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Journal articles on the topic 'Arenaviridae Infections'
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Bowick, Gavin C., Susan M. Fennewald, Barry L. Elsom, Judith F. Aronson, Bruce A. Luxon, David G. Gorenstein, and Norbert K. Herzog. "Differential Signaling Networks Induced by Mild and Lethal Hemorrhagic Fever Virus Infections." Journal of Virology 80, no. 20 (October 15, 2006): 10248–52. http://dx.doi.org/10.1128/jvi.01384-06.
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ABSTRACT The family Arenaviridae includes several National Institutes of Allergy and Infections Diseases category A select agents which cause hemorrhagic fever. There are few vaccines available, and treatment is limited to ribavirin, which varies in efficacy. Development of new antiviral compounds has been hindered by a lack of understanding of the molecular basis of pathogenesis. We used two variants of Pichinde virus, one attenuated and one virulent in the guinea pig model, to delineate the host determinants which lead to either viral clearance or lethal disease. By analyzing protein level changes using pathway analysis, we have identified key intermediates which may be targets for therapeutic intervention.
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Perdomo-Celis, Federico, Maria S. Salvato, Sandra Medina-Moreno, and Juan C. Zapata. "T-Cell Response to Viral Hemorrhagic Fevers." Vaccines 7, no. 1 (January 22, 2019): 11. http://dx.doi.org/10.3390/vaccines7010011.
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Viral hemorrhagic fevers (VHF) are a group of clinically similar diseases that can be caused by enveloped RNA viruses primarily from the families Arenaviridae, Filoviridae, Hantaviridae, and Flaviviridae. Clinically, this group of diseases has in common fever, fatigue, dizziness, muscle aches, and other associated symptoms that can progress to vascular leakage, bleeding and multi-organ failure. Most of these viruses are zoonotic causing asymptomatic infections in the primary host, but in human beings, the infection can be lethal. Clinical and experimental evidence suggest that the T-cell response is needed for protection against VHF, but can also cause damage to the host, and play an important role in disease pathogenesis. Here, we present a review of the T-cell immune responses to VHF and insights into the possible ways to improve counter-measures for these viral agents.
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Mantlo, Paessler, and Huang. "Differential Immune Responses to Hemorrhagic Fever-Causing Arenaviruses." Vaccines 7, no. 4 (October 2, 2019): 138. http://dx.doi.org/10.3390/vaccines7040138.
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The family Arenaviridae contains several pathogens of major clinical importance. The Old World (OW) arenavirus Lassa virus is endemic in West Africa and is estimated to cause up to 300,000 infections each year. The New World (NW) arenaviruses Junín and Machupo periodically cause hemorrhagic fever outbreaks in South America. While these arenaviruses are highly pathogenic in humans, recent evidence indicates that pathogenic OW and NW arenaviruses interact with the host immune system differently, which may have differential impacts on viral pathogenesis. Severe Lassa fever cases are characterized by profound immunosuppression. In contrast, pathogenic NW arenavirus infections are accompanied by elevated levels of Type I interferon and pro-inflammatory cytokines. This review aims to summarize recent findings about interactions of these pathogenic arenaviruses with the innate immune machinery and the subsequent effects on adaptive immunity, which may inform the development of vaccines and therapeutics against arenavirus infections.
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Kim, Yu-Jin, Beatrice Cubitt, Yingyun Cai, Jens H. Kuhn, Daniel Vitt, Hella Kohlhof, and Juan C. de la Torre. "Novel Dihydroorotate Dehydrogenase Inhibitors with Potent Interferon-Independent Antiviral Activity against Mammarenaviruses In Vitro." Viruses 12, no. 8 (July 29, 2020): 821. http://dx.doi.org/10.3390/v12080821.
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Mammarenaviruses cause chronic infections in rodents, which are their predominant natural hosts. Human infection with some of these viruses causes high-consequence disease, posing significant issues in public health. Currently, no FDA-licensed mammarenavirus vaccines are available, and anti-mammarenavirus drugs are limited to an off-label use of ribavirin, which is only partially efficacious and associated with severe side effects. Dihydroorotate dehydrogenase (DHODH) inhibitors, which block de novo pyrimidine biosynthesis, have antiviral activity against viruses from different families, including Arenaviridae, the taxonomic home of mammarenaviruses. Here, we evaluate five novel DHODH inhibitors for their antiviral activity against mammarenaviruses. All tested DHODH inhibitors were potently active against lymphocytic choriomeningitis virus (LCMV) (half-maximal effective concentrations [EC50] in the low nanomolar range, selectivity index [SI] > 1000). The tested DHODH inhibitors did not affect virion cell entry or budding, but rather interfered with viral RNA synthesis. This interference resulted in a potent interferon-independent inhibition of mammarenavirus multiplication in vitro, including the highly virulent Lassa and Junín viruses.
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Pattabhi, Sowmya, Courtney R. Wilkins, Ran Dong, Megan L. Knoll, Jeffrey Posakony, Shari Kaiser, Chad E. Mire, et al. "Targeting Innate Immunity for Antiviral Therapy through Small Molecule Agonists of the RLR Pathway." Journal of Virology 90, no. 5 (December 16, 2015): 2372–87. http://dx.doi.org/10.1128/jvi.02202-15.
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ABSTRACTThe cellular response to virus infection is initiated when pathogen recognition receptors (PRR) engage viral pathogen-associated molecular patterns (PAMPs). This process results in induction of downstream signaling pathways that activate the transcription factor interferon regulatory factor 3 (IRF3). IRF3 plays a critical role in antiviral immunity to drive the expression of innate immune response genes, including those encoding antiviral factors, type 1 interferon, and immune modulatory cytokines, that act in concert to restrict virus replication. Thus, small molecule agonists that can promote IRF3 activation and induce innate immune gene expression could serve as antivirals to induce tissue-wide innate immunity for effective control of virus infection. We identified small molecule compounds that activate IRF3 to differentially induce discrete subsets of antiviral genes. We tested a lead compound and derivatives for the ability to suppress infections caused by a broad range of RNA viruses. Compound administration significantly decreased the viral RNA load in cultured cells that were infected with viruses of the familyFlaviviridae, including West Nile virus, dengue virus, and hepatitis C virus, as well as viruses of the familiesFiloviridae(Ebola virus),Orthomyxoviridae(influenza A virus),Arenaviridae(Lassa virus), andParamyxoviridae(respiratory syncytial virus, Nipah virus) to suppress infectious virus production. Knockdown studies mapped this response to the RIG-I-like receptor pathway. This work identifies a novel class of host-directed immune modulatory molecules that activate IRF3 to promote host antiviral responses to broadly suppress infections caused by RNA viruses of distinct genera.IMPORTANCEIncidences of emerging and reemerging RNA viruses highlight a desperate need for broad-spectrum antiviral agents that can effectively control infections caused by viruses of distinct genera. We identified small molecule compounds that can selectively activate IRF3 for the purpose of identifying drug-like molecules that can be developed for the treatment of viral infections. Here, we report the discovery of a hydroxyquinoline family of small molecules that can activate IRF3 to promote cellular antiviral responses. These molecules can prophylactically or therapeutically control infection in cell culture by pathogenic RNA viruses, including West Nile virus, dengue virus, hepatitis C virus, influenza A virus, respiratory syncytial virus, Nipah virus, Lassa virus, and Ebola virus. Our study thus identifies a class of small molecules with a novel mechanism to enhance host immune responses for antiviral activity against a variety of RNA viruses that pose a significant health care burden and/or that are known to cause infections with high case fatality rates.
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Stepanov, A. V., A. L. Buzmakova, A. V. Potapova, M. A. Yudin, and V. Ya Apchel. "Hemorrhagic fevers of viral nature. State of the problem and directions for creating effective means of prevention and treatment." Bulletin of the Russian Military Medical Academy 22, no. 3 (December 15, 2020): 182–87. http://dx.doi.org/10.17816/brmma50557.
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Abstract. An attempt to summarize the data of available information materials on epidemiological aspects, the state and prospects of prevention and treatment of hemorrhagic fevers was. Hemorrhagic fevers of viral nature-zoonotic diseases caused by viruses containing ribonucleic acid are classified into 4 families: Arenaviridae, Bunyaviridae, Filoviridae and Flaviviridae. They are spread all over the world, and their pathogens are easily transmitted from person to person, thereby spreading quickly enough beyond the main focus of biological infection. That is why the causative agents of hemorrhagic fevers are regarded as highly contagious biological agents, and agents bioterrorism. Unfortunately, there are currently no effective means of specific prevention and treatment of these infections, and therapeutic measures are limited to the use of symptomatic means. In this regard, the search for substances with pronounced antiviral activity against pathogens of hemorrhagic fevers that can effectively protect against these infections, as well as prevent their occurrence and spread is one of the priority areas of research in modern Infectology, and with the involvement of modern achievements in the field of molecular Virology and genetic engineering. The data obtained in this regard allow a more in-depth understanding of the pathogenesis of hemorrhagic fevers, the mechanisms of interaction of the pathogen with the host at the cellular level, the mechanisms of intracellular replication of viruses, the formation of the hosts response to viral invasion and clinical manifestations of diseases.
