Last data update: May 06, 2024. (Total: 46732 publications since 2009)
Records 1-30 (of 34 Records) |
Query Trace: Sealy TK[original query] |
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Sosuga virus detected in Egyptian rousette bats (Rousettus aegyptiacus) in Sierra Leone
Amman BR , Koroma AH , Schuh AJ , Conteh I , Sealy TK , Foday I , Johnny J , Bakarr IA , Whitmer SLM , Wright EA , Gbakima AA , Graziano J , Bangura C , Kamanda E , Osborne A , Saidu E , Musa JA , Bangura DF , Williams SMT , Fefegula GM , Sumaila C , Jabaty J , James FH , Jambai A , Garnett K , Kamara TF , Towner JS , Lebbie A . Viruses 2024 16 (4) Sosuga virus (SOSV), a rare human pathogenic paramyxovirus, was first discovered in 2012 when a person became ill after working in South Sudan and Uganda. During an ecological investigation, several species of bats were sampled and tested for SOSV RNA and only one species, the Egyptian rousette bat (ERBs; Rousettus aegyptiacus), tested positive. Since that time, multiple other species have been sampled and ERBs in Uganda have continued to be the only species of bat positive for SOSV infection. Subsequent studies of ERBs with SOSV demonstrated that ERBs are a competent host for SOSV and shed this infectious virus while exhibiting only minor infection-associated pathology. Following the 2014 Ebola outbreak in West Africa, surveillance efforts focused on discovering reservoirs for zoonotic pathogens resulted in the capture and testing of many bat species. Here, SOSV RNA was detected by qRT-PCR only in ERBs captured in the Moyamba District of Sierra Leone in the central region of the country. These findings represent a substantial range extension from East Africa to West Africa for SOSV, suggesting that this paramyxovirus may occur in ERB populations throughout its sub-Saharan African range. |
Marburgvirus resurgence in Kitaka Mine bat population after extermination attempts, Uganda.
Amman BR , Nyakarahuka L , McElroy AK , Dodd KA , Sealy TK , Schuh AJ , Shoemaker TR , Balinandi S , Atimnedi P , Kaboyo W , Nichol ST , Towner JS . Emerg Infect Dis 2014 20 (10) 1761-4 Marburg virus (MARV) and Ravn virus (RAVV), collectively called marburgviruses, cause Marburg hemorrhagic fever (MHF) in humans. In July 2007, 4 cases of MHF (1 fatal) occurred in miners at Kitaka Mine in southern Uganda. Later, MHF occurred in 2 tourists who visited Python Cave, ≈50 km from Kitaka Mine. One of the tourists was from the United States (December 2007) and 1 was from the Netherlands (July 2008); 1 case was fatal (1,2,3). The cave and the mine each contained 40,000–100,000 Rousettus aegyptiacus bats (Egyptian fruit bats). | | Longitudinal investigations of the outbreaks at both locations were initiated by the Viral Special Pathogens Branch of the Centers for Disease Control and Prevention (CDC, Atlanta, GA, USA, and Entebbe, Uganda) in collaboration with the Uganda Wildlife Authority (UWA) and the Uganda Virus Research Institute (UVRI). During these studies, genetically diverse MARVs and RAVVs were isolated directly from bat tissues, and infection levels of the 2 viruses were found to increase in juvenile bats on a predictable bi-annual basis (4,5). However, investigations at Kitaka Mine were stopped when the miners exterminated the bat colony by restricting egress from the cave with papyrus reed barriers and then entangling the bats in fishing nets draped over the exits. The trapping continued for weeks, and the entrances were then sealed with sticks and plastic. These depopulation efforts were documented by researchers from UVRI, the CDC, the National Institute of Communicable Diseases (Sandringham, South Africa), and UWA during site visits to Kitaka Mine (Technical Appendix Figure). In August 2008, thousands of dead bats were found piled in the forest, and by November 2008, there was no evidence of bats living in the mine; whether 100% extermination was achieved is unknown. CDC, UVRI, and UWA recommended against extermination, believing that any results would be temporary and that such efforts could exacerbate the problem if bat exclusion methods were not complete and permanent (6,7). |
Peripheral immune responses to filoviruses in a reservoir versus spillover hosts reveal transcriptional correlates of disease
Guito JC , Arnold CE , Schuh AJ , Amman BR , Sealy TK , Spengler JR , Harmon JR , Coleman-McCray JD , Sanchez-Lockhart M , Palacios GF , Towner JS , Prescott JB . Front Immunol 2023 14 1306501 Several filoviruses, including Marburg virus (MARV), cause severe disease in humans and nonhuman primates (NHPs). However, the Egyptian rousette bat (ERB, Rousettus aegyptiacus), the only known MARV reservoir, shows no overt illness upon natural or experimental infection, which, like other bat hosts of zoonoses, is due to well-adapted, likely species-specific immune features. Despite advances in understanding reservoir immune responses to filoviruses, ERB peripheral blood responses to MARV and how they compare to those of diseased filovirus-infected spillover hosts remain ill-defined. We thus conducted a longitudinal analysis of ERB blood gene responses during acute MARV infection. These data were then contrasted with a compilation of published primate blood response studies to elucidate gene correlates of filovirus protection versus disease. Our work expands on previous findings in MARV-infected ERBs by supporting both host resistance and disease tolerance mechanisms, offers insight into the peripheral immunocellular repertoire during infection, and provides the most direct known cross-examination between reservoir and spillover hosts of the most prevalently-regulated response genes, pathways and activities associated with differences in filovirus pathogenesis and pathogenicity. |
Micro‒global positioning systems for identifying nightly opportunities for Marburg virus spillover to humans by Egyptian Rousette bats
