Genomic analysis of filoviruses associated with four viral hemorrhagic fever outbreaks in Uganda and the Democratic Republic of the Congo in 2012

Albariño, César G.; Shoemaker, Trevor; Khristova, Marina L.; Wamala, Joseph F.; Muyembe, Jean‐Jacques; Balinandi, Stephen; Tumusiime, Alex; Campbell, Shelley; Cannon, Deborah; Gibbons, Aridth; Bergeron, Éric; Bird, Brian H.; Dodd, Kimberly A.; Spiropoulou, Christina F.; Erickson, Bobbie R.; Guerrero, Lisa Wiggleton; Knust, Barbara; Nichol, Stuart T.; Rollin, Pierre E.; Ströher, Ute

doi:10.1016/j.virol.2013.04.014

Cited by 117 publications

(104 citation statements)

References 11 publications

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“…These activities typically put local workers in frequent contact with bat excreta, providing opportunities for exposure to viruses that may be shed in feces, urine, or saliva. For example, Marburg virus spillover from cave-roosting bats has been linked to gold mining [39,40] and tourism [41] in caves from Democratic Republic of Congo and Uganda. In addition, destruction of foraging sites surrounding caves can serve as an additional stressor to cave-roosting bats that may promote susceptibility to infection.…”

Section: Human-cave Bat Interactionsmentioning

confidence: 99%

A Comparative Analysis of Viral Richness and Viral Sharing in Cave-Roosting Bats

2017

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Caves provide critical roosting habitats for bats globally, but are increasingly disturbed or destroyed by human activities such as tourism and extractive industries. In addition to degrading the habitats of cave-roosting bats, such activities often promote contact between humans and bats, which may have potential impacts on human health. Cave-roosting bats are hosts to diverse viruses, some of which emerged in humans with severe consequences (e.g., severe acute respiratory syndrome coronavirus and Marburg virus). Characterizing patterns of viral richness and sharing among bat species are therefore important first steps for understanding bat-virus dynamics and mitigating future bat-human spillover. Here we compile a database of bat-virus associations and bat species ecological traits, and investigate the importance of roosting behavior as a determinant of viral richness and viral sharing among bat species. We show that cave-roosting species do not host greater viral richness, when accounting for publication bias, diet, body mass, and geographic range size. Our global analyses, however, show that cave-roosting bats do exhibit a greater likelihood of viral sharing, especially those documented in the literature as co-roosting in the same cave. We highlight the importance of caves as critical foci for bat conservation, as well as ideal sites for longitudinal surveillance of bat-virus dynamics.

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Section: Human-cave Bat Interactionsmentioning

confidence: 99%

A Comparative Analysis of Viral Richness and Viral Sharing in Cave-Roosting Bats

2017

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“…The virus was initially discovered in 2007 during an outbreak of hemorrhagic fever in the Bundibugyo district of Uganda that resulted in a case-fatality rate (CFR) of 25% (1,2). A subsequent outbreak occurred in 2012 in the Democratic Republic of Congo, in which the CFR was 36% (3). Ebola virus (EBOV) is also a member of the Ebolavirus genus and is the best known of all filoviruses.…”

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confidence: 99%

“…Outbreaks of EBOV disease can result in a CFR of up to 90%. Although BDBV is related to EBOV, phylogenetic analysis indicates that these two viruses are antigenically distinct, with only 60% sequence similarity for the glycoprotein at the amino acid level (2,3). The natural reservoir for these viruses remains unknown; however, serological evidence suggests that fruit bats may serve as an animal host for EBOV (4,5).…”

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confidence: 99%

Ferrets Infected with Bundibugyo Virus or Ebola Virus Recapitulate Important Aspects of Human Filovirus Disease

