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[PMID]: 28794024 [Au] Autor: Huang C; Kolokoltsova OA; Mateer EJ; Koma T; Paessler S [Ad] Endereço: Department of Pathology and Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, USA chhuang@utmb.edu slpaessl@utmb.edu. [Ti] Título: Highly Pathogenic New World Arenavirus Infection Activates the Pattern Recognition Receptor Protein Kinase R without Attenuating Virus Replication in Human Cells. [So] Source: J Virol;91(20), 2017 Oct 15. [Is] ISSN: 1098-5514 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The arenavirus family consists of several highly pathogenic viruses, including the Old World (OW) arenavirus Lassa fever virus (LASV) and the New World (NW) Junin virus (JUNV) and Machupo virus (MACV). Host response to infection by these pathogenic arenaviruses is distinct in many aspects. JUNV and MACV infections readily induce an interferon (IFN) response in human cells, while LASV infection usually triggers an undetectable or weak IFN response. JUNV induces an IFN response through RIG-I, suggesting that the host non-self RNA sensor readily detects JUNV viral RNAs (vRNAs) during infection and activates IFN response. Double-stranded-RNA (dsRNA)-activated protein kinase R (PKR) is another host non-self RNA sensor classically known for its vRNA recognition activity. Here we report that infection with NW arenaviruses JUNV and MACV, but not OW LASV, activated PKR, concomitant with elevated phosphorylation of the translation initiation factor α subunit of eukaryotic initiation factor 2 (eIF2α). Host protein synthesis was substantially suppressed in MACV- and JUNV-infected cells but was only marginally reduced in LASV-infected cells. Despite the antiviral activity known for PKR against many other viruses, the replication of JUNV and MACV was not impaired but was slightly augmented in wild-type (wt) cells compared to that in PKR-deficient cells, suggesting that PKR or PKR activation did not negatively affect JUNV and MACV infection. Additionally, we found an enhanced IFN response in JUNV- or MACV-infected PKR-deficient cells, which was inversely correlated with virus replication. The detection of viral RNA by host non-self RNA sensors, including RIG-I and MDA5, is critical to the initiation of the innate immune response to RNA virus infection. Among pathogenic arenaviruses, the OW LASV usually does not elicit an interferon response. However, the NW arenaviruses JUNV and MACV readily trigger an IFN response in a RIG-I-dependent manner. Here, we demonstrate for the first time that pathogenic NW arenaviruses JUNV and MACV, but not the OW arenavirus LASV, activated the dsRNA-dependent PKR, another host non-self RNA sensor, during infection. Interestingly, the replication of JUNV and MACV was not restricted but was rather slightly augmented in the presence of PKR. Our data provide new evidence for a distinct interplay between host non-self RNA sensors and pathogenic arenaviruses, which also provides insights into the pathogenesis of arenaviruses and may facilitate the design of vaccines and treatments against arenavirus-caused diseases. [Mh] Termos MeSH primário: Arenavirus do Novo Mundo/patogenicidade Arenavirus do Velho Mundo/patogenicidade Imunidade Inata Vírus Junin/patogenicidade Receptores de Reconhecimento de Padrão/metabolismo Replicação Viral eIF-2 Quinase/metabolismo [Mh] Termos MeSH secundário: Células A549 Arenavirus do Novo Mundo/fisiologia Arenavirus do Velho Mundo/fisiologia Interações Hospedeiro-Patógeno Seres Humanos Interferons/biossíntese Interferons/imunologia Vírus Junin/fisiologia Fosforilação Receptores de Reconhecimento de Padrão/genética Fatores de Transcrição/metabolismo eIF-2 Quinase/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Receptors, Pattern Recognition); 0 (Transcription Factors); 181233-60-3 (ELF2 protein, human); 9008-11-1 (Interferons); EC 2.7.11.1 (EIF2AK2 protein, human); EC 2.7.11.1 (eIF-2 Kinase) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171024 [Lr] Data última revisão: 171024 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170811 [St] Status: MEDLINE