Amman BR , Schuh AJ , Akurut G , Kamugisha K , Namanya D , Sealy TK , Graziano JC , Enyel E , Wright EA , Balinandi S , Lutwama JJ , Kading RC , Atimnedi P , Towner JS . Emerg Infect Dis 2023 29 (11) 2238-2245 Marburg virus disease, caused by Marburg and Ravn orthomarburgviruses, emerges sporadically in sub-Saharan Africa and is often fatal in humans. The natural reservoir is the Egyptian rousette bat (ERB), which sheds virus in saliva, urine, and feces. Frugivorous ERBs discard test-bitten and partially eaten fruit, potentially leaving infectious virus behind that could be consumed by other susceptible animals or humans. Historically, 8 of 17 known Marburg virus disease outbreaks have been linked to human encroachment on ERB habitats, but no linkage exists for the other 9 outbreaks, raising the question of how bats and humans might intersect, leading to virus spillover. We used micro‒global positioning systems to identify nightly ERB foraging locations. ERBs from a known Marburg virus‒infected population traveled long distances to feed in cultivated fruit trees near homes. Our results show that ERB foraging behavior represents a Marburg virus spillover risk to humans and plausibly explains the origins of some past outbreaks. |
Tick salivary gland components dampen Kasokero virus infection and shedding in its vertebrate reservoir, the Egyptian rousette bat (Rousettus aegyptiacus)
Schuh AJ , Amman BR , Guito JC , Graziano JC , Sealy TK , Towner JS . Parasit Vectors 2023 16 (1) 249 BACKGROUND: The human-pathogenic Kasokero virus (KASV) circulates in an enzootic transmission cycle between Egyptian rousette bats (ERBs; Rousettus aegyptiacus) and their argasid tick ectoparasites, Ornithodoros (Reticulinasus) faini. Although tick salivary gland components have been shown to potentiate virus infection in vertebrate non-reservoirs (i.e. incidental hosts or small animal models of disease), there is a lack of information on the effect of tick salivary gland components on viral infection and shedding in vertebrate reservoirs. METHODS: To determine the impact of tick salivary gland components on KASV infection and shedding in ERBs, KASV loads were quantified in blood, oral swab, rectal swab, and urine specimens collected daily through 18 days post inoculation from groups of ERBs intradermally inoculated with KASV or KASV + O. (R.) faini tick salivary gland extract (SGE). RESULTS: Bats inoculated with KASV + tick SGE had significantly lower peak and cumulative KASV viremias and rectal shedding loads compared to bats inoculated with KASV only. CONCLUSIONS: We report for the first time to our knowledge that tick salivary gland components dampen arbovirus infection and shedding in a vertebrate reservoir. This study advances our understanding of biological factors underlying arbovirus maintenance in nature. |
Pathogenesis of Kasokero virus in experimentally infected Egyptian rousette bats (Rousettus aegyptiacus)
Kirejczyk SGM , Schuh AJ , Zhang J , Amman BR , Guito JC , Sealy TK , Graziano JC , Brown CC , Towner JS . Vet Pathol 2023 60 (3) 3009858231158076 Egyptian rousette bats (ERBs; Rousettus aegyptiacus; family Pteropodidae) are associated with a growing number of bunyaviruses of public health importance, including Kasokero virus (KASV), which was first identified as a zoonosis in Uganda in 1977. In this study, formalin-fixed paraffin-embedded tissues from a previous experiment in which KASV infection was confirmed in 18 experimentally infected ERBs were used for an in-depth analysis using histopathology, in situ hybridization (ISH) for detection of viral RNA, immunohistochemistry (IHC) to assess the mononuclear phagocyte system response, and quantitative digital image analysis to investigate virus clearance from the liver and spleen within a spatial context. Significant gross and histological lesions were limited to the liver, where KASV-infected bats developed mild to moderate, acute viral hepatitis, which was first observed at 3 days postinfection (DPI), peaked at 6 DPI, and was resolved by 20 DPI. A subset of bats had glycogen depletion (n = 10) and hepatic necrosis (n = 3), rarely with intralesional bacteria (n = 1). Virus replication was confirmed by ISH in the liver, spleen, lymph nodes, and tongue. In the liver, KASV replicated in the cytoplasm of hepatocytes, to a lesser extent in mononuclear phagocytes, and rarely in presumptive endothelial cells. Most KASV RNA, as detected by ISH, was cleared from the spleen and liver by 6 DPI. It is concluded that ERBs have effective mechanisms to respond to this virus, clearing it without evidence of clinical disease. |
Exposure of Egyptian rousette bats (Rousettus aegyptiacus) and a little free-tailed bat (Chaerephon pumilus) to alphaviruses in Uganda
Kading RC , Borland EM , Mossel EC , Nakayiki T , Nalikka B , Ledermann JP , Crabtree MB , Panella NA , Nyakarahuka L , Gilbert AT , Kerbis-Peterhans JC , Towner JS , Amman BR , Sealy TK , Miller BR , Lutwama JJ , Kityo RM , Powers AM . Diseases 2022 10 (4) The reservoir for zoonotic o'nyong-nyong virus (ONNV) has remained unknown since this virus was first recognized in Uganda in 1959. Building on existing evidence for mosquito blood-feeding on various frugivorous bat species in Uganda, and seroprevalence for arboviruses among bats in Uganda, we sought to assess if serum samples collected from bats in Uganda demonstrated evidence of exposure to ONNV or the closely related zoonotic chikungunya virus (CHIKV). In total, 652 serum samples collected from six bat species were tested by plaque reduction neutralization test (PRNT) for neutralizing antibodies against ONNV and CHIKV. Forty out of 303 (13.2%) Egyptian rousettes from Maramagambo Forest and 1/13 (8%) little free-tailed bats from Banga Nakiwogo, Entebbe contained neutralizing antibodies against ONNV. In addition, 2/303 (0.7%) of these Egyptian rousettes contained neutralizing antibodies to CHIKV, and 8/303 (2.6%) contained neutralizing antibodies that were nonspecifically reactive to alphaviruses. These data support the interepidemic circulation of ONNV and CHIKV in Uganda, although Egyptian rousette bats are unlikely to serve as reservoirs for these viruses given the inconsistent occurrence of antibody-positive bats. |
Natural reservoir Rousettus aegyptiacus bat host model of orthonairovirus infection identifies potential zoonotic spillover mechanisms
