[Marburg virus disease in travellers]. / Maladie à virus Marburg chez les voyageurs.

Marburg virus disease (MVD) is a dreadful but exceptional disease. Formerly mainly identified in Uganda, Angola and the Democratic Republic of Congo, it has recently appeared in the Republic of Guinea, Ghana, Equatorial Guinea and Tanzania, adding West Africa to the affected regions. Humans become infected through exposure to bats Roussettus aegyptiacus or during unprotected care of infected people. Five cases are linked to travellers, the last one dates to 2008 and involved a visit to caves colonized by bats. At present, there is no specific treatment or vaccine. Despite its rarity, adventurous travelers should be aware of the risks of exposure and avoid entering places inhabited by bats.

La maladie à virus Marburg est une maladie redoutable mais exceptionnelle. Autrefois identifiée en Ouganda, Angola et République démocratique du Congo, elle a récemment fait son apparition en République de Guinée, au Ghana, en Guinée équatoriale et en Tanzanie, ajoutant l'Afrique de l'Ouest aux régions touchées. Les humains s'infectent lors d'une exposition avec les chauves-souris roussettes d'Égypte ou lors de la prise en charge sans protection de personnes infectées. Cinq cas sont liés à des voyageurs, le dernier remonte à 2008 et était associé à la visite de grottes colonisées par des roussettes d'Égypte. Actuellement, il n'existe aucun traitement spécifique ni vaccin. Malgré sa rareté, les voyageurs aventureux doivent être informés des risques d'exposition et éviter de pénétrer dans des lieux habités par des chauves-souris.

Past and current advances in Marburg virus disease: a review.

Marburg Virus (MARV), along with the Ebola virus, belongs to the family of Filovirus and is cause of a lethal and severely affecting hemorrhagic fever. The Marburgvirus genus includes two viruses: MARV and Ravn. MARV has been recognized as one of utmost importance by the World Health Organization (WHO). The case fatality rate of the virus ranges from 24.0 to 88.0% which demonstrates its lethal nature and the need for its widespread information. The first case of the Marburgvirus disease (MARD) was reported in 1967 when lab personnel working with African green monkeys got infected in Germany and Serbia simultaneously. Following the initial case, many more outbreaks occurred around the world such as Uganda, Angola, Congo, Kenya and even in the United States in 2008. It was soon found out that the MARV was a zoonotic virus and mainly contracted from animal-to-human contact and further transmitted via human-to-human contact. The Egyptian fruit bat (Rousettus aegyptiacus) is known to be one of the significant sources of the infection and tourists visiting caves inhabited by these bats or workers accessing mines, populated by the bats, are at an increased risk of contracting the illness. The incubation period ranges from 2-21 days and the clinical outcome can be broken down into three phases: initial generalized phase (day 1-4), early organ phase (day 5 to 13) and either a late organ/convalescence phase (day 13 onwards). Furthermore, the treatment of MARD is solely based on supportive care. Much has been investigated in over the past half-century of the initial infection but only a few treatment options show promising results. In addition, special precaution is advised whilst handling the patient or the biospecimens. Disease-modifying agents and inhibitors of viral replications show constructive outcomes. It is crucial to identify the host of the virus and educate the populations that are greatly at risk of the disease. While much is being investigated to devise a vaccine, it is important to educate Health Care Workers (HCWs) and close contacts facing the illness. Stopping the transmission remains the best measure that can be taken.

Viral genomics in Ebola virus research.

Filoviruses such as Ebola virus continue to pose a substantial health risk to humans. Advances in the sequencing and functional characterization of both pathogen and host genomes have provided a wealth of knowledge to clinicians, epidemiologists and public health responders during outbreaks of high-consequence viral disease. Here, we describe how genomics has been historically used to investigate Ebola virus disease outbreaks and how new technologies allow for rapid, large-scale data generation at the point of care. We highlight how genomics extends beyond consensus-level sequencing of the virus to include intra-host viral transcriptomics and the characterization of host responses in acute and persistently infected patients. Similar genomics techniques can also be applied to the characterization of non-human primate animal models and to known natural reservoirs of filoviruses, and metagenomic sequencing can be the key to the discovery of novel filoviruses. Finally, we outline the importance of reverse genetics systems that can swiftly characterize filoviruses as soon as their genome sequences are available.

