to characterize its transmission from a hypothetical reservoir host(s) to humans. This research has comprised investigations on a variety of animals and their characterization as intermediate, incidental, amplifying, reservoir, or vector hosts. A viral transmission chain was recently unveiled after a long absence of epidemic Ebola fever. Animal trapping missions were carried out in the Central African rain forest in an area where several epidemics and epizootics had occurred between 2001 and 2005. Among the various animals captured and analyzed, three species of fruit bats (suborder Megachiroptera) were found asymptomatically and naturally infected with Ebola virus: Hypsignathus monstrosus (hammer-headed fruit beats), Epomops franqueti (singing fruit bats), and Myonycteris torquata (little collared fruit bats). From experimental data, serological studies and virus genetic analysis, these findings confirm the importance of these bat species as potential reservoir species of Ebola virus in Central Africa. While feeding bats drop partially eaten fruit and masticated fruit pulp (spats) to the ground, possibly promoting indirect transmission of Ebola virus to certain ground dwelling mammals, if virus is being shed in saliva by chronically and asymptomatically infected bats. Great apes and forest duikers are particularly sensitive to lethal Ebola virus infection. These terrestrial mammals feed on fallen fruits and possibly spats, suggesting a chain of events leading to Ebola virus spillover to these incidental hosts. This chain of events may occur sporadically at different sites and times depending on a combination of the phenology of fruit production by different trees, animal behavior, and various, but as yet still unknown environmental factors, which could include drought. During the reproductive period, infected body fluid can also be shed in the environment and present a potential risk for indirect transmission to other vertebrates.

Lessons from nosocomial viral haemorrhagic fever outbreaks.

The outbreak of Marburg haemorrhagic fever in Angola in 2004-2005 shows once again the devastating and rapid spread of viral haemorrhagic fevers in medical settings where hygiene practices are poorly applied or ignored. The legacy of years of war and poverty in Angola has resulted in very poor medical education and services. The initial high rate of infection among infants in Angola may have been related to poor hospital practices, possibly administration of vaccines. Though the outbreak in Angola was in a part of Africa not previously known to have filovirus infection, prior ecological modelling had predicted this location and many others. Prevention of future outbreaks will not be easy. The urgent need is dissemination of knowledge and the training, discipline and resources for good clinical practice. Educating the public to demand higher standards could be a powerful tool. Good practices are difficult to establish and maintain on the scale needed.

Hemorrhagic fever viruses as biological weapons: medical and public health management.

OBJECTIVE: To develop consensus-based recommendations for measures to be taken by medical and public health professionals if hemorrhagic fever viruses (HFVs) are used as biological weapons against a civilian population. PARTICIPANTS: The Working Group on Civilian Biodefense included 26 representatives from academic medical centers, public health, military services, governmental agencies, and other emergency management institutions. EVIDENCE: MEDLINE was searched from January 1966 to January 2002. Retrieved references, relevant material published prior to 1966, and additional sources identified by participants were reviewed. CONSENSUS PROCESS: Three formal drafts of the statement that synthesized information obtained in the evidence-gathering process were reviewed by the working group. Each draft incorporated comments and judgments of the members. All members approved the final draft. CONCLUSIONS: Weapons disseminating a number of HFVs could cause an outbreak of an undifferentiated febrile illness 2 to 21 days later, associated with clinical manifestations that could include rash, hemorrhagic diathesis, and shock. The mode of transmission and clinical course would vary depending on the specific pathogen. Diagnosis may be delayed given clinicians' unfamiliarity with these diseases, heterogeneous clinical presentation within an infected cohort, and lack of widely available diagnostic tests. Initiation of ribavirin therapy in the early phases of illness may be useful in treatment of some of these viruses, although extensive experience is lacking. There are no licensed vaccines to treat the diseases caused by HFVs.