Schuh AJ , Amman BR , Guito JC , Graziano JC , Sealy TK , Kirejczyk SGM , Towner JS . Sci Rep 2022 12 (1) 20936 The human-pathogenic Kasokero virus (KASV; genus Orthonairovirus) has been isolated from the sera of Egyptian rousette bats (ERBs; Rousettus aegyptiacus) captured in Uganda and unengorged Ornithodoros (Reticulinasus) faini ticks collected from the rock crevices of ERB colonies in South Africa and Uganda. Although evidence suggests that KASV is maintained in an enzootic transmission cycle between O. (R.) faini ticks and ERBs with potential for incidental virus spillover to humans through the bite of an infected tick, the vertebrate reservoir status of ERBs for KASV has never been experimentally evaluated. Furthermore, the potential for bat-to-bat and bat-to-human transmission of KASV is unknown. Herein, we inoculate two groups of ERBs with KASV; one group of bats is serially sampled to assess viremia, oral, fecal, and urinary shedding and the second group of bats is serially euthanized to assess virus-tissue tropism. Throughout the study, none of the bats exhibit overt signs of clinical disease. Following the detection of high KASV loads of long duration in blood, oral, fecal, and urine specimens collected from ERBs in the serial sampling group, all bats seroconvert to KASV. ERBs from the serial euthanasia group exhibit high KASV loads indicative of virus replication in the skin at the inoculation site, spleen, and inguinal lymph node tissue, and histopathology and in situ hybridization reveal virus replication in the liver and self-limiting, KASV-induced lymphohistiocytic hepatitis. The results of this study suggest that ERBs are competent, natural vertebrate reservoir hosts for KASV that can sustain viremias of appropriate magnitude and duration to support virus maintenance through bat-tick-bat transmission cycles. Viral shedding data suggests that KASV might also be transmitted bat-to-bat and highlights the potential for KASV spillover to humans through contact with infectious oral secretions, feces, or urine. |
Histopathologic and immunohistochemical evaluation of induced lesions, tissue tropism and host responses following experimental infection of Egyptian rousette bats (Rousettus aegyptiacus) with the zoonotic paramyxovirus, Sosuga virus
Kirejczyk SGM , Amman BR , Schuh AJ , Sealy TK , Albariño CG , Zhang J , Brown CC , Towner JS . Viruses 2022 14 (6) Ecological and experimental infection studies have identified Egyptian rousette bats (ERBs; Rousettus aegyptiacus: family Pteropodidae) as a reservoir host for the zoonotic rubula-like paramyxovirus Sosuga virus (SOSV). A serial sacrifice study of colony-bred ERBs inoculated with wild-type, recombinant SOSV identified small intestines and salivary gland as major sites of viral replication. In the current study, archived formalin-fixed paraffin-embedded (FFPE) tissues from the serial sacrifice study were analyzed in depth-histologically and immunohistochemically, for SOSV, mononuclear phagocytes and T cells. Histopathologic lesion scores increased over time and viral antigen persisted in a subset of tissues, indicating ongoing host responses and underscoring the possibility of chronic infection. Despite the presence of SOSV NP antigen and villus ulcerations in the small intestines, there were only mild increases in mononuclear phagocytes and T cells, a host response aligned with disease tolerance. In contrast, there was a statistically significant, robust and targeted mononuclear phagocyte cell responses in the salivary glands at 21 DPI, where viral antigen was sparse. These findings may have broader implications for chiropteran-paramyxovirus interactions, as bats are hypothesized to be the ancestral hosts of this diverse virus family and for ERB immunology in general, as this species is also the reservoir host for the marburgviruses Marburg virus (MARV) and Ravn virus (RAVV) (family Filoviridae). |
Subgenomic flavivirus RNA (sfRNA) associated with Asian lineage Zika virus identified in three species of Ugandan bats (family Pteropodidae).
Fagre AC , Lewis J , Miller MR , Mossel EC , Lutwama JJ , Nyakarahuka L , Nakayiki T , Kityo R , Nalikka B , Towner JS , Amman BR , Sealy TK , Foy B , Schountz T , Anderson J , Kading RC . Sci Rep 2021 11 (1) 8370 Serological cross-reactivity among flaviviruses makes determining the prior arbovirus exposure of animals challenging in areas where multiple flavivirus strains are circulating. We hypothesized that prior infection with ZIKV could be confirmed through the presence of subgenomic flavivirus RNA (sfRNA) of the 3' untranslated region (UTR), which persists in tissues due to XRN-1 stalling during RNA decay. We amplified ZIKV sfRNA but not NS5 from three experimentally-infected Jamaican fruit bats, supporting the hypothesis of sfRNA tissue persistence. Applying this approach to 198 field samples from Uganda, we confirmed presence of ZIKV sfRNA, but not NS5, in four bats representing three species: Eidolon helvum (n = 2), Epomophorus labiatus (n = 1), and Rousettus aegyptiacus (n = 1). Amplified sequence was most closely related to Asian lineage ZIKV. Our results support the use of sfRNA as a means of identifying previous flavivirus infection and describe the first detection of ZIKV RNA in East African bats. |
Human-pathogenic Kasokero virus in field-collected ticks
Schuh AJ , Amman BR , Patel K , Sealy TK , Swanepoel R , Towner JS . Emerg Infect Dis 2020 26 (12) 2944-2950 Kasokero virus (KASV; genus Orthonairovirus) was first isolated in 1977 at Uganda Virus Research Institute from serum collected from Rousettus aegyptiacus bats captured at Kasokero Cave, Uganda. During virus characterization studies at the institute, 4 laboratory-associated infections resulted in mild to severe disease. Although orthonairoviruses are typically associated with vertebrate and tick hosts, a tick vector of KASV never has been reported. We tested 786 Ornithodoros (Reticulinasus) faini tick pools (3,930 ticks) for KASV. The ticks were collected from a large R. aegyptiacus bat roosting site in western Uganda. We detected KASV RNA in 43 tick pools and recovered 2 infectious isolates, 1 of which was derived from host blood-depleted ticks. Our findings suggest that KASV is maintained in an enzootic transmission cycle involving O. (R.) faini ticks and R. aegyptiacus bats and has the potential for incidental virus spillover to humans. |
Asymptomatic Infection of Marburg Virus Reservoir Bats Is Explained by a Strategy of Immunoprotective Disease Tolerance.