Kozak

Kroeker

et al. 2016

J Virol

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Bundibugyo virus (BDBV) is the etiological agent of a severe hemorrhagic fever in humans with a case-fatality rate ranging from 25 to 36%. Despite having been known to the scientific and medical communities for almost 1 decade, there is a dearth of studies on this pathogen due to the lack of a small animal model. Domestic ferrets are commonly used to study other RNA viruses, including members of the order Mononegavirales. To investigate whether ferrets were susceptible to filovirus infections, ferrets were challenged with a clinical isolate of BDBV. Animals became viremic within 4 days and succumbed to infection between 8 and 9 days, and a petechial rash was observed with moribund ferrets. Furthermore, several hallmarks of human filoviral disease were recapitulated in the ferret model, including substantial decreases in lymphocyte and platelet counts and dysregulation of key biochemical markers related to hepatic/renal function, as well as coagulation abnormalities. Virological, histopathological, and immunohistochemical analyses confirmed uncontrolled BDBV replication in the major organs. Ferrets were also infected with Ebola virus (EBOV) to confirm their susceptibility to another filovirus species and to potentially establish a virus transmission model. Similar to what was seen with BDBV, important hallmarks of human filoviral disease were observed in EBOV-infected ferrets. This study demonstrates the potential of this small animal model for studying BDBV and EBOV using wild-type isolates and will accelerate efforts to understand filovirus pathogenesis and transmission as well as the development of specific vaccines and antivirals. IMPORTANCEThe 2013-2016 outbreak of Ebola virus in West Africa has highlighted the threat posed by filoviruses to global public health. Bundibugyo virus (BDBV) is a member of the genus Ebolavirus and has caused outbreaks in the past but is relatively understudied, likely due to the lack of a suitable small animal model. Such a model for BDBV is crucial to evaluating vaccines and therapies and potentially understanding transmission. To address this, we demonstrated that ferrets are susceptible models to BDBV infection as well as to Ebola virus infection and that no virus adaptation is required. Moreover, these animals develop a disease that is similar to that seen in humans and nonhuman primates. We believe that this will improve the ability to study BDBV and provide a platform to test vaccines and therapeutics.

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“…In 2005, during an outbreak in Angola, a new strain of MARV resulted in a 90% fatality rate (5). More recent reports of MVD describe outbreaks in 2007, 2012, and 2014 in Uganda (6,7), an imported case in the Netherlands in 2008 (8,9), and a likely imported case in Colorado, USA, also in 2008 (10). Recent modeling data suggest that as many as 27 countries with more than 100 million people are at risk for Marburg virus infection (11).…”

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confidence: 99%

Transcriptional Profiling of the Immune Response to Marburg Virus Infection

Connor

Yen

Caballero

et al. 2015

J Virol

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Marburg virus is a genetically simple RNA virus that causes a severe hemorrhagic fever in humans and nonhuman primates. The mechanism of pathogenesis of the infection is not well understood, but it is well accepted that pathogenesis is appreciably driven by a hyperactive immune response. To better understand the overall response to Marburg virus challenge, we undertook a transcriptomic analysis of immune cells circulating in the blood following aerosol exposure of rhesus macaques to a lethal dose of Marburg virus. Using two-color microarrays, we analyzed the transcriptomes of peripheral blood mononuclear cells that were collected throughout the course of infection from 1 to 9 days postexposure, representing the full course of the infection. The response followed a 3-stage induction (early infection, 1 to 3 days postexposure; midinfection, 5 days postexposure; late infection, 7 to 9 days postexposure) that was led by a robust innate immune response. The host response to aerosolized Marburg virus was evident at 1 day postexposure. Analysis of cytokine transcripts that were overexpressed during infection indicated that previously unanalyzed cytokines are likely induced in response to exposure to Marburg virus and further suggested that the early immune response is skewed toward a Th2 response that would hamper the development of an effective antiviral immune response early in disease. Late infection events included the upregulation of coagulation-associated factors. These findings demonstrate very early host responses to Marburg virus infection and provide a rich data set for identification of factors expressed throughout the course of infection that can be investigated as markers of infection and targets for therapy. IMPORTANCEMarburg virus causes a severe infection that is associated with high mortality and hemorrhage. The disease is associated with an immune response that contributes to the lethality of the disease. In this study, we investigated how the immune cells circulating in the blood of infected primates respond following exposure to Marburg virus. Our results show that there are three discernible stages of response to infection that correlate with presymptomatic, early, and late symptomatic stages of infection, a response format similar to that seen following challenge with other hemorrhagic fever viruses. In contrast to the ability of the virus to block innate immune signaling in vitro, the earliest and most sustained response is an interferon-like response. Our analysis also identifies a number of cytokines that are transcriptionally upregulated during late stages of infection and suggest that there is a Th2-skewed response to infection. When correlated with companion data describing the animal model from which our samples were collected, our results suggest that the innate immune response may contribute to overall pathogenesis.

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Genomic analysis of filoviruses associated with four viral hemorrhagic fever outbreaks in Uganda and the Democratic Republic of the Congo in 2012

Cited by 117 publications

References 11 publications

A Comparative Analysis of Viral Richness and Viral Sharing in Cave-Roosting Bats

A Comparative Analysis of Viral Richness and Viral Sharing in Cave-Roosting Bats

Ferrets Infected with Bundibugyo Virus or Ebola Virus Recapitulate Important Aspects of Human Filovirus Disease

Transcriptional Profiling of the Immune Response to Marburg Virus Infection

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