A Forgotten Episode of Marburg Virus Disease: Belgrade, Yugoslavia, 1967.

In 1967, several workers involved in poliomyelitis vaccine development and production fell ill at three different locations in Europe with a severe and often lethal novel disease associated with grivets (Chlorocebus aethiops) imported from Uganda. This disease was named Marburg virus disease (MVD) after the West German town of Marburg an der Lahn, where most human infections and deaths had been recorded. Consequently, the Marburg episode received the most scientific and media attention. Cases that occurred in Frankfurt am Main, West Germany, were also described in commonly accessible scientific literature, although they were less frequently cited than those pertaining to the Marburg infections. However, two infections occurring in a third location, in Belgrade, Yugoslavia, have seemingly been all but forgotten. Due in part to their absence in commonly used databases and in part to the fact that they were written in languages other than English, the important articles describing this part of the outbreak are very rarely cited. Here, we summarize this literature and correct published inaccuracies to remind a younger generation of scientists focusing on Marburg virus and its closest filoviral relatives of this important historical context. Importantly, and unfortunately, the three episodes of infection of 1967 still represent the best in-depth clinical look at MVD in general and in the context of "modern" medicine (fully resourced versus less-resourced capacity) in particular. Hence, each individual case of these episodes holds crucial information for health care providers who may be confronted with MVD today.

Marburgviruses: An Update.

Ebolaviruses have gained much attention recently due to the outbreak from 2014 through 2016. The related marburgviruses also have been responsible for large outbreaks with high case fatality rates. The purpose of this article is to provide the clinical laboratory scientist with a review of the most current developments in marburgvirus research. The PubMed database was reviewed using the keywords "Marburg virus," "Ravn virus," and "marburgviruses," with publication dates from January 1, 2015 through June 20, 2017. The search yielded 345 articles. In total, 52 articles met the inclusion criteria and were reviewed. Advances have been made in the areas of ecology and host reservoir studies, seroprevalence studies, pathology and pathogenesis studies, laboratory assay development, and treatment and vaccine development. Marburgviruses are highly lethal viruses that pose a significant threat to the human population. Although numerous advances have been made, there are still large gaps in knowledge, and it is imperative that scientists gain more information to fully understand virus/host interactions. An approved vaccine and treatment remain elusive.

Marburg Virus Infection in Egyptian Rousette Bats, South Africa, 2013-20141.

We detected a high seroprevalence of Marburg virus (MARV) antibodies in fruit bats in South Africa; 19.1% of recaptured bats seroconverted. The MARV RNA isolated closely resembled the 1975 Ozolin strain. These findings indicate endemic MARV circulation in bats in South Africa and should inform policies on MARV disease risk reduction.

Filovirus Research: How it Began.

The first reported filovirus outbreak occurred in August 1967, when laboratory workers in Marburg and Frankfurt, Germany, and Belgrade, Yugoslavia (now Serbia) became infected with an unknown highly pathogenic agent. The disease was characterized by high fever, malaise, rash, hemorrhagic and tetanic manifestations, and high lethality, amounting to 25%. The disease was introduced to Europe by grivets (Chlorocebus aethiops), which were used for biomedical research and vaccine production. The causative agent, Marburg virus, was isolated and identified by scientists of the University of Marburg, Germany in cooperation with specialists for viral electron microscopy at the Bernhard Nocht Institute in Hamburg, Germany. In this chapter, Dr. Slenczka, who was involved in the first isolation of Marburg virus in 1967, describes the desperate hunt of the causative agent of this first filovirus disease outbreak in the center of Europe, its successful isolation, the likely route of transmission from a monkey trading station to vaccine production facilities in Germany and Yugoslavia, and the consequences of this outbreak, including a shortage in the production of poliomyelitis vaccine In addition, this chapter provides insight into some of the peculiarities of filovirus infection, such as sexual virus transmission several months after recovery and the role of Ca2+-loss in Marburg virus pathogenesis, which were already observed during this first well-documented Marburg virus disease outbreak.