Guito JC , Prescott JB , Arnold CE , Amman BR , Schuh AJ , Spengler JR , Sealy TK , Harmon JR , Coleman-McCray JD , Kulcsar KA , Nagle ER , Kumar R , Palacios GF , Sanchez-Lockhart M , Towner JS . Curr Biol 2020 31 (2) 257-270 e5 Marburg virus (MARV) is among the most virulent pathogens of primates, including humans. Contributors to severe MARV disease include immune response suppression and inflammatory gene dysregulation ("cytokine storm"), leading to systemic damage and often death. Conversely, MARV causes little to no clinical disease in its reservoir host, the Egyptian rousette bat (ERB). Previous genomic and in vitro data suggest that a tolerant ERB immune response may underlie MARV avirulence, but no significant examination of this response in vivo yet exists. Here, using colony-bred ERBs inoculated with a bat isolate of MARV, we use species-specific antibodies and an immune gene probe array (NanoString) to temporally characterize the transcriptional host response at sites of MARV replication relevant to primate pathogenesis and immunity, including CD14(+) monocytes/macrophages, critical immune response mediators, primary MARV targets, and skin at the inoculation site, where highest viral loads and initial engagement of antiviral defenses are expected. Our analysis shows that ERBs upregulate canonical antiviral genes typical of mammalian systems, such as ISG15, IFIT1, and OAS3, yet demonstrate a remarkable lack of significant induction of proinflammatory genes classically implicated in primate filoviral pathogenesis, including CCL8, FAS, and IL6. Together, these findings offer the first in vivo functional evidence for disease tolerance as an immunological mechanism by which the bat reservoir asymptomatically hosts MARV. More broadly, these data highlight factors determining disparate outcomes between reservoir and spillover hosts and defensive strategies likely utilized by bat hosts of other emerging pathogens, knowledge that may guide development of effective antiviral therapies. |
Experimental infection of Egyptian rousette bats (Rousettus aegyptiacus) with Sosuga virus demonstrates potential transmission routes for a bat-borne human pathogenic paramyxovirus
Amman BR , Schuh AJ , Sealy TK , Spengler JR , Welch SR , Kirejczyk SGM , Albarino CG , Nichol ST , Towner JS . PLoS Negl Trop Dis 2020 14 (3) e0008092 In August 2012, a wildlife biologist became severely ill after becoming infected with a novel paramyxovirus, termed Sosuga virus. In the weeks prior to illness, the patient worked with multiple species of bats in South Sudan and Uganda, including Egyptian rousette bats (ERBs: Rousettus aegyptiacus). A follow-up study of Ugandan bats found multiple wild-caught ERBs to test positive for SOSV in liver and spleen. To determine the competency of these bats to act as a natural reservoir host for SOSV capable of infecting humans, captive-bred ERBs were inoculated with a recombinant SOSV, representative of the patient's virus sequence. The bats were inoculated subcutaneously, sampled daily (blood, urine, fecal, oral and rectal swabs) and serially euthanized at predetermined time points. All inoculated bats became infected with SOSV in multiple tissues and blood, urine, oral, rectal and fecal swabs tested positive for SOSV RNA. No evidence of overt morbidity or mortality were observed in infected ERBs, although histopathological examination showed subclinical disease in a subset of tissues. Importantly, SOSV was isolated from oral/rectal swabs, urine and feces, demonstrating shedding of infectious virus concomitant with systemic infection. All bats euthanized at 21 days post-inoculation (DPI) seroconverted to SOSV between 16 and 21 DPI. These results are consistent with ERBs being competent reservoir hosts for SOSV with spillover potential to humans. |
Isolation of Angola-like Marburg virus from Egyptian rousette bats from West Africa
Amman BR , Bird BH , Bakarr IA , Bangura J , Schuh AJ , Johnny J , Sealy TK , Conteh I , Koroma AH , Foday I , Amara E , Bangura AA , Gbakima AA , Tremeau-Bravard A , Belaganahalli M , Dhanota J , Chow A , Ontiveros V , Gibson A , Turay J , Patel K , Graziano J , Bangura C , Kamanda ES , Osborne A , Saidu E , Musa J , Bangura D , Williams SMT , Wadsworth R , Turay M , Edwin L , Mereweather-Thompson V , Kargbo D , Bairoh FV , Kanu M , Robert W , Lungai V , Guetiya Wadoum RE , Coomber M , Kanu O , Jambai A , Kamara SM , Taboy CH , Singh T , Mazet JAK , Nichol ST , Goldstein T , Towner JS , Lebbie A . Nat Commun 2020 11 (1) 510 Marburg virus (MARV) causes sporadic outbreaks of severe Marburg virus disease (MVD). Most MVD outbreaks originated in East Africa and field studies in East Africa, South Africa, Zambia, and Gabon identified the Egyptian rousette bat (ERB; Rousettus aegyptiacus) as a natural reservoir. However, the largest recorded MVD outbreak with the highest case-fatality ratio happened in 2005 in Angola, where direct spillover from bats was not shown. Here, collaborative studies by the Centers for Disease Control and Prevention, Njala University, University of California, Davis USAID-PREDICT, and the University of Makeni identify MARV circulating in ERBs in Sierra Leone. PCR, antibody and virus isolation data from 1755 bats of 42 species shows active MARV infection in approximately 2.5% of ERBs. Phylogenetic analysis identifies MARVs that are similar to the Angola strain. These results provide evidence of MARV circulation in West Africa and demonstrate the value of pathogen surveillance to identify previously undetected threats. |
Rousette Bat Dendritic Cells Overcome Marburg Virus-Mediated Antiviral Responses by Upregulation of Interferon-Related Genes While Downregulating Proinflammatory Disease Mediators.