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Petrov, A. A., V. N. Lebedev, T. M. Plekhanova, L. F. Stobva, O. N. Sidorova, E. V. Mel’Nikova, and S. V. Borisevich. "Future Developments and Applications of the Vaccines against Dangerous Viral Infections, RNA-Replicon-Based, Obtained from the Venezuelan Equine Encephalomyelitis Virus." Problems of Particularly Dangerous Infections, no. 3 (September 20, 2014): 86–91. http://dx.doi.org/10.21055/0370-1069-2014-3-86-91.
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The members of the Filoviridae (Marburg and Ebola viruses) and Arenaviridae (Lassa, Lujo, Machupo, Junin, Guanarito, Sabia viruses) families are the etiological agents of particularly dangerous viral hemorrhagic fevers. These agents pose a potential threat to public health care in view of the possibility of their unintended import into the non-endemic regions, and thus construction of specific medical protectors as regards induced by them diseases is a pressing issue. According to leading experts, vaccination of the cohorts that fall in the risk groups is the most effective and least expensive method to prevent the development of epidemics. The review contains information on a new prospective line of protective preparations development as regards particularly dangerous viral infections - construction of alphavirus-replicon-based vaccine. Elaboration of recombinant replicons does not require cultivation of pathogenic microorganisms. RNA-replicons are distinguished by their incapacity to produce infective progeny, which is of a great importance for the development of vaccines against particularly dangerous viral hemorrhagic fevers. Advantages of alphaviral replicons over other RNA-replicons are as follows: high levels of heterologous gene expression and resistance to anti-vector immunity. RNA-replicons of alphaviruses combine the safety of inactivated, and immunogenicity of live attenuated vaccines. Alphaviruses-based replicons are suitable for express vaccine development with the purpose of specific prophylaxis of viral infectious diseases.
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Gowen, Brian B., Min-Hui Wong, Kie-Hoon Jung, Andrew B. Sanders, Michelle Mendenhall, Kevin W. Bailey, Yousuke Furuta, and Robert W. Sidwell. "In Vitro and In Vivo Activities of T-705 against Arenavirus and Bunyavirus Infections." Antimicrobial Agents and Chemotherapy 51, no. 9 (July 2, 2007): 3168–76. http://dx.doi.org/10.1128/aac.00356-07.
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ABSTRACT There is a need for the development of effective antivirals for the treatment of severe viral diseases caused by members of the virus families Bunyaviridae and Arenaviridae. The pyrazine derivative T-705 (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) has demonstrated remarkable antiviral activity against influenza virus and, to a lesser degree, against some other RNA viruses (Y. Furuta, K. Takahashi, Y. Fukuda, M. Kuno, T. Kamiyama, K. Kozaki, N. Nomura, H. Egawa, S. Minami, Y. Watanabe, H. Narita, and K. Shiraki, Antimicrob. Agents Chemother., 46:977-981, 2002). Here, we report that T-705 is highly active against a panel of bunyaviruses (La Crosse, Punta Toro, Rift Valley fever, and sandfly fever viruses) and arenaviruses (Junin, Pichinde, and Tacaribe viruses) by cytopathic effect and virus yield reduction cell-based assays. The 50% effective concentrations for T-705 ranged from 5 to 30 μg/ml and 0.7 to 1.2 μg/ml against the bunyaviruses and arenaviruses examined, respectively. We also demonstrate that orally administered T-705 is efficacious in treating Punta Toro virus in the mouse and hamster infection models, as well as Pichinde virus infection in hamsters. When administered twice daily for 5 to 6 days, beginning 4 h pre- or 24 h post-Punta Toro virus challenge, a 30-mg/kg of body weight/day dose provided complete protection from death and limited viral burden and liver disease. A dose of 50 mg/kg/day was found to be optimal for treating Pichinde infection and limiting viral replication and disease severity. In general, T-705 was found to be more active than ribavirin in cell-based assays and in vivo, as reflected by substantially greater therapeutic indexes. Our results suggest that T-705 may be a viable alternative for the treatment of life-threatening bunyaviral and arenaviral infections.
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Goldsmith, C. S., H. G. Morrison, D. D. Auperin, S. G. Whitfield, and E. L. Palmer. "Vaccinia-lassa recombinant produces lassa-like inclusions." Proceedings, annual meeting, Electron Microscopy Society of America 47 (August 6, 1989): 1036–37. http://dx.doi.org/10.1017/s0424820100157164.
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Lassa virus, a member of the Arenaviridae, is the etiologic agent of Lassa fever. The virus is endemic in widespread areas of West Africa, particularly Nigeria, Liberia, and Sierra Leone. Rough estimates indicate that there are upwards of 300,000 human infections annually, resulting in approximately 5000 fatalities. A safe and effective vaccine for Lassa fever is not yet available. Recent studies in our laboratories have focused on the development of recombinant vaccinia viruses that express the nucleoprotein and envelope glycoproteins of Lassa virus as potential vaccine candidates. Tissue culture cells infected with various recombinant viruses were examined by thin-section TEH for any morphological alterations.Tissue culture cells were infected with wild-type Lassa virus or with recombinant vaccinia viruses expressing either the Lassa virus nucleoprotein (NP). the envelope glycoproteins (GPI,GP2), or NP, GPI, and GP2 in combination. Cells were fixed in 2.5% glutaraldehyde in 0.2M cacodylate buffer, postfixed in buffered 1% osmium tetroxide, and en bloc stained with 4% uranyl acetate. The samples were dehydrated and embedded in Polysciences Epon-substitute and Araldite. Sections were stained with uranyl acetate and lead citrate.
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Iannacone, Matteo, Giovanni Sitia, Masanori Isogawa, Jason K. Whitmire, Patrizia Marchese, Francis V. Chisari, Zaverio M. Ruggeri, and Luca G. Guidotti. "Platelets Mediate Clearance of Lymphocytic Choriomeningitis Virus Infection Preventing Lethal Hemorrhage." Blood 108, no. 11 (November 16, 2006): 1089. http://dx.doi.org/10.1182/blood.v108.11.1089.1089.
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Abstract Lymphocytic choriomeningitis virus (LCMV) is a noncytopathic mouse pathogen of the arenaviridae family. Acute LCMV infection in adult mice has been extensively studied and found to be systemic, essentially asymptomatic and associated with a bone marrow aplasia that produces a transient pancytopenic state. The initial lymphopenia is rapidly reversed, such that within one week of LCMV exposure the mice display lymphocytosis and clear the infection through a response mediated by virus-specific cytotoxic T cells (CTLs). In spite of the thrombocytopenia, the occurrence of hemorrhage in these animals has not been previously investigated, likely because of the lack of overt bleeding symptoms. Other arenaviruses (such as Lassa and Junin) produce systemic infections in humans and cause hemorrhagic diseases that are often lethal. Hemorrhage, mostly mucosal and cutaneous, occurs in the context of profound thrombocytopenia (characteristic of Junin infection) and/or platelet dysfunction (characteristic of Lassa infection), but without disseminated intravascular coagulation (DIC) or other coagulation defects. The pathogenesis of arenavirus infections in humans remains elusive, although disease severity has been associated with the extent of hemorrhage, impaired cellular immunity and lack of viral clearance. We recently showed that platelets may contribute to viral pathogenesis by facilitating the accumulation of virus-specific CTLs at sites of infection. Thus, we reasoned that the thrombocytopenia and/or platelet dysfunction that typify arenavirus infections in humans might not only predispose to the development of hemorrhage but also compromise CTL-mediated viral clearance. Here we report our studies based on the model of LCMV infection in mice. We found that normal inbred mice infected with different isolates of LCMV develop thrombocytopenia associated with decreased platelet function, but show only limited mucosal hemorrhage prior to CD8+ T cell-mediated viral clearance. In contrast, mice depleted of platelets, but not those given anticoagulant treatment, fail to produce a normal CD8+ T cell response or clear LCMV; instead, they develop an interferon (IFN)-α/β-dependent lethal hemorrhagic infection. Transfusion of normal but not activation-blocked platelets into these animals restored the CD8+ T cell responses and allowed clearance of the infection, preventing hemorrhage and death. These results indicate that activated platelets are required for CD8+ T cells to clear LCMV infection and for protecting the host against the induction of an IFN-α/β-dependent, lethal hemorrhagic diathesis.
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Zaki, Sherif R., and Cynthia S. Goldsmith. "Emerging Viral Hemorrhagic Fevers." Microscopy and Microanalysis 7, S2 (August 2001): 166–67. http://dx.doi.org/10.1017/s1431927600026908.