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[PMID]: 27605671 [Au] Autor: Zhang LK; Xin QL; Zhu SL; Wan WW; Wang W; Xiao G [Ad] Endereço: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China. [Ti] Título: Activation of the RLR/MAVS Signaling Pathway by the L Protein of Mopeia Virus. [So] Source: J Virol;90(22):10259-10270, 2016 Nov 15. [Is] ISSN: 1098-5514 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: 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. [Mh] Termos MeSH primário: Proteínas Adaptadoras de Transdução de Sinal/metabolismo Infecções por Arenaviridae/metabolismo Arenavirus do Velho Mundo/metabolismo Transdução de Sinais/fisiologia Proteínas Virais/metabolismo [Mh] Termos MeSH secundário: Animais Infecções por Arenaviridae/imunologia Infecções por Arenaviridae/virologia Arenavirus/imunologia Arenavirus/metabolismo Arenavirus do Velho Mundo/imunologia Linhagem Celular Linhagem Celular Tumoral Cercopithecus aethiops RNA Polimerases Dirigidas por DNA/metabolismo Células HEK293 Células HeLa Interações Hospedeiro-Patógeno/imunologia Interações Hospedeiro-Patógeno/fisiologia Seres Humanos Imunidade Inata/imunologia Interferon Tipo I/metabolismo Células Vero [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Adaptor Proteins, Signal Transducing); 0 (Interferon Type I); 0 (VISA protein, human); 0 (Viral Proteins); EC 2.7.7.6 (DNA-Directed RNA Polymerases) [Em] Mês de entrada: 1705 [Cu] Atualização por classe: 170508 [Lr] Data última revisão: 170508 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160909 [St] Status: MEDLINE

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[PMID]: 24068704 [Au] Autor: McLay L; Liang Y; Ly H [Ad] Endereço: Department of Veterinary and Biomedical Sciences, University of Minnesota, Twin Cities, MN 55108, USA. [Ti] Título: Comparative analysis of disease pathogenesis and molecular mechanisms of New World and Old World arenavirus infections. [So] Source: J Gen Virol;95(Pt 1):1-15, 2014 Jan. [Is] ISSN: 1465-2099 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Arenaviruses can cause fatal human haemorrhagic fever (HF) diseases for which vaccines and therapies are extremely limited. Both the New World (NW) and Old World (OW) groups of arenaviruses contain HF-causing pathogens. Although these two groups share many similarities, important differences with regard to pathogenicity and molecular mechanisms of virus infection exist. These closely related pathogens share many characteristics, including genome structure, viral assembly, natural host selection and the ability to interfere with innate immune signalling. However, members of the NW and OW viruses appear to use different receptors for cellular entry, as well as different mechanisms of virus internalization. General differences in disease signs and symptoms and pathological lesions in patients infected with either NW or OW arenaviruses are also noted and discussed herein. Whilst both the OW Lassa virus (LASV) and the NW Junin virus (JUNV) can cause disruption of the vascular endothelium, which is an important pathological feature of HF, the immune responses to these related pathogens seem to be quite distinct. Whereas LASV infection results in an overall generalized immune suppression, patients infected with JUNV seem to develop a cytokine storm. Additionally, the type of immune response required for recovery and clearance of the virus is different between NW and OW infections. These differences may be important to allow the viruses to evade host immune detection. Understanding these differences will aid the development of new vaccines and treatment strategies against deadly HF viral infections. [Mh] Termos MeSH primário: Infecções por Arenaviridae/patologia Infecções por Arenaviridae/virologia Arenavirus do Novo Mundo/genética Arenavirus do Velho Mundo/genética Febres Hemorrágicas Virais/patologia Febres Hemorrágicas Virais/virologia [Mh] Termos MeSH secundário: Animais Infecções por Arenaviridae/imunologia Arenavirus do Novo Mundo/classificação Arenavirus do Novo Mundo/imunologia Arenavirus do Novo Mundo/patogenicidade Arenavirus do Velho Mundo/classificação Arenavirus do Velho Mundo/imunologia Arenavirus do Velho Mundo/patogenicidade Febres Hemorrágicas Virais/imunologia Seres Humanos [Pt] Tipo de publicação: COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; REVIEW [Em] Mês de entrada: 1403 [Cu] Atualização por classe: 161019 [Lr] Data última revisão: 161019 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 130927 [St] Status: MEDLINE [do] DOI: 10.1099/vir.0.057000-0