Prescott J , Guito JC , Spengler JR , Arnold CE , Schuh AJ , Amman BR , Sealy TK , Guerrero LW , Palacios GF , Sanchez-Lockhart M , Albarino CG , Towner JS . mSphere 2019 4 (6) Dysregulated and maladaptive immune responses are at the forefront of human diseases caused by infection with zoonotic viral hemorrhagic fever viruses. Elucidating mechanisms of how the natural animal reservoirs of these viruses coexist with these agents without overt disease, while permitting sufficient replication to allow for transmission and maintenance in a population, is important for understanding the viral ecology and spillover to humans. The Egyptian rousette bat (ERB) has been identified as a reservoir for Marburg virus (MARV), a filovirus and the etiological agent of the highly lethal Marburg virus disease. Little is known regarding how these bats immunologically respond to MARV infection. In humans, macrophages and dendritic cells (DCs) are primary targets of infection, and their dysregulation is thought to play a central role in filovirus diseases, by disturbing their normal functions as innate sensors and adaptive immune response facilitators while serving as amplification and dissemination agents for the virus. The infection status and responses to MARV in bat myeloid-lineage cells are uncharacterized and likely represent an important modulator of the bat's immune response to MARV infection. Here, we generate DCs from the bone marrow of rousette bats. Infection with a bat isolate of MARV resulted in a low level of transcription in these cells and significantly downregulated DC maturation and adaptive immune-stimulatory pathways while simultaneously upregulating interferon-related pathogen-sensing pathways. This study provides a first insight into how the bat immune response is directed toward preventing aberrant inflammatory responses while mounting an antiviral response to defend against MARV infection.IMPORTANCE Marburg viruses (MARVs) cause severe human disease resulting from aberrant immune responses. Dendritic cells (DCs) are primary targets of infection and are dysregulated by MARV. Dysregulation of DCs facilitates MARV replication and virus dissemination and influences downstream immune responses that result in immunopathology. Egyptian rousette bats (ERBs) are natural reservoirs of MARV, and infection results in virus replication and shedding, with asymptomatic control of the virus within weeks. The mechanisms that bats employ to appropriately respond to infection while avoiding disease are unknown. Because DC infection and modulation are important early events in human disease, we measured the transcriptional responses of ERB DCs to MARV. The significance of this work is in identifying cell type-specific coevolved responses between ERBs and MARV, which gives insight into how bat reservoirs are able to harbor MARV and permit viral replication, allowing transmission and maintenance in the population while simultaneously preventing immunopathogenesis. |
Discovery and Characterization of Bukakata orbivirus ( Reoviridae:Orbivirus ), a Novel Virus from a Ugandan Bat.
Fagre AC , Lee JS , Kityo RM , Bergren NA , Mossel EC , Nakayiki T , Nalikka B , Nyakarahuka L , Gilbert AT , Peterhans JK , Crabtree MB , Towner JS , Amman BR , Sealy TK , Schuh AJ , Nichol ST , Lutwama JJ , Miller BR , Kading RC . Viruses 2019 11 (3) While serological and virological evidence documents the exposure of bats to medically-important arboviruses, their role as reservoirs or amplifying hosts is less well-characterized. We describe a novel orbivirus (Reoviridae:Orbivirus) isolated from an Egyptian fruit bat (Rousettus aegyptiacus leachii) trapped in 2013 in Uganda and named Bukakata orbivirus. This is the fifth orbivirus isolated from a bat, however genetic information had previously only been available for one bat-associated orbivirus. We performed whole-genome sequencing on Bukakata orbivirus and three other bat-associated orbiviruses (Fomede, Ife, and Japanaut) to assess their phylogenetic relationship within the genus Orbivirus and develop hypotheses regarding potential arthropod vectors. Replication kinetics were assessed for Bukakata orbivirus in three different vertebrate cell lines. Lastly, qRT-PCR and nested PCR were used to determine the prevalence of Bukakata orbivirus RNA in archived samples from three populations of Egyptian fruit bats and one population of cave-associated soft ticks in Uganda. Complete coding sequences were obtained for all ten segments of Fomede, Ife, and Japanaut orbiviruses and for nine of the ten segments for Bukakata orbivirus. Phylogenetic analysis placed Bukakata and Fomede in the tick-borne orbivirus clade and Ife and Japanaut within the Culicoides/phlebotomine sandfly orbivirus clade. Further, Bukakata and Fomede appear to be serotypes of the Chobar Gorge virus species. Bukakata orbivirus replicated to high titers (10(6)(-)10(7) PFU/mL) in Vero, BHK-21 [C-13], and R06E (Egyptian fruit bat) cells. Preliminary screening of archived bat and tick samples do not support Bukakata orbivirus presence in these collections, however additional testing is warranted given the phylogenetic associations observed. This study provided complete coding sequence for several bat-associated orbiviruses and in vitro characterization of a bat-associated orbivirus. Our results indicate that bats may play an important role in the epidemiology of viruses in the genus Orbivirus and further investigation is warranted into vector-host associations and ongoing surveillance efforts. |
Clinical, histopathologic, and immunohistochemical characterization of experimental Marburg virus infection in a natural reservoir host, the Egyptian rousette bat (Rousettus aegyptiacus)
