Last data update: Sep 16, 2024. (Total: 47680 publications since 2009)
Records 1-7 (of 7 Records) |
Query Trace: Uebelhoer LS [original query] |
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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. |
The Egyptian Rousette Genome Reveals Unexpected Features of Bat Antiviral Immunity.
Pavlovich SS , Lovett SP , Koroleva G , Guito JC , Arnold CE , Nagle ER , Kulcsar K , Lee A , Thibaud-Nissen F , Hume AJ , Muhlberger E , Uebelhoer LS , Towner JS , Rabadan R , Sanchez-Lockhart M , Kepler TB , Palacios G . Cell 2018 173 (5) 1098-1110 e18 Bats harbor many viruses asymptomatically, including several notorious for causing extreme virulence in humans. To identify differences between antiviral mechanisms in humans and bats, we sequenced, assembled, and analyzed the genome of Rousettus aegyptiacus, a natural reservoir of Marburg virus and the only known reservoir for any filovirus. We found an expanded and diversified KLRC/KLRD family of natural killer cell receptors, MHC class I genes, and type I interferons, which dramatically differ from their functional counterparts in other mammals. Such concerted evolution of key components of bat immunity is strongly suggestive of novel modes of antiviral defense. An evaluation of the theoretical function of these genes suggests that an inhibitory immune state may exist in bats. Based on our findings, we hypothesize that tolerance of viral infection, rather than enhanced potency of antiviral defenses, may be a key mechanism by which bats asymptomatically host viruses that are pathogenic in humans. |
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. |
Recombinant Marburg viruses containing mutations in the IID region of VP35 prevent inhibition of Host immune responses.
Albarino CG , Wiggleton Guerrero L , Spengler JR , Uebelhoer LS , Chakrabarti AK , Nichol ST , Towner JS . Virology 2014 476c 85-91 Previous in vitro studies have demonstrated that Ebola and Marburg virus (EBOV and MARV) VP35 antagonize the host cell immune response. Moreover, specific mutations in the IFN inhibitory domain (IID) of EBOV and MARV VP35 that abrogate their interaction with virus-derived dsRNA, lack the ability to inhibit the host immune response. To investigate the role of MARV VP35 in the context of infectious virus, we used our reverse genetics system to generate two recombinant MARVs carrying specific mutations in the IID region of VP35. Our data show that wild-type and mutant viruses grow to similar titers in interferon deficient cells, but exhibit attenuated growth in interferon-competent cells. Furthermore, in contrast to wild-type virus, both MARV mutants were unable to inhibit expression of various antiviral genes. The MARV VP35 mutants exhibit similar phenotypes to those previously described for EBOV, suggesting the existence of a shared immune-modulatory strategy between filoviruses. |
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. |
High-throughput, luciferase-based reverse genetics systems for identifying inhibitors of Marburg and Ebola viruses.
Uebelhoer LS , Albarino CG , McMullan LK , Chakrabarti AK , Vincent JP , Nichol ST , Towner JS . Antiviral Res 2014 106 86-94 Marburg virus (MARV) and Ebola virus (EBOV), members of the family Filoviridae, represent a significant challenge to global public health. Currently, no licensed therapies exist to treat filovirus infections, which cause up to 90% mortality in human cases. To facilitate development of antivirals against these viruses, we established two distinct screening platforms based on MARV and EBOV reverse genetics systems that express secreted Gaussia luciferase (gLuc). The first platform is a mini-genome replicon to screen viral replication inhibitors using gLuc quantification in a BSL-2 setting. The second platform is complementary to the first and expresses gLuc as a reporter gene product encoded in recombinant infectious MARV and EBOV, thereby allowing for rapid quantification of viral growth during treatment with antiviral compounds. We characterized these viruses by comparing luciferase activity to virus production, and validated luciferase activity as an authentic real-time measure of viral growth. As proof of concept, we adapt both mini-genome and infectious virus platforms to high-throughput formats, and demonstrate efficacy of several antiviral compounds. We anticipate that both approaches will prove highly useful in the development of anti-filovirus therapies, as well as in basic research on the filovirus life cycle. |
Development of a reverse genetics system to generate recombinant Marburg virus derived from a bat isolate.
Albarino CG , Uebelhoer LS , Vincent JP , Khristova ML , Chakrabarti AK , McElroy A , Nichol ST , Towner JS . Virology 2013 446 230-7 Recent investigations have shown the Egyptian fruit bat (Rousettus aegyptiacus) to be a natural reservoir for marburgviruses. To better understand the life cycle of these viruses in the natural host, a new reverse genetics system was developed for the reliable rescue of a Marburg virus (MARV) originally isolated directly from a R. aegyptiacus bat (371Bat). To develop this system, the exact terminal sequences were first determined by 5' and 3' RACE, followed by the cloning of viral proteins NP, VP35, VP30 and L into expression plasmids. Novel conditions were then developed to efficiently replicate virus mini-genomes followed by the construction of full-length genomic clones from which recombinant wild type and GFP-containing MARVs were rescued. Surprisingly, when these recombinant MARVs were propagated in primary human macrophages, a dramatic difference was found in their ability to grow and to elicit anti-viral cytokine responses. |
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