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Clinically, the combination of fever and hemorrhage can be caused by many pathogens, including viruses, rickettsiae, bacteria, protozoans, and fungi. However, the term viral hemorrhagic fever (VHF) is usually reserved for systemic infections characterized by fever and hemorrhage caused by a special group of viruses that belong to four different families: Filoviridae, Arenaviridae, Bunyaviridae, and Flaviviridae. All members are lipid-enveloped RNA viruses; except for filoviruses, where the resorvoir remains unknown, these viruses are transmitted to humans by arthropods and rodents. The VHFs are characterized by abnormal vascular regulation and damage. The VHFs all have similar clinical pictures with mortality rates of 15-30% or in the case of Ebola virus, up to 80%. Between 1993 and 2001, more different VHFs and related diseases were reported than during any comparable period over the past several decades. These diseases include Ebola VHF in Uganda in 2000, in Zaire in 1995 and in Gabon between 1994 and 1996; ongoing cases of Marburg hemorrhagic fever in the Democratic Republic of Congo beginning in 1998; Rift Valley fever in Saudi Arabia and Yemen in 2000 and in Kenya in 1997; Lassa fever in Sierra Leone in 1997; hantavirus pulmonary syndrome in the Americas since 1993; and imported cases of dengue hemorrhagic fever from Central and South America, and yellow fever from Africa during the 1990s.
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Fulhorst, C. F., R. D. Bradley, L. L. Peppers, and M. L. Milazzo. "Experimental infection of Neotoma albigula (Muridae) with Whitewater Arroyo virus (Arenaviridae)." American Journal of Tropical Medicine and Hygiene 65, no. 2 (August 1, 2001): 147–51. http://dx.doi.org/10.4269/ajtmh.2001.65.147.
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Papageorgiou, Nicolas, Maria Spiliopoulou, Thi-Hong Van Nguyen, Afroditi Vaitsopoulou, Elsie Yekwa Laban, Karine Alvarez, Irene Margiolaki, Bruno Canard, and François Ferron. "Brothers in Arms: Structure, Assembly and Function of Arenaviridae Nucleoprotein." Viruses 12, no. 7 (July 17, 2020): 772. http://dx.doi.org/10.3390/v12070772.
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Arenaviridae is a family of viruses harbouring important emerging pathogens belonging to the Bunyavirales order. Like in other segmented negative strand RNA viruses, the nucleoprotein (NP) is a major actor of the viral life cycle being both (i) the necessary co-factor of the polymerase present in the L protein, and (ii) the last line of defence of the viral genome (vRNA) by physically hiding its presence in the cytoplasm. The NP is also one of the major players interfering with the immune system. Several structural studies of NP have shown that it features two domains: a globular RNA binding domain (NP-core) in its N-terminal and an exonuclease domain (ExoN) in its C-terminal. Further studies have observed that significant conformational changes are necessary for RNA encapsidation. In this review we revisited the most recent structural and functional data available on Arenaviridae NP, compared to other Bunyavirales nucleoproteins and explored the structural and functional implications. We review the variety of structural motif extensions involved in NP–NP binding mode. We also evaluate the major functional implications of NP interactome and the role of ExoN, thus making the NP a target of choice for future vaccine and antiviral therapy.
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Ferron, François, Friedemann Weber, Juan Carlos de la Torre, and Juan Reguera. "Transcription and replication mechanisms of Bunyaviridae and Arenaviridae L proteins." Virus Research 234 (April 2017): 118–34. http://dx.doi.org/10.1016/j.virusres.2017.01.018.
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Fernandes, Jorlan, Renata Carvalho de Oliveira, Alexandro Guterres, Débora Ferreira Barreto-Vieira, Ana Claudia Pereira Terças, Bernardo Rodrigues Teixeira, Marcos Alexandre Nunes da Silva, et al. "Detection of Latino virus (Arenaviridae: Mammarenavirus) naturally infecting Calomys callidus." Acta Tropica 179 (March 2018): 17–24. http://dx.doi.org/10.1016/j.actatropica.2017.12.003.
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Piszczyk, Jarosław. "Viral hemorrhagic fevers or West Nile fever – surprise in the journey." Diagnostyka Laboratoryjna 52, no. 1 (April 18, 2016): 51–56. http://dx.doi.org/10.5604/01.3001.0009.3631.
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Viral hemorrhagic fevers (VHFs) represent a group of similar clinical entities contagious constitutional diseases, caused by four different types of RNA viruses: Flaviviridae, Bunyaviridae, Arenaviridae i Filoviridae. These diseases proceed with high fever and damage of the circulatory system leading to homeostasis disorders, commonly accompanied by symptoms of hemorrhagic diathesis. VHFs are typically transmitted through infection vectors (mosquito) or through direct physical contact with infectious material. West Nile fever is the disease which is caused by West Nile virus from the Flaviviridae family. It begins flu-like symptoms, then it appears maculopapular rash and lymphadenopathy. At the most cases the symptoms retreat idiopathically. This disease can proceed as West Nile Neurological Disease in 1% of infected. The article presents three diseases, which can be present in tropical climate such as: Ebola hemorrhagic fever, dengue hemorrhagic fever, West Nile fever.
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Vasconcelos, Pedro Fernando da Costa, Amélia Paes de Andrade Travassos da Rosa, Sueli Guerreiro Rodrigues, Robert Tesh, Jorge Fernando Soares Travassos da Rosa, and Elizabeth Salbé Travassos da Rosa. "Laboratory acquired infection by the virus SP H 114202 (Arenavirus: Arenaviridae): clinical and laboratory findings." Revista do Instituto de Medicina Tropical de São Paulo 35, no. 6 (December 1993): 521–25. http://dx.doi.org/10.1590/s0036-46651993000600008.
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Here in is described the clinical and laboratorial findings of a laboratory-acquired infection caused by the virus SP H 114202 (Arenavirus, family Arenaviridae) a recently discovered agent responsible for a viral hemorrhagic fever. The patient was sick for 13 days. The disease had an abrupt onset characterized by high fever (39ºC.), headache, chills and myalgias for 8 days. In addition, on the 3rd day, the patient developed nauseas and vomiting, and in the 10th, epigastralgia, diarrheia and gengivorrhagia. Leucopenia was seen within the 1 st week of onset, with counts as low as 2,500 white cells per mm³. Counts performed after the 23th day of the onset were within normal limits. With the exception of moderate lymphocitosis, no changes were observed in differential counts. An increase in the liter of antibodies by complement fixation, neutralization and ELISA (IgM) was detected. Suckling mice and baby hamsters were inoculated intracerebrally with 0.02 ml of blood samples collected in the 2nd and 7th days of disease. Attempts to isolate the virus were also made in Vero cells. No virus was isolated. This virus was isolated before in a single occasion in São Paulo State, in 1990, from the blood of a patient with hemorrhagic fever with a fatal outcome. The manipulation of the virus under study, must be done carefully, since the transmission can occur through aerosols.
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Zadeh, Vahid Rajabali, Shuzo Urata, Miako Sakaguchi, and Jiro Yasuda. "Human BST-2/tetherin inhibits Junin virus release from host cells and its inhibition is partially counteracted by viral nucleoprotein." Journal of General Virology 101, no. 6 (June 1, 2020): 573–86. http://dx.doi.org/10.1099/jgv.0.001414.
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Bone marrow stromal cell antigen-2 (BST-2), also known as tetherin, is an interferon-inducible membrane-associated protein. It effectively targets enveloped viruses at the release step of progeny viruses from host cells, thereby restricting the further spread of viral infection. Junin virus (JUNV) is a member of Arenaviridae, which causes Argentine haemorrhagic fever that is associated with a high rate of mortality. In this study, we examined the effect of human BST-2 on the replication and propagation of JUNV. The production of JUNV Z-mediated virus-like particles (VLPs) was significantly inhibited by over-expression of BST-2. Electron microscopy analysis revealed that BST-2 functions by forming a physical link that directly retains VLPs on the cell surface. Infection using JUNV showed that infectious JUNV production was moderately inhibited by endogenous or exogenous BST-2. We also observed that JUNV infection triggers an intense interferon response, causing an upregulation of BST-2, in infected cells. However, the expression of cell surface BST-2 was reduced upon infection. Furthermore, the expression of JUNV nucleoprotein (NP) partially recovered VLP production from BST-2 restriction, suggesting that the NP functions as an antagonist against antiviral effect of BST-2. We further showed that JUNV NP also rescued the production of Ebola virus VP40-mediated VLP from BST-2 restriction as a broad spectrum BST-2 antagonist. To our knowledge, this is the first report showing that an arenavirus protein counteracts the antiviral function of BST-2.
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Shah, Waris A., Huashan Peng, and Salvatore Carbonetto. "Role of non-raft cholesterol in lymphocytic choriomeningitis virus infection via α-dystroglycan." Journal of General Virology 87, no. 3 (March 1, 2006): 673–78. http://dx.doi.org/10.1099/vir.0.81444-0.