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[PMID]: 24075870 [Au] Autor: Koma T; Huang C; Kolokoltsova OA; Brasier AR; Paessler S [Ad] Endereço: Department of Pathology and Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77550, USA. [Ti] Título: Innate immune response to arenaviral infection: a focus on the highly pathogenic New World hemorrhagic arenaviruses. [So] Source: J Mol Biol;425(24):4893-903, 2013 Dec 13. [Is] ISSN: 1089-8638 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Arenaviruses are enveloped, negative-stranded RNA viruses that belong to the family Arenaviridae. This diverse family can be further classified into OW (Old World) and NW (New World) arenaviruses based on their antigenicity, phylogeny, and geographical distribution. Many of the NW arenaviruses are highly pathogenic viruses that cause systemic human infections characterized by hemorrhagic fever and/or neurological manifestations, constituting public health problems in their endemic regions. NW arenavirus infection induces a variety of host innate immune responses, which could contribute to the viral pathogenesis and/or influence the final outcome of virus infection in vitro and in vivo. On the other hand, NW arenaviruses have also developed several strategies to counteract the host innate immune response. We will review current knowledge regarding the interplay between the host innate immune response and NW arenavirus infection in vitro and in vivo, with emphasis on viral-encoded proteins and their effect on the type I interferon response. [Mh] Termos MeSH primário: Infecções por Arenaviridae/imunologia Arenavirus do Novo Mundo/imunologia Imunidade Inata/imunologia Interferon Tipo I/metabolismo Proteínas Virais/metabolismo [Mh] Termos MeSH secundário: Animais Infecções por Arenaviridae/virologia Arenavirus do Novo Mundo/genética Arenavirus do Novo Mundo/fisiologia Arenavirus do Velho Mundo/imunologia Interações Hospedeiro-Patógeno/imunologia Seres Humanos Evasão da Resposta Imune Interferon Tipo I/genética Camundongos Modelos Moleculares Proteínas Virais/genética [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW [Nm] Nome de substância: 0 (Interferon Type I); 0 (Viral Proteins) [Em] Mês de entrada: 1401 [Cu] Atualização por classe: 170220 [Lr] Data última revisão: 170220 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 131001 [St] Status: MEDLINE

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[PMID]: 23536681 [Au] Autor: Burri DJ; da Palma JR; Seidah NG; Zanotti G; Cendron L; Pasquato A; Kunz S [Ad] Endereço: Institute of Microbiology, University Hospital Center and University of Lausanne, Lausanne, Switzerland. [Ti] Título: Differential recognition of Old World and New World arenavirus envelope glycoproteins by subtilisin kexin isozyme 1 (SKI-1)/site 1 protease (S1P). [So] Source: J Virol;87(11):6406-14, 2013 Jun. [Is] ISSN: 1098-5514 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The arenaviruses are an important family of emerging viruses that includes several causative agents of severe hemorrhagic fevers in humans that represent serious public health problems. A crucial step of the arenavirus life cycle is maturation of the envelope glycoprotein precursor (GPC) by the cellular subtilisin kexin isozyme 1 (SKI-1)/site 1 protease (S1P). Comparison of the currently known sequences of arenavirus GPCs revealed the presence of a highly conserved aromatic residue at position P7 relative to the SKI-1/S1P cleavage side in Old World and clade C New World arenaviruses but not in New World viruses of clades A and B or cellular substrates of SKI-1/S1P. Using a combination of molecular modeling and structure-function analysis, we found that residue Y285 of SKI-1/S1P, distal from the catalytic triad, is implicated in the molecular recognition of the aromatic "signature residue" at P7 in the GPC