Modelling filovirus maintenance in nature by experimental transmission of Marburg virus between Egyptian rousette bats.

The Egyptian rousette bat (ERB) is a natural reservoir host for Marburg virus (MARV); however, the mechanisms by which MARV is transmitted bat-to-bat and to other animals are unclear. Here we co-house MARV-inoculated donor ERBs with naive contact ERBs. MARV shedding is detected in oral, rectal and urine specimens from inoculated bats from 5-19 days post infection. Simultaneously, MARV is detected in oral specimens from contact bats, indicating oral exposure to the virus. In the late study phase, we provide evidence that MARV can be horizontally transmitted from inoculated to contact ERBs by finding MARV RNA in blood and oral specimens from contact bats, followed by MARV IgG antibodies in these same bats. This study demonstrates that MARV can be horizontally transmitted from inoculated to contact ERBs, thereby providing a model for filovirus maintenance in its natural reservoir host and a potential mechanism for virus spillover to other animals.

Chaperone-Mediated Autophagy Protein BAG3 Negatively Regulates Ebola and Marburg VP40-Mediated Egress.

Ebola (EBOV) and Marburg (MARV) viruses are members of the Filoviridae family which cause outbreaks of hemorrhagic fever. The filovirus VP40 matrix protein is essential for virus assembly and budding, and its PPxY L-domain motif interacts with WW-domains of specific host proteins, such as Nedd4 and ITCH, to facilitate the late stage of virus-cell separation. To identify additional WW-domain-bearing host proteins that interact with VP40, we used an EBOV PPxY-containing peptide to screen an array of 115 mammalian WW-domain-bearing proteins. Using this unbiased approach, we identified BCL2 Associated Athanogene 3 (BAG3), a member of the BAG family of molecular chaperone proteins, as a specific VP40 PPxY interactor. Here, we demonstrate that the WW-domain of BAG3 interacts with the PPxY motif of both EBOV and MARV VP40 and, unexpectedly, inhibits budding of both eVP40 and mVP40 virus-like particles (VLPs), as well as infectious VSV-EBOV recombinants. BAG3 is a stress induced protein that regulates cellular protein homeostasis and cell survival through chaperone-mediated autophagy (CMA). Interestingly, our results show that BAG3 alters the intracellular localization of VP40 by sequestering VP40 away from the plasma membrane. As BAG3 is the first WW-domain interactor identified that negatively regulates budding of VP40 VLPs and infectious virus, we propose that the chaperone-mediated autophagy function of BAG3 represents a specific host defense strategy to counteract the function of VP40 in promoting efficient egress and spread of virus particles.

Natural History of Aerosol Exposure with Marburg Virus in Rhesus Macaques.

Marburg virus causes severe and often lethal viral disease in humans, and there are currently no Food and Drug Administration (FDA) approved medical countermeasures. The sporadic occurrence of Marburg outbreaks does not allow for evaluation of countermeasures in humans, so therapeutic and vaccine candidates can only be approved through the FDA animal rule-a mechanism requiring well-characterized animal models in which efficacy would be evaluated. Here, we describe a natural history study where rhesus macaques were surgically implanted with telemetry devices and central venous catheters prior to aerosol exposure with Marburg-Angola virus, enabling continuous physiologic monitoring and blood sampling without anesthesia. After a three to four day incubation period, all animals developed fever, viremia, and lymphopenia before developing tachycardia, tachypnea, elevated liver enzymes, decreased liver function, azotemia, elevated D-dimer levels and elevated pro-inflammatory cytokines suggesting a systemic inflammatory response with organ failure. The final, terminal period began with the onset of sustained hypotension, dehydration progressed with signs of major organ hypoperfusion (hyperlactatemia, acute kidney injury, hypothermia), and ended with euthanasia or death. The most significant pathologic findings were marked infection of the respiratory lymphoid tissue with destruction of the tracheobronchial and mediastinal lymph nodes, and severe diffuse infection in the liver, and splenitis.

No evidence for the involvement of the argasid tick Ornithodoros faini in the enzootic maintenance of marburgvirus within Egyptian rousette bats Rousettus aegyptiacus.