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Dystroglycan (DG) is an extracellular matrix receptor necessary for the development of metazoans from flies to humans and is also an entry route for various pathogens. Lymphocytic choriomeningitis virus (LCMV), a member of the family Arenaviridae, infects by binding to α-DG. Here, the role of cholesterol lipid rafts in infection by LCMV via α-DG was investigated. The cholesterol-sequestering drugs methyl-β-cyclodextrin (MβCD), filipin and nystatin inhibited the infectivity of LCMV selectively, but did not affect infection by vesicular stomatitis virus. Cholesterol loading after depletion with MβCD restored infectivity to control levels. DG was not found in lipid rafts identified with the raft marker ganglioside GM1. Treatment with MβCD, however, enhanced the solubility of DG. This may reflect the association of DG with cholesterol outside lipid rafts and suggests that association of DG with non-raft cholesterol is critical for infection by LCMV through α-DG.
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Cajimat, Maria N. B., Mary Louise Milazzo, Matthew R. Mauldin, Robert D. Bradley, and Charles F. Fulhorst. "Diversity among Tacaribe serocomplex viruses (Family Arenaviridae) associated with the southern plains woodrat (Neotoma micropus)." Virus Research 178, no. 2 (December 2013): 486–94. http://dx.doi.org/10.1016/j.virusres.2013.10.004.
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Cajimat, Maria N. B., Mary Louise Milazzo, Jeff N. Borchert, Ken D. Abbott, Robert D. Bradley, and Charles F. Fulhorst. "Diversity among Tacaribe serocomplex viruses (family Arenaviridae) naturally associated with the Mexican woodrat (Neotoma mexicana)." Virus Research 133, no. 2 (May 2008): 211–17. http://dx.doi.org/10.1016/j.virusres.2008.01.005.
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Takenaga, Toru, Zihan Zhang, Yukiko Muramoto, Sarah Katharina Fehling, Ai Hirabayashi, Yuki Takamatsu, Junichi Kajikawa, et al. "CP100356 Hydrochloride, a P-Glycoprotein Inhibitor, Inhibits Lassa Virus Entry: Implication of a Candidate Pan-Mammarenavirus Entry Inhibitor." Viruses 13, no. 9 (September 3, 2021): 1763. http://dx.doi.org/10.3390/v13091763.
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Lassa virus (LASV)—a member of the family Arenaviridae—causes Lassa fever in humans and is endemic in West Africa. Currently, no approved drugs are available. We screened 2480 small compounds for their potential antiviral activity using pseudotyped vesicular stomatitis virus harboring the LASV glycoprotein (VSV-LASVGP) and a related prototypic arenavirus, lymphocytic choriomeningitis virus (LCMV). Follow-up studies confirmed that CP100356 hydrochloride (CP100356), a specific P-glycoprotein (P-gp) inhibitor, suppressed VSV-LASVGP, LCMV, and LASV infection with half maximal inhibitory concentrations of 0.52, 0.54, and 0.062 μM, respectively, without significant cytotoxicity. Although CP100356 did not block receptor binding at the cell surface, it inhibited low-pH-dependent membrane fusion mediated by arenavirus glycoproteins. P-gp downregulation did not cause a significant reduction in either VSV-LASVGP or LCMV infection, suggesting that P-gp itself is unlikely to be involved in arenavirus entry. Finally, our data also indicate that CP100356 inhibits the infection by other mammarenaviruses. Thus, our findings suggest that CP100356 can be considered as an effective virus entry inhibitor for LASV and other highly pathogenic mammarenaviruses.
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Garry, Courtney E., and Robert F. Garry. "Proteomics Computational Analyses Suggest that the Antennavirus Glycoprotein Complex Includes a Class I Viral Fusion Protein (α-Penetrene) with an Internal Zinc-Binding Domain and a Stable Signal Peptide." Viruses 11, no. 8 (August 14, 2019): 750. http://dx.doi.org/10.3390/v11080750.
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A metatranscriptomic study of RNA viruses in cold-blooded vertebrates identified two related viruses from frogfish (Antennarius striatus) that represent a new genus Antennavirus in the family Arenaviridae (Order: Bunyavirales). Computational analyses were used to identify features common to class I viral fusion proteins (VFPs) in antennavirus glycoproteins, including an N-terminal fusion peptide, two extended alpha-helices, an intrahelical loop, and a carboxyl terminal transmembrane domain. Like mammarenavirus and hartmanivirus glycoproteins, the antennavirus glycoproteins have an intracellular zinc-binding domain and a long virion-associated stable signal peptide (SSP). The glycoproteins of reptarenaviruses are also class I VFPs, but do not contain zinc-binding domains nor do they encode SSPs. Divergent evolution from a common progenitor potentially explains similarities of antennavirus, mammarenavirus, and hartmanivirus glycoproteins, with an ancient recombination event resulting in a divergent reptarenavirus glycoprotein.
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Sizikova, T. E., V. N. Lebedev, S. I. Syromyatnikova, and S. V. Borisevich. "LUJO HEMORRHAGIC FEVER." Problems of Virology, Russian journal 62, no. 4 (August 20, 2017): 149–53. http://dx.doi.org/10.18821/0507-4088-2017-62-4-149-153.
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Lujo hemorrhagic fever (LHF) is a viral disease accompanied with fever, headache, vomiting, diarrhea, arthralgia, myalgia and numerous signs of hemorrhagic syndrome. LHF causes a clinical syndrome remarkably similar to Lassa hemorrhagic fever. The first case of LHF occurred in Johannesburg, South Africa, in 2008. There was a secondary transmission from the index patient to four healthcare workers. Four of the five patients died. The etiologic agent of LHF is Lujo virus (LUJV) belonging to Arenavirus genus of the Arenaviridae Family. Virus Lujo is the second pathogenic arenavirus, after Lassa virus, to be recognized in Africa during the last 40 years. Data about epidemiology, clinical characteristics and diagnostics of LHF, properties of Lujo virus (according to phylogenetic analysis), and recommended precautions for preventing secondary transmission are considered in this paper.
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Xiao, S. Y., Y. Yang, H. Zhang, and R. B. Tesh. "Pirital virus (Arenaviridae) infection in the syrian golden hamster, Mesocricetus auratus: a new animal model for arenaviral hemorrhagic fever." American Journal of Tropical Medicine and Hygiene 64, no. 3 (March 1, 2001): 111–18. http://dx.doi.org/10.4269/ajtmh.2001.64.111.
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Fulhorst, Charles F., Thomas G. Ksiazek, Clarence J. Peters, and Robert B. Tesh. "Experimental Infection of the Cane MouseZygodontomys brevicauda(Family Muridae) with Guanarito Virus (Arenaviridae), the Etiologic Agent of Venezuelan Hemorrhagic Fever." Journal of Infectious Diseases 180, no. 4 (October 1999): 966–69. http://dx.doi.org/10.1086/315029.
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Armstrong, Lori R., Louise-Marie Dembry, Petrie M. Rainey, Mark B. Russi, Ali S. Khan, Steven H. Fischer, Stephen C. Edberg, Thomas G. Ksiazek, Pierre E. Rollin, and C. J. Peters. "Management of a Sabiá Virus-Infected Patient in a US Hospital." Infection Control & Hospital Epidemiology 20, no. 03 (March 1999): 176–82. http://dx.doi.org/10.1086/501607.
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AbstractObjective:To describe the hospital precautions used to isolate a Sabiá virus (arenavirus: Arenaviridae)-infected patient in a US hospital and to protect hospital staff and visitors.Design:Investigation of a single case of arenavirus laboratory-acquired infection and associated case-contacts.Setting:A 900-bed, tertiary-care, university-affiliated medical center.Patients or other Participants:The case-patient became ill with Sabiá virus infection. The case-contacts consisted of healthcare workers, coworkers, friends, and relatives of the case-patient.Intervention:Enhanced isolation precautions for treatment of a viral hemorrhagic fever (VHF) patient were implemented in the clinical laboratory and patient-care setting to prevent nosocomial transmission. The enhanced precautions included preventing aerosol spread of the virus from the patient or his clinical specimens. All case-contacts were tested for Sabiá virus antibodies and monitored for signs and symptoms of early disease.Results:No cases of secondary infection occurred among 142 case-contacts.Conclusions:With the frequency of worldwide travel, patients with VHF can be admitted to a local hospital at any time in the United States. The use of enhanced isolation precautions for VHF appeared to be effective in preventing secondary cases by limiting the number of contacts and promoting proper handling of laboratory specimens. Patients with VHF can be managed safely in a local hospital setting, provided that appropriate precautions are planned and implemented.
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SBRANA, ELENA, PATRICK C. NEWMAN, VSEVOLOD L. POPOV, SHU-YUAN XIAO, ROBERT B. TESH, and ROSA I. MATEO. "CLINICAL LABORATORY, VIROLOGIC, AND PATHOLOGIC CHANGES IN HAMSTERS EXPERIMENTALLY INFECTED WITH PIRITAL VIRUS (ARENAVIRIDAE): A RODENT MODEL OF LASSA FEVER." American Journal of Tropical Medicine and Hygiene 74, no. 6 (June 1, 2006): 1096–102. http://dx.doi.org/10.4269/ajtmh.2006.74.1096.