of Old World Lassa virus. Using a quantitative biochemical approach, we show that Y285 of SKI-1/S1P is crucial for the efficient processing of peptides derived from Old World and clade C New World arenavirus GPCs but not of those from clade A and B New World arenavirus GPCs. The data suggest that during coevolution with their mammalian hosts, GPCs of Old World and clade C New World viruses expanded the molecular contacts with SKI-1/S1P beyond the classical four-amino-acid recognition sequences and currently occupy an extended binding pocket. [Mh] Termos MeSH primário: Infecções por Arenaviridae/enzimologia Arenavirus do Novo Mundo/metabolismo Arenavirus do Velho Mundo/metabolismo Pró-Proteína Convertases/metabolismo Serina Endopeptidases/metabolismo Proteínas do Envelope Viral/metabolismo [Mh] Termos MeSH secundário: Motivos de Aminoácidos Sequência de Aminoácidos Animais Infecções por Arenaviridae/genética Infecções por Arenaviridae/virologia Arenavirus do Novo Mundo/classificação Arenavirus do Novo Mundo/genética Arenavirus do Velho Mundo/classificação Arenavirus do Velho Mundo/genética Células CHO Cricetinae Seres Humanos Dados de Sequência Molecular Pró-Proteína Convertases/química Pró-Proteína Convertases/genética Processamento de Proteína Pós-Traducional Alinhamento de Sequência Serina Endopeptidases/química Serina Endopeptidases/genética Proteínas do Envelope Viral/química Proteínas do Envelope Viral/genética [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Viral Envelope Proteins); EC 3.4.21.- (Proprotein Convertases); EC 3.4.21.- (Serine Endopeptidases); EC 3.4.21.112 (membrane-bound transcription factor peptidase, site 1) [Em] Mês de entrada: 1307 [Cu] Atualização por classe: 161125 [Lr] Data última revisão: 161125 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 130329 [St] Status: MEDLINE [do] DOI: 10.1128/JVI.00072-13

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[PMID]: 23041432 [Au] Autor: Goyens J; Reijniers J; Borremans B; Leirs H [Ad] Endereço: University of Antwerp, Evolutionary Ecology Group, Groenenborgerlaan 171, B-2020 Antwerpen, Belgium. jana.goyens@ua.ac.be [Ti] Título: Density thresholds for Mopeia virus invasion and persistence in its host Mastomys natalensis. [So] Source: J Theor Biol;317:55-61, 2013 Jan 21. [Is] ISSN: 1095-8541 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Well-established theoretical models predict host density thresholds for invasion and persistence of parasites with a density-dependent transmission. Studying such thresholds in reality, however, is not obvious because it requires long-term data for several fluctuating populations of different size. We developed a spatially explicit and individual-based SEIR model of Mopeia virus in multimammate mice Mastomys natalensis. This is an interesting model system for studying abundance thresholds because the host is the most common African rodent, populations fluctuate considerably and the virus is closely related to Lassa virus but non-pathogenic to humans so can be studied safely in the field. The simulations show that, while host density clearly is important, sharp thresholds are only to be expected for persistence (and not for invasion), since at short time-spans (as during invasion), stochasticity is determining. Besides host density, also the spatial extent of the host population is important. We observe the repeated local occurrence of herd immunity, leading to a decrease in transmission of the virus, while even a limited amount of dispersal can have a strong influence in spreading and re-igniting the transmission. The model is most sensitive to the duration of the infectious stage, the size of the home range and the transmission coefficient, so these are important factors to determine experimentally in the future. [Mh] Termos MeSH primário: Arenavirus do Velho Mundo/fisiologia Interações Hospedeiro-Patógeno/fisiologia Murinae/virologia Doenças dos Roedores/epidemiologia Doenças dos Roedores/virologia [Mh] Termos MeSH secundário: Animais Simulação por Computador Progressão da Doença Camundongos Modelos Biológicos Densidade Demográfica Fatores de Risco Análise de Sobrevida [Pt] Tipo de publicação: JOURNAL ARTICLE [Em] Mês de entrada: 1305 [Cu] Atualização por classe: 121224 [Lr] Data última revisão: 121224 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 121009 [St] Status: MEDLINE