Jones MEB , Amman BR , Sealy TK , Uebelhoer LS , Schuh AJ , Flietstra T , Bird BH , Coleman-McCray JD , Zaki SR , Nichol ST , Towner JS . Viruses 2019 11 (3) Egyptian rousette bats (Rousettus aegyptiacus) are natural reservoir hosts of Marburg virus (MARV), and Ravn virus (RAVV; collectively called marburgviruses) and have been linked to human cases of Marburg virus disease (MVD). We investigated the clinical and pathologic effects of experimental MARV infection in Egyptian rousettes through a serial euthanasia study and found clear evidence of mild but transient disease. Three groups of nine, captive-born, juvenile male bats were inoculated subcutaneously with 10,000 TCID50 of Marburg virus strain Uganda 371Bat2007, a minimally passaged virus originally isolated from a wild Egyptian rousette. Control bats (n = 3) were mock-inoculated. Three animals per day were euthanized at 3, 5(-)10, 12 and 28 days post-inoculation (DPI); controls were euthanized at 28 DPI. Blood chemistry analyses showed a mild, statistically significant elevation in alanine aminotransferase (ALT) at 3, 6 and 7 DPI. Lymphocyte and monocyte counts were mildly elevated in inoculated bats after 9 DPI. Liver histology revealed small foci of inflammatory infiltrate in infected bats, similar to lesions previously described in wild, naturally-infected bats. Liver lesion severity scores peaked at 7 DPI, and were correlated with both ALT and hepatic viral RNA levels. Immunohistochemical staining detected infrequent viral antigen in liver (3(-)8 DPI, n = 8), spleen (3(-)7 DPI, n = 8), skin (inoculation site; 3(-)12 DPI, n = 20), lymph nodes (3(-)10 DPI, n = 6), and oral submucosa (8(-)9 DPI, n = 2). Viral antigen was present in histiocytes, hepatocytes and mesenchymal cells, and in the liver, antigen staining co-localized with inflammatory foci. These results show the first clear evidence of very mild disease caused by a filovirus in a reservoir bat host and provide support for our experimental model of this virus-reservoir host system. |
Antibody-mediated virus neutralization is not a universal mechanism of Marburg, Ebola or Sosuga virus clearance in Egyptian rousette bats
Schuh AJ , Amman BR , Sealy TK , Kainulainen MH , Chakrabarti AK , Guerrero LW , Nichol ST , Albarino CG , Towner JS . J Infect Dis 2018 219 (11) 1716-1721 Although bats are increasingly being recognized as natural reservoir hosts of emerging zoonotic viruses, little is known about how they control and clear virus infection in the absence of clinical disease. Here, we test >50 convalescent sera from Egyptian rousette bats (ERBs) experimentally primed or prime-boosted with Marburg virus, Ebola virus or Sosuga virus for the presence of virus-specific neutralizing antibodies using infectious reporter viruses. After serum neutralization testing, we conclude that antibody-mediated virus neutralization does not contribute significantly to the control and clearance of Marburg virus, Ebola virus or Sosuga virus infection in ERBs. |
Neutralizing antibodies against flaviviruses, Babanki virus, and Rift Valley fever virus in Ugandan bats
Kading RC , Kityo RM , Mossel EC , Borland EM , Nakayiki T , Nalikka B , Nyakarahuka L , Ledermann JP , Panella NA , Gilbert AT , Crabtree MB , Peterhans JK , Towner JS , Amman BR , Sealy TK , Nichol ST , Powers AM , Lutwama JJ , Miller BR . Infect Ecol Epidemiol 2018 8 (1) 1439215 Introduction: A number of arboviruses have previously been isolated from naturally-infected East African bats, however the role of bats in arbovirus maintenance is poorly understood. The aim of this study was to investigate the exposure history of Ugandan bats to a panel of arboviruses. Materials and methods: Insectivorous and fruit bats were captured from multiple locations throughout Uganda during 2009 and 2011-2013. All serum samples were tested for neutralizing antibodies against West Nile virus (WNV), yellow fever virus (YFV), dengue 2 virus (DENV-2), Zika virus (ZIKV), Babanki virus (BBKV), and Rift Valley fever virus (RVFV) by plaque reduction neutralization test (PRNT). Sera from up to 626 bats were screened for antibodies against each virus. Results and Discussion: Key findings include the presence of neutralizing antibodies against RVFV in 5/52 (9.6%) of little epauletted fruit bats (Epomophorus labiatus) captured from Kawuku and 3/54 (5.6%) Egyptian rousette bats from Kasokero cave. Antibodies reactive to flaviviruses were widespread across bat taxa and sampling locations. Conclusion: The data presented demonstrate the widespread exposure of bats in Uganda to arboviruses, and highlight particular virus-bat associations that warrant further investigation. |
Egyptian rousette bats maintain long-term protective immunity against Marburg virus infection despite diminished antibody levels
Schuh AJ , Amman BR , Sealy TK , Spengler JR , Nichol ST , Towner JS . Sci Rep 2017 7 (1) 8763 Although bats are natural reservoir hosts for numerous zoonotic viruses, little is known about the long-term dynamics of the host immune response following infection and how these viruses are maintained in nature. The Egyptian rousette bat (ERB) is a known reservoir host for Marburg virus (MARV). Following infection of ERBs with MARV, virus-specific IgG antibodies are induced but rapidly wane and by 3 months post-infection the bats are seronegative. To determine whether reinfection of ERBs plays a role in MARV maintenance, we challenge groups of ERBs that were "naturally" or experimentally infected with MARV 17-24 months prior. No bats in either group exhibit evidence of MARV replication or shedding and all bats develop virus-specific secondary immune responses. This study demonstrates that infection of ERBs with MARV induces long-term protective immunity against reinfection and indicates that other factors, such as host population dynamics, drive MARV maintenance in nature. |
Modelling filovirus maintenance in nature by experimental transmission of Marburg virus between Egyptian rousette bats
Schuh AJ , Amman BR , Jones ME , Sealy TK , Uebelhoer LS , Spengler JR , Martin BE , Coleman-McCray JA , Nichol ST , Towner JS . Nat Commun 2017 8 14446 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. |
Ebola Virus Disease Diagnostics, Sierra Leone: Analysis of Real-time Reverse Transcription-Polymerase Chain Reaction Values for Clinical Blood and Oral Swab Specimens.