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Hugot, J. P., J. P. Gonzalez, and C. Denys. "Evolution of the Old World Arenaviridae and their rodent hosts: generalized host-transfer or association by descent?" Infection, Genetics and Evolution 1, no. 1 (July 2001): 13–20. http://dx.doi.org/10.1016/s1567-1348(01)00003-x.
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Borden, Katherine L. B., Elizabeth J. Campbell Dwyer, and Maria S. Salvato. "An Arenavirus RING (Zinc-Binding) Protein Binds the Oncoprotein Promyelocyte Leukemia Protein (PML) and Relocates PML Nuclear Bodies to the Cytoplasm." Journal of Virology 72, no. 1 (January 1, 1998): 758–66. http://dx.doi.org/10.1128/jvi.72.1.758-766.1998.
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ABSTRACT The promyelocytic leukemia protein (PML) forms nuclear bodies which are altered in some disease conditions. We report that the cytoplasmic RNA virus lymphocytic choriomeningitis virus (LCMV) influences the distribution of PML bodies. In cells infected with LCMV, the Z protein and PML form large bodies primarily in the cytoplasm. Transient transfection studies indicate that Z alone is sufficient to redistribute PML to the cytoplasm and that PML and Z colocalize. Coimmunoprecipitation studies show specific interaction between PML and Z proteins. A similar result was observed with a Z protein from another arenavirus, Lassa virus, suggesting that this is a general feature of the Arenaviridae. Genetically engineered mutations in PML were used to show that the Z protein binds the N-terminal region of PML and does not need the PML RING or the nuclear localization signal to colocalize. The Z protein acts dominantly to overcome the diffuse phenotype observed in several PML mutants. The interaction between PML and Z may influence certain unique characteristics of arenavirus infection.
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Grimwood, Rebecca M., Edward C. Holmes, and Jemma L. Geoghegan. "A Novel Rubi-Like Virus in the Pacific Electric Ray (Tetronarce californica) Reveals the Complex Evolutionary History of the Matonaviridae." Viruses 13, no. 4 (March 31, 2021): 585. http://dx.doi.org/10.3390/v13040585.
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Rubella virus (RuV) is the causative agent of rubella (“German measles”) and remains a global health concern. Until recently, RuV was the only known member of the genus Rubivirus and the only virus species classified within the Matonaviridae family of positive-sense RNA viruses. Recently, two new rubella-like matonaviruses, Rustrela virus and Ruhugu virus, have been identified in several mammalian species, along with more divergent viruses in fish and reptiles. To screen for the presence of additional novel rubella-like viruses, we mined published transcriptome data using genome sequences from Rubella, Rustrela, and Ruhugu viruses as baits. From this, we identified a novel rubella-like virus in a transcriptome of Tetronarce californica—order Torpediniformes (Pacific electric ray)—that is more closely related to mammalian Rustrela virus than to the divergent fish matonavirus and indicative of a complex pattern of cross-species virus transmission. Analysis of host reads confirmed that the sample analysed was indeed from a Pacific electric ray, and two other viruses identified in this animal, from the Arenaviridae and Reoviridae, grouped with other fish viruses. These findings indicate that the evolutionary history of the Matonaviridae is more complex than previously thought and highlights the vast number of viruses that remain undiscovered.
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Martínez-Sobrido, Luis, Elina I. Zúñiga, Debralee Rosario, Adolfo García-Sastre, and Juan Carlos de la Torre. "Inhibition of the Type I Interferon Response by the Nucleoprotein of the Prototypic Arenavirus Lymphocytic Choriomeningitis Virus." Journal of Virology 80, no. 18 (September 15, 2006): 9192–99. http://dx.doi.org/10.1128/jvi.00555-06.
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ABSTRACT The prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) is a formidable battle horse for the study of viral immunology, as well as viral persistence and associated diseases. Investigations with LCMV have uncovered basic mechanisms by which viruses avoid elimination by the host adaptive immune response. In this study we show that LCMV also disables the host innate defense by interfering with beta interferon (IFN-β) production in response to different stimuli, including infection with Sendai virus and liposome-mediated DNA transfection. Inhibition of IFN production in LCMV-infected cells was caused by an early block in the IFN regulatory factor 3 (IRF-3) activation pathway. This defect was restored in cells cured of LCMV, indicating that one or more LCMV products are responsible for the inhibition of IRF-3 activation. Using expression plasmids encoding individual LCMV proteins, we found that expression of the LCMV nucleoprotein (NP) was sufficient to inhibit both IFN production and nuclear translocation of IRF-3. To our knowledge, this is the first evidence of an IFN-counteracting viral protein in the Arenaviridae family. Inhibition of IFN production by the arenavirus NP is likely to be a determinant of virulence in vivo.
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Johnson, Dylan, Jenny Jokinen, and Igor Lukashevich. "Attenuated Replication of Lassa Virus Vaccine Candidate ML29 in STAT-1-/- Mice." Pathogens 8, no. 1 (January 15, 2019): 9. http://dx.doi.org/10.3390/pathogens8010009.
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Lassa virus (LASV), a highly prevalent mammalian arenavirus endemic in West Africa, can cause Lassa fever (LF), which is responsible for thousands of deaths annually. LASV is transmitted to humans from naturally infected rodents. At present, there is not an effective vaccine nor treatment. The genetic diversity of LASV is the greatest challenge for vaccine development. The reassortant ML29 carrying the L segment from the nonpathogenic Mopeia virus (MOPV) and the S segment from LASV is a vaccine candidate under current development. ML29 demonstrated complete protection in validated animal models against a Nigerian strain from clade II, which was responsible for the worst outbreak on record in 2018. This study demonstrated that ML29 was more attenuated than MOPV in STAT1-/- mice, a small animal model of human LF and its sequelae. ML29 infection of these mice resulted in more than a thousand-fold reduction in viremia and viral load in tissues and strong LASV-specific adaptive T cell responses compared to MOPV-infected mice. Persistent infection of Vero cells with ML29 resulted in generation of interfering particles (IPs), which strongly interfered with the replication of LASV, MOPV and LCMV, the prototype of the Arenaviridae. ML29 IPs induced potent cell-mediated immunity and were fully attenuated in STAT1-/- mice. Formulation of ML29 with IPs will improve the breadth of the host’s immune responses and further contribute to development of a pan-LASV vaccine with full coverage meeting the WHO requirements.
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Franchini, Genoveffa, Richard F. Ambinder, and Michèle Barry. "Viral Disease in Hematology." Hematology 2000, no. 1 (January 1, 2000): 409–23. http://dx.doi.org/10.1182/asheducation.v2000.1.409.20000409.
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As part of the international outreach of the American Society of Hematology, this review addresses some aspects of the genetics, biology, epidemiology, and clinical relevance of viruses that cause a variety of hematopoietic disorders in human populations. The viruses described here have a different pattern of geographical distribution, and the disease manifestations may vary according to environmental and/or genetic characteristics of the host. Epstein-Barr virus, a linear double-stranded DNA virus (herpesvirus), and the human T-cell leukemia virus, a retrovirus with a single-stranded diploid RNA genome, are associated among other diseases with lymphoma and leukemia/lymphoma, respectively. Both viruses cause a lifelong infection, but only a small percentage of infected individuals develop hematopoietic neoplasms. Epidemiological data suggest that the time of infection may be important in determining disease outcome in both HTLV-I and EBV infection. The pathogenic mechanisms used by these viruses are of most interest since they may recapitulate growth dysregulation steps also occurring in other hematopoietic malignancies.In Section I Dr. Franchini reviews the biology, genetics and diseases associated with HTLV-I and HTLV-II. In Section II, Dr. Ambinder reviews the biology of EBV infection and its relationship to the pathogenesis of Hodgkin's disease and other malignancies.In Section III, Dr. Barry reviews the viral hemorrhagic fevers caused by RNA viruses such as Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae, which can lead to acute syndromes that can be fatal. However, prompt diagnosis is key for patient management as well as for limiting their spread to others. These syndromes have become the focus of public concern and represent not only a clinical challenge, since in most cases no specific antiviral treatment is available, but also a challenge for future basic research on their biology and pathogenesis since little is known at present.
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Franchini, Genoveffa, Richard F. Ambinder, and Michèle Barry. "Viral Disease in Hematology." Hematology 2000, no. 1 (January 1, 2000): 409–23. http://dx.doi.org/10.1182/asheducation.v2000.1.409.409.