BACKGROUND: The cave-dwelling Egyptian rousette bat (ERB; Rousettus aegyptiacus) was recently identified as a natural reservoir host of marburgviruses. However, the mechanisms of transmission for the enzootic maintenance of marburgviruses within ERBs are unclear. Previous ecological investigations of large ERB colonies inhabiting Python Cave and Kitaka Mine, Uganda revealed that argasid ticks (Ornithodoros faini) are hematophagous ectoparasites of ERBs. Yet, their potential role as transmission vectors for marburgvirus has not been sufficiently assessed. FINDINGS: In the present study, 3,125 O. faini were collected during April 2013 from the rock crevices of Python Cave, Uganda. None of the ticks tested positive for marburgvirus-specific RNA by Q-RT-PCR. The probability of failure to detect marburgvirus at a conservative prevalence of 0.1 % was 0.05. CONCLUSIONS: The absence of marburgvirus RNA in O. faini suggests they do not play a significant role in the transmission and enzootic maintenance of marburgvirus within their natural reservoir host.

Risk factors for transmission of Ebola or Marburg virus disease: a systematic review and meta-analysis.

BACKGROUND: The Ebola virus disease outbreak that started in Western Africa in 2013 was unprecedented because it spread within densely populated urban environments and affected many thousands of people. As a result, previous advice and guidelines need to be critically reviewed, especially with regard to transmission risks in different contexts. METHODS: Scientific and grey literature were searched for articles about any African filovirus. Articles were screened for information about transmission (prevalence or odds ratios especially). Data were extracted from eligible articles and summarized narratively with partial meta-analysis. Study quality was also evaluated. RESULTS: A total of 31 reports were selected from 6552 found in the initial search. Eight papers gave numerical odds for contracting filovirus illness; 23 further articles provided supporting anecdotal observations about how transmission probably occurred for individuals. Many forms of contact (conversation, sharing a meal, sharing a bed, direct or indirect touching) were unlikely to result in disease transmission during incubation or early illness. Among household contacts who reported directly touching a case, the attack rate was 32% [95% confidence interval (CI) 26-38%]. Risk of disease transmission between household members without direct contact was low (1%; 95% CI 0-5%). Caring for a case in the community, especially until death, and participation in traditional funeral rites were strongly associated with acquiring disease, probably due to a high degree of direct physical contact with case or cadaver. CONCLUSIONS: Transmission of filovirus is unlikely except through close contact, especially during the most severe stages of acute illness. More data are needed about the context, intimacy and timing of contact required to raise the odds of disease transmission. Risk factors specific to urban settings may need to be determined.

Ebola hemorrhagic fever/Ebola virus disease - Marburg disease - Lassa fever.

Ebola virus disease, Marburg disease, and Lassa fever are viral hemorrhagic fevers with similar clinical manifestations. Given the recent expanding movement of people around the world, persons infected with any of these hemorrhagic fever viruses might develop symp- toms in Japan. Clinicians should be aware of the latest situation once viral hemorrhagic fever is reported from any country. Obtaining travel history is crucial in suspecting viral hemorrha- gic fever when an acute febrile patient visits a medical facility. Secure implementation of standard precautions would limit further nosocomial transmission even before diagnosis. In order to investigate promptly a suspected case, medical facilities and health authorities should collaborate closely and effectively to break the transmission chain as soon as possi- ble.

Ebola virus disease and Marburg disease in pregnancy: a review and management considerations for filovirus infection.

The largest-ever recorded outbreak of viral hemorrhagic fever is ongoing. As a result of the epidemic and rural nature of outbreaks, little is published about the Filovirus infections Ebola virus disease and Marburg disease in pregnancy. This review of viral hemorrhagic fever focusing on Marburg and Ebola uses knowledge of disease in nonpregnant individuals and pregnancy-specific data to inform management for pregnant women. Filovirus infection presentation is similar between pregnant and nonpregnant patients, although infections may be more severe in pregnancy. Although labeled as hemorrhagic fevers, Marburg and Ebola do not commonly cause gross bleeding and should be conceptualized as diseases of high gastrointestinal losses. Early, aggressive supportive care is the mainstay of Filovirus infection management with massive fluid resuscitation as the key management principle. Patients often require 5-10 L or more per day of intravenous or oral fluid to maintain circulating blood volume in the setting of ongoing gastrointestinal loss. Fluid shifts warrant aggressive monitoring and correction of potassium levels and acid-base disturbances to prevent life-threatening arrhythmias and metabolic complications. Regardless of maternal survival, fetal loss rates are nearly 100% in Filovirus infection, likely resulting from unchecked transplacental and hematogenous viral spread. High fetal loss rates support the placenta as a difficult-to-eradicate Filovirus infection reservoir. In conclusion, the management of Filovirus infection in pregnancy should focus on stabilizing the mother with intensive monitoring and aggressive fluid and electrolyte repletion as well as maintaining strict infection control to minimize transmission to others.