Erickson BR , Sealy TK , Flietstra T , Morgan L , Kargbo B , Matt-Lebby VE , Gibbons A , Chakrabarti AK , Graziano J , Presser L , Flint M , Bird BH , Brown S , Klena JD , Blau DM , Brault AC , Belser JA , Salzer JS , Schuh AJ , Lo M , Zivcec M , Priestley RA , Pyle M , Goodman C , Bearden S , Amman BR , Basile A , Bergeron E , Bowen MD , Dodd KA , Freeman MM , McMullan LK , Paddock CD , Russell BJ , Sanchez AJ , Towner JS , Wang D , Zemtsova GE , Stoddard RA , Turnsek M , Guerrero LW , Emery SL , Stovall J , Kainulainen MH , Perniciaro JL , Mijatovic-Rustempasic S , Shakirova G , Winter J , Sexton C , Liu F , Slater K , Anderson R , Andersen L , Chiang CF , Tzeng WP , Crowe SJ , Maenner MJ , Spiropoulou CF , Nichol ST , Stroher U . J Infect Dis 2016 214 S258-S262 During the Ebola virus outbreak of 2013-2016, the Viral Special Pathogens Branch field laboratory in Sierra Leone tested approximately 26 000 specimens between August 2014 and October 2015. Analysis of the B2M endogenous control Ct values showed its utility in monitoring specimen quality, comparing results with different specimen types, and interpretation of results. For live patients, blood is the most sensitive specimen type and oral swabs have little diagnostic utility. However, swabs are highly sensitive for diagnostic testing of corpses. |
Laboratory response to Ebola - West Africa and United States
Sealy TK , Erickson BR , Taboy CH , Stroher U , Towner JS , Andrews SE , Rose LE , Weirich E , Lowe L , Klena JD , Spiropoulou CF , Rayfield MA , Bird BH . MMWR Suppl 2016 65 (3) 44-9 The 2014-2016 Ebola virus disease (Ebola) epidemic in West Africa highlighted the need to maintain organized laboratory systems or networks that can be effectively reorganized to implement new diagnostic strategies and laboratory services in response to large-scale events. Although previous Ebola outbreaks enabled establishment of critical laboratory practice safeguards and diagnostic procedures, this Ebola outbreak in West Africa highlighted the need for planning and preparedness activities that are better adapted to emerging pathogens or to pathogens that have attracted little commercial interest. The crisis underscored the need for better mechanisms to streamline development and evaluation of new diagnostic assays, transfer of material and specimens between countries and organizations, and improved processes for rapidly deploying health workers with specific laboratory expertise. The challenges and events of the outbreak forced laboratorians to examine not only the comprehensive capacities of existing national laboratory systems to recognize and respond to events, but also their sustainability over time and the mechanisms that need to be pre-established to ensure effective response. Critical to this assessment was the recognition of how response activities (i.e., infrastructure support, logistics, and workforce supplementation) can be used or repurposed to support the strengthening of national laboratory systems during the postevent transition to capacity building and recovery. This report compares CDC's domestic and international laboratory response engagements and lessons learned that can improve future responses in support of the International Health Regulations and Global Health Security Agenda initiatives.The activities summarized in this report would not have been possible without collaboration with many U.S. and international partners (http://www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/partners.html). |
No evidence for the involvement of the argasid tick Ornithodoros faini in the enzootic maintenance of marburgvirus within Egyptian rousette bats Rousettus aegyptiacus
Schuh AJ , Amman BR , Apanaskevich DA , Sealy TK , Nichol ST , Towner JS . Parasit Vectors 2016 9 (1) 128 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. |
Humanized mouse model of Ebola virus disease mimics immune responses in human disease
Bird BH , Spengler JR , Chakrabarti AK , Khristova ML , Sealy TK , Coleman-McCray JD , Martin BE , Dodd KA , Goldsmith CS , Sanders J , Zaki SR , Nichol ST , Spiropoulou CF . J Infect Dis 2015 213 (5) 703-11 Animal models recapitulating human Ebola virus disease (EVD) are critical for insights into virus pathogenesis. Ebola virus (EBOV) isolates derived directly from human specimens do not cause disease in immunocompetent adult rodents without adaptation. Here we describe EVD in humanized BLT mice (hu-BLT) engrafted with human immune cells. Hu-BLT mice developed EVD following wild-type EBOV infection. Infection with high-dose EBOV resulted in rapid lethal EVD with high viral loads, alterations in key human antiviral immune cytokines and chemokines, and severe histopathology similar to that shown in the limited human post-mortem data available. A dose- and donor- dependent clinical course was observed in hu-BLT infected with lower doses of either Mayinga (1976) or Makona (2014) isolates derived from human EBOV cases. Engraftment of the human cellular immune system appeared to be essential for the observed virulence, as non-engrafted mice did not support productive EBOV replication or develop lethal disease. Hu-BLT mice offer a unique model for investigating the human immune response in EVD; and offer an alternative animal model for EVD pathogenesis studies and therapeutic screening. |
Ebola virus diagnostics: the US Centers for Disease Control and Prevention laboratory in Sierra Leone, August 2014 to March 2015
Flint M , Goodman CH , Bearden S , Blau DM , Amman BR , Basile AJ , Belser JA , Bergeron E , Bowen MD , Brault AC , Campbell S , Chakrabarti AK , Dodd KA , Erickson BR , Freeman MM , Gibbons A , Guerrero LW , Klena JD , Lash RR , Lo MK , McMullan LK , Momoh G , Massally JL , Goba A , Paddock CD , Priestley RA , Pyle M , Rayfield M , Russell BJ , Salzer JS , Sanchez AJ , Schuh AJ , Sealy TK , Steinau M , Stoddard RA , Taboy C , Turnsek M , Wang D , Zemtsova GE , Zivcec M , Spiropoulou CF , Stroher U , Towner JS , Nichol ST , Bird BH . J Infect Dis 2015 212 Suppl 2 S350-8 In August 2014, the Viral Special Pathogens Branch of the US Centers for Disease Control and Prevention established a field laboratory in Sierra Leone in response to the ongoing Ebola virus outbreak. Through March 2015, this laboratory tested >12 000 specimens from throughout Sierra Leone. We describe the organization and procedures of the laboratory located in Bo, Sierra Leone. |
Comparison of FilmArray® and qRT-PCR for the detection of Zaire ebolavirus from contrived and clinical specimens.