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Abstract As part of the international outreach of the American Society of Hematology, this review addresses some aspects of the genetics, biology, epidemiology, and clinical relevance of viruses that cause a variety of hematopoietic disorders in human populations. The viruses described here have a different pattern of geographical distribution, and the disease manifestations may vary according to environmental and/or genetic characteristics of the host. Epstein-Barr virus, a linear double-stranded DNA virus (herpesvirus), and the human T-cell leukemia virus, a retrovirus with a single-stranded diploid RNA genome, are associated among other diseases with lymphoma and leukemia/lymphoma, respectively. Both viruses cause a lifelong infection, but only a small percentage of infected individuals develop hematopoietic neoplasms. Epidemiological data suggest that the time of infection may be important in determining disease outcome in both HTLV-I and EBV infection. The pathogenic mechanisms used by these viruses are of most interest since they may recapitulate growth dysregulation steps also occurring in other hematopoietic malignancies. In Section I Dr. Franchini reviews the biology, genetics and diseases associated with HTLV-I and HTLV-II. In Section II, Dr. Ambinder reviews the biology of EBV infection and its relationship to the pathogenesis of Hodgkin's disease and other malignancies. In Section III, Dr. Barry reviews the viral hemorrhagic fevers caused by RNA viruses such as Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae, which can lead to acute syndromes that can be fatal. However, prompt diagnosis is key for patient management as well as for limiting their spread to others. These syndromes have become the focus of public concern and represent not only a clinical challenge, since in most cases no specific antiviral treatment is available, but also a challenge for future basic research on their biology and pathogenesis since little is known at present.
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Kumar, Naveen, Nishi R. Sharma, Hinh Ly, Tristram G. Parslow, and Yuying Liang. "Receptor Tyrosine Kinase Inhibitors That Block Replication of Influenza A and Other Viruses." Antimicrobial Agents and Chemotherapy 55, no. 12 (September 19, 2011): 5553–59. http://dx.doi.org/10.1128/aac.00725-11.
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ABSTRACTWe have previously reported that two receptor tyrosine kinase inhibitors (RTKIs), called AG879 and tyrphostin A9 (A9), can each block the replication of influenza A virus in cultured cells. In this study, we further characterized thein vitroantiviral efficacies and specificities of these agents. The 50% effective concentration (EC50) of each against influenza A was found to be in the high nanomolar range, and the selectivity index (SI = 50% cytotoxic concentration [CC50]/EC50) was determined to be >324 for AG879 and 50 for A9, indicating that therapeutically useful concentrations of each drug produce only low levels of cytotoxicity. Each compound showed efficacy against representative laboratory strains of both human influenza A (H1N1 or H3N2) and influenza B viruses. Importantly, no drug-resistant influenza virus strains emerged even after 25 viral passages in the presence of AG879, whereas viruses resistant to amantadine appeared after only 3 passages. AG879 and A9 each also exhibited potent inhibitory activity against a variety of other RNA and DNA viruses, including Sendai virus (Paramyxoviridae), herpes simplex virus (Herpesviridae), mouse hepatitis virus (Coronaviridae), and rhesus rotavirus (Reoviridae), but not against Pichinde virus (Arenaviridae). These results together suggest that RTKIs may be useful as therapeutics against viral pathogens, including but not limited to influenza, due to their high selectivity indices, low frequency of drug resistance, and broad-spectrum antiviral activities.
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Zhang, Lei-Ke, Qi-Lin Xin, Sheng-Lin Zhu, Wei-Wei Wan, Wei Wang, and Gengfu Xiao. "Activation of the RLR/MAVS Signaling Pathway by the L Protein of Mopeia Virus." Journal of Virology 90, no. 22 (September 7, 2016): 10259–70. http://dx.doi.org/10.1128/jvi.01292-16.
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ABSTRACT The family Arenaviridae includes several important human pathogens that can cause severe hemorrhagic fever and greatly threaten public health. As a major component of the innate immune system, the RLR/MAVS signaling pathway is involved in recognizing viral components and initiating antiviral activity. It has been reported that arenavirus infection can suppress the innate immune response, and NP and Z proteins of pathogenic arenaviruses can disrupt RLR/MAVS signaling, thus inhibiting production of type I interferon (IFN-I). However, recent studies have shown elevated IFN-I levels in certain arenavirus-infected cells. The mechanism by which arenavirus infection induces IFN-I responses remains unclear. In this study, we determined that the L polymerase (Lp) of Mopeia virus (MOPV), an Old World (OW) arenavirus, can activate the RLR/MAVS pathway and thus induce the production of IFN-I. This activation is associated with the RNA-dependent RNA polymerase activity of Lp. This study provides a foundation for further studies of interactions between arenaviruses and the innate immune system and for the elucidation of arenavirus pathogenesis. IMPORTANCE Distinct innate immune responses are observed when hosts are infected with different arenaviruses. It has been widely accepted that NP and certain Z proteins of arenaviruses inhibit the RLR/MAVS signaling pathway. The viral components responsible for the activation of the RLR/MAVS signaling pathway remain to be determined. In the current study, we demonstrate for the first time that the Lp of MOPV, an OW arenavirus, can activate the RLR/MAVS signaling pathway and thus induce the production of IFN-I. Based on our results, we proposed that dynamic interactions exist among Lp-produced RNA, NP, and the RLR/MAVS signaling pathway, and the outcome of these interactions may determine the final IFN-I response pattern: elevated or reduced. Our study provides a possible explanation for how IFN-I can become activated during arenavirus infection and may help us gain insights into the interactions that form between different arenavirus components and the innate immune system.
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Han, Ziying, Michael Schwoerer, Philip Hicks, Jingjing Liang, Gordon Ruthel, Corbett Berry, Bruce Freedman, et al. "Host Protein BAG3 is a Negative Regulator of Lassa VLP Egress." Diseases 6, no. 3 (July 13, 2018): 64. http://dx.doi.org/10.3390/diseases6030064.
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Lassa fever virus (LFV) belongs to the Arenaviridae family and can cause acute hemorrhagic fever in humans. The LFV Z protein plays a central role in virion assembly and egress, such that independent expression of LFV Z leads to the production of virus-like particles (VLPs) that mimic egress of infectious virus. LFV Z contains both PTAP and PPPY L-domain motifs that are known to recruit host proteins that are important for mediating efficient virus egress and spread. The viral PPPY motif is known to interact with specific host WW-domain bearing proteins. Here we identified host WW-domain bearing protein BCL2 Associated Athanogene 3 (BAG3) as a LFV Z PPPY interactor using our proline-rich reading array of WW-domain containing mammalian proteins. BAG3 is a stress-induced molecular co-chaperone that functions to regulate cellular protein homeostasis and cell survival via Chaperone-Assisted Selective Autophagy (CASA). Similar to our previously published findings for the VP40 proteins of Ebola and Marburg viruses, our results using VLP budding assays, BAG3 knockout cells, and confocal microscopy indicate that BAG3 is a WW-domain interactor that negatively regulates egress of LFV Z VLPs, rather than promoting VLP release. Our results suggest that CASA and specifically BAG3 may represent a novel host defense mechanism, whereby BAG3 may dampen egress of several hemorrhagic fever viruses by interacting and interfering with the budding function of viral PPxY-containing matrix proteins.
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Kazachinskaya, E. I., V. S. Aripov, A. V. Zaikovskaya, and A. M. Shestopalov. "Lassa virus: characterization of infectious agent, biological models for pathogenesis studies and variants of vaccine." Medical Immunology (Russia) 23, no. 1 (March 1, 2021): 35–48. http://dx.doi.org/10.15789/1563-0625-lvc-2060.
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Lassa virus (LASV) is classified into genus Mammarenavirus of Arenaviridae family. This virus is etiological agent of Lassa fever (LF) which is widespread in Africa. On average, in four out of five infected people, LF occurs without symptoms. The annual incidence ranges from 100,000 to 500,000 registered clinical cases, at a mortality rate of 1-2%. Among hospitalized patients with severe symptoms of hemorrhagic fever, this figure may be from 14 to 89.5%. Signs of an adverse outcome in LF are open bleeding and disorders of CNS (convulsions, tremor, disorientation and coma). Death occurs from multiple organ failure. Severely ill people recover slowly and may have relapses and complications such as pneumonia, myocarditis, psychosis, and hearing loss.Transmission of the virus in endemic territories occurs by alimentary way, air-dust and airborne droplets from a zoonotic source – rodents of the species African multimammate rat (Mastomys natalensis), by accidental contacts of people with their secretions (urine, feces, saliva) as well as when butchering carcasses and eating rodents. These animals are characterized by asymptomatic carrier and life-long persistence of the virus. Cases of transmission of the virus from person to person through the blood or other body fluids of patients are described. A sick person is contagious for two months, because the virus circulates in the blood despite high levels of antibodies. Infection of medical staff occurs during emergency surgical operations, or when the rules of contact precautions are not observed. Currently, with the ongoing LF outbreak in Nigeria, since 2016, hospitals have registered mortality rates of 22 and 8% for patients and health workers, respectively. During 1969-2016, 33 imported cases of this disease were described from West Africa to non-endemic territories (in the USA, Canada, Great Britain, the Netherlands, Germany, Israel and Japan). The mortality rate among these patients was 39%.The lack of prophylactic vaccines and specific therapeutic drugs is the major challenge for the prevention of LF. Thus, this review considers biological models (cell cultures and animals) that are suitable for studying the pathogenesis of this disease, preclinical studies of the specific activity and harmlessness of candidate vaccines, as well as options for these developments based on the platforms such as inactivated LASV and its DNA, the reassortant of Mopeia arenavirus, and measles virus attenuated strains, recombinant and replication-defective viruses (smallpox vaccine, Venezuelan equine encephalitis, bovine vesicular stomatitis, adenovirus of chimpanzee) and virus-like particles.