Lack of Marburg Virus Transmission From Experimentally Infected to Susceptible In-Contact Egyptian Fruit Bats.

Egyptian fruit bats (Rousettus aegyptiacus) were inoculated subcutaneously (n = 22) with Marburg virus (MARV). No deaths, overt signs of morbidity, or gross lesions was identified, but microscopic pathological changes were seen in the liver of infected bats. The virus was detected in 15 different tissues and plasma but only sporadically in mucosal swab samples, urine, and fecal samples. Neither seroconversion nor viremia could be demonstrated in any of the in-contact susceptible bats (n = 14) up to 42 days after exposure to infected bats. In bats rechallenged (n = 4) on day 48 after infection, there was no viremia, and the virus could not be isolated from any of the tissues tested. This study confirmed that infection profiles are consistent with MARV replication in a reservoir host but failed to demonstrate MARV transmission through direct physical contact or indirectly via air. Bats develop strong protective immunity after infection with MARV.

Mapping the zoonotic niche of Marburg virus disease in Africa.

BACKGROUND: Marburg virus disease (MVD) describes a viral haemorrhagic fever responsible for a number of outbreaks across eastern and southern Africa. It is a zoonotic disease, with the Egyptian rousette (Rousettus aegyptiacus) identified as a reservoir host. Infection is suspected to result from contact between this reservoir and human populations, with occasional secondary human-to-human transmission. METHODS: Index cases of previous human outbreaks were identified and reports of infection in animals recorded. These data were modelled within a species distribution modelling framework in order to generate a probabilistic surface of zoonotic transmission potential of MVD across sub-Saharan Africa. RESULTS: Areas suitable for zoonotic transmission of MVD are predicted in 27 countries inhabited by 105 million people. Regions are suggested for exploratory surveys to better characterise the geographical distribution of the disease, as well as for directing efforts to communicate the risk of practices enhancing zoonotic contact. CONCLUSIONS: These maps can inform future contingency and preparedness strategies for MVD control, especially where secondary transmission is a risk. Coupling this risk map with patient travel histories could be used to guide the differential diagnosis of highly transmissible pathogens, enabling more rapid response to outbreaks of haemorrhagic fever.

Tissue and cellular tropism, pathology and pathogenesis of Ebola and Marburg viruses.

Ebola viruses and Marburg viruses include some of the most virulent and fatal pathogens known to humans. These viruses cause severe haemorrhagic fevers, with case fatality rates in the range 25-90%. The diagnosis of filovirus using formalin-fixed tissues from fatal cases poses a significant challenge. The most characteristic histopathological findings are seen in the liver; however, the findings overlap with many other viral and non-viral haemorrhagic diseases. The need to distinguish filovirus infections from other haemorrhagic fevers, particularly in areas with multiple endemic viral haemorrhagic agents, is of paramount importance. In this review we discuss the current state of knowledge of filovirus infections and their pathogenesis, including histopathological findings, epidemiology, modes of transmission and filovirus entry and spread within host organisms. The pathogenesis of filovirus infections is complex and involves activation of the mononuclear phagocytic system, with release of pro-inflammatory cytokines, chemokines and growth factors, endothelial dysfunction, alterations of the innate and adaptive immune systems, direct organ and endothelial damage from unrestricted viral replication late in infection, and coagulopathy. Although our understanding of the pathogenesis of filovirus infections has rapidly increased in the past few years, many questions remain unanswered.