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[PMID]: 23038847 [Au] Autor: Centers for Disease Control and Prevention (CDC), Department of Health and Human Services (HHS) [Ti] Título: Possession, use, and transfer of select agents and toxins; biennial review. Final rule. [So] Source: Fed Regist;77(194):61083-115, 2012 Oct 05. [Is] ISSN: 0097-6326 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: In accordance with the Public Health Security and Bioterrorism Preparedness and Response Act of 2002, the Centers for Disease Control and Prevention (CDC) located within the Department of Health and Human Services (HHS) has reviewed the list of biological agents and toxins that have the potential to pose a severe threat to public health and safety and is republishing that list. As a result of our review, we have added Chapare virus, Lujo virus, and SARS-associated coronavirus (SARS-CoV) to the list of HHS select agents and toxins. We have also removed from the list of HHS and overlap select agents and toxins, or excluded from compliance with part 73, the agents and toxins described in the Executive Summary. Further, in accordance with Executive Order 13546, "Optimizing the Security of Biological Select Agents and Toxins in the United States," HHS/CDC has designated those select agents and toxins that present the greatest risk of deliberate misuse with the most significant potential for mass casualties or devastating effects to the economy, critical infrastructure; or public confidence as "Tier 1" agents; established new security requirements for entities possessing Tier 1 agents, including the requirement to conduct pre-access assessments and on-going monitoring of personnel with access to Tier 1 agents and toxins; and made revisions to the regulations to clarify regulatory language concerning security, training, biosafety, and incident response. In a companion document published in this issue of the Federal Register, the United States Department of Agriculture (USDA) has made parallel regulatory changes. [Mh] Termos MeSH primário: Produtos Biológicos Bioterrorismo/legislação & jurisprudência Surtos de Doenças/legislação & jurisprudência Pandemias/legislação & jurisprudência Medidas de Segurança/legislação & jurisprudência Toxinas Biológicas [Mh] Termos MeSH secundário: Arenavirus do Novo Mundo Arenavirus do Velho Mundo Centers for Disease Control and Prevention (U.S.) Regulamentação Governamental Seres Humanos Vírus da SARS Estados Unidos [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Biological Products); 0 (Toxins, Biological) [Em] Mês de entrada: 1210 [Cu] Atualização por classe: 131121 [Lr] Data última revisão: 131121 [Sb] Subgrupo de revista: T [Da] Data de entrada para processamento: 121009 [St] Status: MEDLINE

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[PMID]: 22815269 [Au] Autor: Ishii A; Thomas Y; Moonga L; Nakamura I; Ohnuma A; Hang'ombe BM; Takada A; Mweene AS; Sawa H [Ad] Endereço: Research Center for Zoonosis Control, Hokkaido University, Sapporo, Hokkaido, Japan. ishiia@czc.hokudai.ac.jp [Ti] Título: Molecular surveillance and phylogenetic analysis of Old World arenaviruses in Zambia. [So] Source: J Gen Virol;93(Pt 10):2247-51, 2012 Oct. [Is] ISSN: 1465-2099 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: In order to survey arenaviruses in the Republic of Zambia, we captured 335 rodents from three cities between 2010 and 2011. Eighteen Luna virus (LUNV) and one lymphocytic choriomeningitis virus (LCMV)-related virus RNAs were detected by one-step RT-PCR from Mastomys natalensis and Mus minutoides, respectively. Four LUNV strains and one LCMV-related virus were isolated, and the whole genome nucleotide sequence was determined by pyrosequencing. Phylogenetic analyses revealed that the LUNV clade consists of two branches that are distinguished by geographical location and that the LCMV-related virus belongs to the LCMV clade, but diverges from the typical LCMVs. Comparison of nucleoprotein amino