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Petersen, Lyle R., Duane J. Gubler, and Daniel R. Kuritzkes. "Viral Zoonoses." DeckerMed Medicine, January 8, 2021. http://dx.doi.org/10.2310/im.1148.
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Human infection by zoonotic viruses—pathogens that normally infect animals—may result in no obvious illness, a nonspecific viral syndrome, or more severe illness typically characterized by hemorrhagic fever, encephalitis, or rash arthralgia. Transmission usually occurs by direct contact with or a bite from an infected animal or arthropod. Viral families discussed include Flaviviridae, Bunyaviridae, Arenaviridae, Filoviridae, Togaviridae, Rhabdoviridae, Paramyxoviridae, and Reoviridae, with consideration given to the epidemiology, diagnosis, treatment, and prevention of specific viruses. Hemorrhagic fevers addressed include dengue fever, dengue hemorrhagic fever, yellow fever, Crimean-Congo hemorrhagic fever, and Rift Valley fever; hantavirus infections; and the Marburg and Ebola viruses. Encephalitic fever–causing viruses discussed include La Crosse; Japanese; Murray Valley; St. Louis; tick-borne; West Nile; Powassan; eastern, western, and Venezuelan equine; rabies; Nipah; Barmah Forest; and Colorado tick fever. Rash arthralgia may be caused by the Barmah Forest, Chikungunya, Mayaro, O’nyong-nyong, Ross River, and dengue viruses. Other viral zoonoses considered include monkey B virus, ruminant and primate poxvirus, Newcastle, and foot-and-mouth diseases, as well as vesicular stomatitis virus infection. A diagram depicts the generalized arbovirus maintenance cycle. Tables list the important viral zoonoses that cause human disease, the principal hantaviruses that cause human disease, the arenaviruses that cause significant human illness, and the viral zoonoses endemic in the United States. This review contains 1 figure, 32 tables, and 80 references. Key words: dengue, diagnosis, encephalitis, epidemic, epidemiology, infection, rabies, virus, vaccine
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Amanat, Fatima, James Duehr, Lisa Oestereich, Kathryn M. Hastie, Erica Ollmann Saphire, and Florian Krammer. "Antibodies to the Glycoprotein GP2 Subunit Cross-React between Old and New World Arenaviruses." mSphere 3, no. 3 (May 2, 2018). http://dx.doi.org/10.1128/msphere.00189-18.
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ABSTRACT Arenaviruses pose a major public health threat and cause numerous infections in humans each year. Although most viruses belonging to this family do not cause disease in humans, some arenaviruses, such as Lassa virus and Machupo virus, are the etiological agents of lethal hemorrhagic fevers. The absence of a currently licensed vaccine and the highly pathogenic nature of these viruses both make the necessity of developing viable vaccines and therapeutics all the more urgent. Arenaviruses have a single glycoprotein on the surface of virions, the glycoprotein complex (GPC), and this protein can be used as a target for vaccine development. Here, we describe immunization strategies to generate monoclonal antibodies (MAbs) that cross-react between the glycoprotein complexes of both Old World and New World arenaviruses. Several monoclonal antibodies isolated from immunized mice were highly cross-reactive, binding a range of Old World arenavirus glycoproteins, including that of Lassa virus. One such monoclonal antibody, KL-AV-2A1, bound to GPCs of both New World and Old World viruses, including Lassa and Machupo viruses. These cross-reactive antibodies bound to epitopes present on the glycoprotein 2 subunit of the glycoprotein complex, which is relatively conserved among arenaviruses. Monoclonal antibodies binding to these epitopes, however, did not inhibit viral entry as they failed to neutralize a replication-competent vesicular stomatitis virus pseudotyped with the Lassa virus glycoprotein complex in vitro . In addition, no protection from virus challenge was observed in in vivo mouse models. Even so, these monoclonal antibodies might still prove to be useful in the development of clinical and diagnostic assays. IMPORTANCE Several viruses in the Arenaviridae family infect humans and cause severe hemorrhagic fevers which lead to high case fatality rates. Due to their pathogenicity and geographic tropisms, these viruses remain very understudied. As a result, an effective vaccine or therapy is urgently needed. Here, we describe efforts to produce cross-reactive monoclonal antibodies that bind to both New and Old World arenaviruses. All of our MAbs seem to be nonneutralizing and nonprotective and target subunit 2 of the glycoprotein. Due to the lack of reagents such as recombinant glycoproteins and antibodies for rapid detection assays, our MAbs could be beneficial as analytic and diagnostic tools.
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Hassan, Yahaya, Abdulhadi Sale Kumurya, Ibrahim Aminu, Sanusi Rahinatu Sharfadi, and Abdullahi Alhassan Sharif. "Lassa Virus Diagnostic Platforms: Limitations and Prospects." Asian Journal of Research in Infectious Diseases, July 22, 2020, 5–17. http://dx.doi.org/10.9734/ajrid/2020/v4i330147.
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Background: Lassa virus (LASV) is the cause of lassa fever (LF) belonging to the Arenaviridae family. Clinical diagnosis is often difficult because of symptoms commonality with other infectious diseases. Early and rapid diagnosis is critical for therapy initiation and LF transmission prevention and control.
Aims: This review aims to highlight current diagnostic platforms and prospects of new emerging sensitive platforms.
Methodology: Available published articles on LASV diagnostics with a focus on current methods: virus culture, enzyme-linked immunosorbent assay (ELISA), reverse transcriptase-polymerase chain reaction (RT – PCR) and rapid diagnostic tests (RDT) were reviewed based on their performances and limitations. Prospects of new diagnostic platforms: mobile health, microfluidic, clustered regularly interspaced short palindromic repeats (CRISPR)-associated (Cas), Loop-mediated isothermal amplification (LAMP) for LASV diagnosis were also reviewed.
Results: Low sensitivity of the ELISA platform during the window period of LASV infection was observed. Moreover, RT – PCR findings indicated limitation of expertise necessity, cost of thermal cycler, and dedicated facility. Molecular-based point-of-care (POC) diagnostic development should be prioritized to increase speed and sensitivity.
Conclusion: The integration of POC device into molecular isothermal method against LASV scourge will be a success story in curving intermittent outbreaks in endemic areas and prompt clinical management.
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Zeller, H., K. Leitmeyer, C. Varela Santos, and D. Coulombier. "Unknown disease in South Africa identified as arenavirus infection." Eurosurveillance 13, no. 42 (October 16, 2008). http://dx.doi.org/10.2807/ese.13.42.19008-en.
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On 12 September 2008, a tourist guide organising safari trips, residing in Lusaka, Zambia, was evacuated in a critical condition to Johannesburg, South Africa. She was admitted to a clinic where she died on 14 September about 10 days after the onset of symptoms. The symptoms included a prodromal phase with fever, myalgia, vomiting, diarrhoea, followed by rash, liver dysfunction and convulsions [1]. Cerebral oedema was detected on scan examination. No laboratory specimen was available for investigation. The paramedic who had cared for the index case during her evacuation to Johannesburg developed prodromal symptoms similar to the index case. He was hospitalised on 27 September. His condition deteriorated and he died on 2 October. An intensive care unit nurse who cared for the index case in Johannesburg developed similar flu-like symptoms and was hospitalised on 1 October. Her condition deteriorated on 4 October and she died on 5 October of acute respiratory distress syndrome. In both cases, the incubation period is estimated to have been about one week. On 13 October, the World Health Organization (WHO) posted a website update informing about a fourth case affecting a nurse who had been in contact with the paramedic [2]. On 12 October 2008, the National Institute for Communicable Diseases (NICD) in South Africa provided preliminary evidence that the causative agent of the disease was a virus from the Arenaviridae family [3]. Specimens were shipped to the United States Centers for Disease Control and Prevention (CDC) in Atlanta for additional investigations.
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Monteiro, Ajit, Karl O. A. Yu, and Mark D. Hicar. "Peptide-based Fusion Inhibitors for Preventing the Six-helix Bundle Formation of Class I Fusion Proteins: HIV and Beyond." Current HIV Research 19 (September 8, 2021). http://dx.doi.org/10.2174/1570162x19666210908115231.
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: A number of different viral families have developed convergent methods to infect cells. Class I fusion proteins are commonly used by members of Arenaviridae, Coronaviridae, Filovirdae, Orthomyxoviridae, Paramyxoviridae, and Retroviridae. Class I viral fusion proteins are trimers that are involved in recognizing the cellular receptor, with a region that is responsible for fusing the viral and target cell membranes. During the fusion process, the fusion region folds into a six-helix bundle (6HB) which approximates the two membranes leading to fusion. For human immunodeficiency virus (HIV), the gp41 subunit is responsible for the formation of this 6HB. The fusion inhibitor drug enfuvirtide, or T20, is the only US Food and Drug Administration and European Medicines Agency approved drug which targets this crucial step and has been widely used in combination regimens for the treatment of HIV since March 2003. In this review, we describe the current state of peptide-based fusion inhibitors in the treatment of HIV, and review how the field of HIV research is driving advances in the development of similar therapeutics in other viral systems, including the severe acute respiratory syndrome (SARS) coronaviruses.