Southern TR , Racsa LD , Albarino CG , Fey PD , Hinrichs SH , Murphy CN , Herrera VL , Sambol AR , Hill CE , Ryan EL , Kraft CS , Campbell S , Sealy TK , Schuh A , Ritchie JC , Lyon GM 3rd , Mehta AK , Varkey JB , Ribner BS , Brantly KP , Stroher U , Iwen PC , Burd EM . J Clin Microbiol 2015 53 (9) 2956-60 Rapid, reliable and easy to use diagnostic assays for detection of Zaire ebolavirus (ZEBOV) are urgently needed. The goal of this study was to examine the percentage agreement among Emergency Use Authorization (EUA) tests for the detection of ZEBOV nucleic acid including the BioFire FilmArray(R) BioThreat (BT) panel, the FilmArray BT E-panel and the NP2 and VP40 quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR) assays from the Centers for Disease Control and Prevention (CDC). Specimens used in this study included whole blood spiked with inactivated ZEBOV at known titers and whole blood, plasma and urine clinical specimens from persons diagnosed with Ebola virus disease (EVD). The percentage agreement for FilmArray and qRT-PCR assays using contrived whole blood specimens was 100% (6/6) for each ZEBOV dilution from 4x107-4x102 virus/ml as well as the no-virus negative control. The limit of detection for FilmArray and qRT-PCR based on duplicate positive results was determined to be 4x102 inactivated ZEBOV/ml. Percentage agreement between FilmArray and qRT-PCR using clinical specimens from patients with EVD was 85% (23/27) when testing whole blood, 90%(18/20) when testing whole blood by FilmArray and matched plasma by qRT-PCR and 85% (11/13) when testing urine. Of 60 specimens, eight discordant results were noted with ZEBOV nucleic acid detected only by FilmArray in four specimens and only by qRT-PCR in the remaining four. These findings demonstrate that the rapid and easy to use FilmArray panels are effective tests for evaluating patients with EVD. |
Experimental inoculation of Egyptian rousette bats (Rousettus aegyptiacus) with viruses of the Ebolavirus and Marburgvirus genera
Jones ME , Schuh AJ , Amman BR , Sealy TK , Zaki SR , Nichol ST , Towner JS . Viruses 2015 7 (7) 3420-42 The Egyptian rousette bat (Rousettus aegyptiacus) is a natural reservoir for marburgviruses and a consistent source of virus spillover to humans. Cumulative evidence suggests various bat species may also transmit ebolaviruses. We investigated the susceptibility of Egyptian rousettes to each of the five known ebolaviruses (Sudan, Ebola, Bundibugyo, Tai Forest, and Reston), and compared findings with Marburg virus. In a pilot study, groups of four juvenile bats were inoculated with one of the ebolaviruses or Marburg virus. In ebolavirus groups, viral RNA tissue distribution was limited, and no bat became viremic. Sudan viral RNA was slightly more widespread, spurring a second, 15-day Sudan virus serial euthanasia study. Low levels of Sudan viral RNA disseminated to multiple tissues at early time points, but there was no viremia or shedding. In contrast, Marburg virus RNA was widely disseminated, with viremia, oral and rectal shedding, and antigen in spleen and liver. This is the first experimental infection study comparing tissue tropism, viral shedding, and clinical and pathologic effects of six different filoviruses in the Egyptian rousette, a known marburgvirus reservoir. Our results suggest Egyptian rousettes are unlikely sources for ebolaviruses in nature, and support a possible single filovirus-single reservoir host relationship. |
A Recently Discovered Pathogenic Paramyxovirus, Sosuga Virus, is Present in Rousettus aegyptiacus Fruit Bats at Multiple Locations in Uganda.
Amman BR , Albarino CG , Bird BH , Nyakarahuka L , Sealy TK , Balinandi S , Schuh AJ , Campbell SM , Stroher U , Jones ME , Vodzack ME , Reeder DM , Kaboyo W , Nichol ST , Towner JS . J Wildl Dis 2015 51 (3) 774-9 In August 2012, a wildlife biologist became ill immediately following a 6-wk field trip to collect bats and rodents in South Sudan and Uganda. After returning to the US, the biologist was admitted to the hospital with multiple symptoms including fever, malaise, headache, generalized myalgia and arthralgia, stiffness in the neck, and sore throat. Soon after admission, the patient developed a maculopapular rash and oropharynx ulcerations. The patient remained hospitalized for 14 d. Several suspect pathogens, including viral hemorrhagic fever viruses such as Ebola viruses and Marburg viruses, were ruled out through standard diagnostic testing. However, deep sequencing and metagenomic analyses identified a novel paramyxovirus, later named Sosuga virus, in the patient's blood. To determine the potential source, bat tissues collected during the 3-wk period just prior to the onset of symptoms were tested for Sosuga virus, and several Egyptian rousette bats (Rousettus aegyptiacus) were found to be positive. Further analysis of archived Egyptian rousette tissues collected at other localities in Uganda found additional Sosuga virus-positive bats, suggesting this species could be a potential natural reservoir for this novel paramyxovirus. |
Oral shedding of Marburg virus in experimentally infected Egyptian Fruit Bats (Rousettus aegyptiacus)
Amman BR , Jones ME , Sealy TK , Uebelhoer LS , Schuh AJ , Bird BH , Coleman-McCray JD , Martin BE , Nichol ST , Towner JS . J Wildl Dis 2014 51 (1) 113-24 Marburg virus (Marburg marburgvirus; MARV) causes sporadic outbreaks of Marburg hemorrhagic fever (MHF) in Africa. The Egyptian fruit bat (Rousettus aegyptiacus) has been identified as a natural reservoir based most-recently on the repeated isolation of MARV directly from bats caught at two locations in southwestern Uganda where miners and tourists separately contracted MHF from 2007-2008. Despite learning much about the ecology of MARV through extensive field investigations, there remained unanswered questions such as determining the primary routes of virus shedding and the severity of disease, if any, caused by MARV in infected bats. To answer these questions and others, we experimentally infected captive-bred R. aegyptiacus with MARV under high (biosafety level 4) containment. These experiments have shown infection profiles consistent with R. aegyptiacus being a bona fide natural reservoir host for MARV and shown routes of viral shedding capable of infecting humans and other animals. |
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