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"Validation of Сhoice of Laboratory Model for Preclinical Estimation of Medical Protectors Against Bolivian Hemorrhagic Fever." Journal of NBC Protection Corps 3, no. 4 (December 5, 2019): 319–28. http://dx.doi.org/10.35825/2587-5728-2019-3-4-319-328.
Full textAbstract:
Th is review is dedicated to the peculiarities of pathogenesis of the experimental Bolivian hemorrhagic fever (BHF) – the disease, caused by Machupo virus (Arenaviridae family). Th e authors come to the conclusion that for carrying out preclinical researches of the medical means of protection (MMP) in vivo on small laboratory animals it is expedient to use guinea pigs, infected with a strain of Chicava or with a variant of Carvallo strain, adapted for these animals. Th e use of guinea pigs as small laboratory animals when studying pathogenesis of the disease caused by Machupo virus allows to carry out statistically reliable defi nition of quantitative indices of an experimental infection and to select medicines for the fi nal stage of preclinical assessment. As arenaviruses block the process of formation of interferon (IFN) in the infected organism, mice, defective by IFN formation, are the perspective animal models for the study of BHF pathogenesis and may be used for the study of attenuated variants of Machupo virus. Th e Javanese macaques (Macaca fascicularis) are the laboratory animals, modeling the pathogenetic manifestations of BHF in humans. Th ey can be used when carrying out the fi nal stages of preclinical assessment of means of medical protection
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Hulseberg, Christine E., Lucie Fénéant, Katarzyna M. Szymańska, and Judith M. White. "Lamp1 Increases the Efficiency of Lassa Virus Infection by Promoting Fusion in Less Acidic Endosomal Compartments." mBio 9, no. 1 (January 2, 2018). http://dx.doi.org/10.1128/mbio.01818-17.
Full textAbstract:
ABSTRACT Lassa virus (LASV) is an arenavirus whose entry into host cells is mediated by a glycoprotein complex (GPC) comprised of a receptor binding subunit, GP1, a fusogenic transmembrane subunit, GP2, and a stable signal peptide. After receptor-mediated internalization, arenaviruses converge in the endocytic pathway, where they are thought to undergo low-pH-triggered, GPC-mediated fusion with a late endosome membrane. A unique feature of LASV entry is a pH-dependent switch from a primary cell surface receptor (α-dystroglycan) to an endosomal receptor, lysosomal-associated membrane protein (Lamp1). Despite evidence that the interaction between LASV GP1 and Lamp1 is critical, the function of Lamp1 in promoting LASV infection remains poorly characterized. Here we used wild-type (WT) and Lamp1 knockout (KO) cells to show that Lamp1 increases the efficiency of, but is not absolutely required for, LASV entry and infection. We then used cell-cell and pseudovirus-cell surface fusion assays to demonstrate that LASV GPC-mediated fusion occurs at a significantly higher pH when Lamp1 is present compared to when Lamp1 is missing. Correspondingly, we found that LASV entry occurs through less acidic endosomes in WT (Lamp1-positive) versus Lamp1 KO cells. We propose that, by elevating the pH threshold for fusion, Lamp1 allows LASV particles to exit the endocytic pathway before they encounter an increasingly acidic and harsh proteolytic environment, which could inactivate a significant percentage of incoming viruses. In this manner Lamp1 increases the overall efficiency of LASV entry and infection. IMPORTANCE Lassa virus is the most clinically important member of the Arenaviridae, a family that includes six additional biosafety level 4 (BSL4) hemorrhagic fever viruses. The lack of specific antiviral therapies for Lassa fever drives an urgent need to identify druggable targets, and interventions that block infection at the entry stage are particularly attractive. Lassa virus is only the second virus known to employ an intracellular receptor, the first being Ebola virus. Here we show that interaction with its intracellular receptor, Lamp1, enhances and upwardly shifts the pH dependence of fusion and consistently permits Lassa virus entry into cells through less acidic endosomes. We propose that in this manner, Lamp1 increases the overall efficiency of Lassa virus infection.
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Maruyama, Junki, John T. Manning, Elizabeth J. Mateer, Rachel Sattler, Natalya Bukreyeva, Cheng Huang, and Slobodan Paessler. "Lethal Infection of Lassa Virus Isolated from a Human Clinical Sample in Outbred Guinea Pigs without Adaptation." mSphere 4, no. 5 (September 25, 2019). http://dx.doi.org/10.1128/msphere.00428-19.
Full textAbstract:
ABSTRACT Lassa virus (LASV), a member of the family Arenaviridae, is the causative agent of Lassa fever. Lassa virus is endemic in West African countries, such as Nigeria, Guinea, Liberia, and Sierra Leone, and causes outbreaks annually. Lassa fever onset begins with “flu-like” symptoms and may develop into lethal hemorrhagic disease in severe cases. Although Lassa virus is one of the most alarming pathogens from a public health perspective, there are few licensed vaccines or therapeutics against Lassa fever. The fact that animal models are limited and the fact that mostly laboratory-derived viruses are used for studies limit the successful development of countermeasures. In this study, we demonstrated that the LASV isolate LF2384-NS-DIA-1 (LF2384), which was directly isolated from a serum sample from a fatal human Lassa fever case in the 2012 Sierra Leone outbreak, causes uniformly lethal infection in outbred Hartley guinea pigs without virus-host adaptation. This is the first report of a clinically isolated strain of LASV causing lethal infection in outbred guinea pigs. This novel guinea pig model of Lassa fever may contribute to Lassa fever research and the development of vaccines and therapeutics. IMPORTANCE Lassa virus, the causative agent of Lassa fever, is a zoonotic pathogen causing annual outbreaks in West African countries. Human patients can develop lethal hemorrhagic fever in severe cases. Although Lassa virus is one of the most alarming pathogens from a public health perspective, there are few available countermeasures, such as antiviral drugs or vaccines. Moreover, the fact that animal models are not readily accessible and the fact that mostly laboratory viruses, which have been passaged many times after isolation, are used for studies further limits the successful development of countermeasures. In this study, we demonstrate that a human isolate of Lassa virus causes lethal infection uniformly in Hartley guinea pigs. This novel animal model of Lassa fever may contribute to Lassa fever research and the development of vaccines and therapeutics.
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Foscaldi, Sabrina, Alejandra D'Antuono, María Gabriela Noval, Gonzalo de Prat Gay, Luis Scolaro, and Nora Lopez. "Regulation of Tacaribe Mammarenavirus Translation: Positive 5′ and Negative 3′ Elements and Role of Key Cellular Factors." Journal of Virology 91, no. 14 (May 3, 2017). http://dx.doi.org/10.1128/jvi.00084-17.
Full textAbstract:
ABSTRACT Mammarenaviruses are enveloped viruses with a bisegmented negative-stranded RNA genome that encodes the nucleocapsid protein (NP), the envelope glycoprotein precursor (GPC), the RNA polymerase (L), and a RING matrix protein (Z). Viral proteins are synthesized from subgenomic mRNAs bearing a capped 5′ untranslated region (UTR) and lacking 3′ poly(A) tail. We analyzed the translation strategy of Tacaribe virus (TCRV), a prototype of the New World mammarenaviruses. A virus-like transcript that carries a reporter gene in place of the NP open reading frame and transcripts bearing modified 5′ and/or 3′ UTR were evaluated in a cell-based translation assay. We found that the presence of the cap structure at the 5′ end dramatically increases translation efficiency and that the viral 5′ UTR comprises stimulatory signals while the 3′ UTR,specifically the presence of a terminal C+G-rich sequence and/or a stem-loop structure, down-modulates translation. Additionally, translation was profoundly reduced in eukaryotic initiation factor (eIF) 4G-inactivated cells, whereas depletion of intracellular levels of eIF4E had less impact on virus-like mRNA translation than on a cell-like transcript. Translation efficiency was independent of NP expression or TCRV infection. Our results indicate that TCRV mRNAs are translated using a cap-dependent mechanism, whose efficiency relies on the interplay between stimulatory signals in the 5′ UTR and a negative modulatory element in the 3′ UTR. The low dependence on eIF4E suggests that viral mRNAs may engage yet-unknown noncanonical host factors for a cap-dependent initiation mechanism. IMPORTANCE Several members of the Arenaviridae family cause serious hemorrhagic fevers in humans. In the present report, we describe the mechanism by which Tacaribe virus, a prototypic nonpathogenic New World mammarenavirus, regulates viral mRNA translation. Our results highlight the impact of untranslated sequences and key host translation factors on this process. We propose a model that explains how viral mRNAs outcompete cellular mRNAs for the translation machinery. A better understanding of the mechanism of translation regulation of this virus can provide the bases for the rational design of new antiviral tools directed to pathogenic arenaviruses.