acid sequences indicated that the LCMV-related virus could be designated a novel arenavirus, which was tentatively named as the Lunk virus. Amino acid sequences of the GP, NP, Z and L proteins showed poor similarity among the three Zambian arenavirus strains, i.e. Luna, Lunk and Lujo virus. [Mh] Termos MeSH primário: Arenavirus do Velho Mundo/classificação Genoma Viral Nucleoproteínas/genética [Mh] Termos MeSH secundário: Sequência de Aminoácidos Animais Arenavirus do Velho Mundo/genética Sequência de Bases Dados de Sequência Molecular Filogenia RNA Viral/genética Roedores/genética Roedores/virologia Zâmbia [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Nucleoproteins); 0 (RNA, Viral) [Em] Mês de entrada: 1302 [Cu] Atualização por classe: 120917 [Lr] Data última revisão: 120917 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 120721 [St] Status: MEDLINE [do] DOI: 10.1099/vir.0.044099-0

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[PMID]: 22234266 [Au] Autor: Goicochea MA; Zapata JC; Bryant J; Davis H; Salvato MS; Lukashevich IS [Ad] Endereço: Institute of Human Virology, University of Maryland, School of Medicine, Baltimore, MD 21201, United States. mgoic001@umaryland.edu [Ti] Título: Evaluation of Lassa virus vaccine immunogenicity in a CBA/J-ML29 mouse model. [So] Source: Vaccine;30(8):1445-52, 2012 Feb 14. [Is] ISSN: 1873-2518 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: Lassa fever (LF) is one of the most prevalent viral hemorrhagic fevers in West Africa responsible for thousands of deaths annually. The BSL-4 containment requirement and lack of small animal model to evaluate Lassa virus (LASV)-specific cell-mediated immunity (CMI) complicate development of effective LF vaccines. Here we have described a CBA/J-ML29 model allowing evaluation of LASV-specific CMI responses in mice. This model is based on Mopeia virus reassortant clone ML29, an attractive immunogenic surrogate for LASV. A single intraperitoneal (i.p.) immunization of CBA/J mice with ML29 protected animals against a lethal homologous intracerebral (i.c.) challenge with 588 LD(50). The ML29-immunized mice displayed negligible levels of LASV-specific antibody titers, but LASV-specific CMI responses were detectable early and peaked on day 8-10 after immunization. A T cell cytotoxicity assay in vivo showed a correlation between LASV-specific cytotoxicity and the timing of protection induced by the ML29 immunization. Notably, CBA/J mice that received CD8+ T cell-depleted splenocytes from ML29-immunized donors all succumbed to a lethal i.c. challenge, demonstrating that CD8+ T cells are critical in protection. The CBA/J-ML29 model can be useful immunological tool for the preliminary evaluation of immunogenicity and efficacy of vaccine candidates against LASV outside of BSL-4 containment facilities. [Mh] Termos MeSH primário: Arenavirus do Velho Mundo/imunologia Febre Lassa/prevenção & controle Linfócitos T Citotóxicos/imunologia Vacinas Virais/administração & dosagem Vacinas Virais/imunologia [Mh] Termos MeSH secundário: Animais Anticorpos Antivirais/sangue Modelos Animais de Doenças Injeções Intraperitoneais Depleção Linfocítica/métodos Camundongos Camundongos Endogâmicos CBA Vírus Reordenados/imunologia Análise de Sobrevida [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL [Nm] Nome de substância: 0 (Antibodies, Viral); 0 (Viral Vaccines) [Em] Mês de entrada: 1205 [Cu] Atualização por classe: 161019 [Lr] Data última revisão: 161019 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 120112 [St] Status: MEDLINE [do] DOI: 10.1016/j.vaccine.2011.12.134

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[PMID]: 22154237 [Au] Autor: Pasquato A; Rochat C; Burri DJ; Pasqual G; de la Torre JC; Kunz S [Ad] Endereço: Institute of Microbiology, University Hospital Center and University of Lausanne, Lausanne, Switzerland. [Ti] Título: Evaluation of the anti-arenaviral activity of the subtilisin kexin isozyme-1/site-1 protease inhibitor PF-429242. [So] Source: Virology;423(1):14-22, 2012 Feb 05. [Is] ISSN: 1096-0341 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The cellular protease subtilisin kexin isozyme-1 (SKI-1)/site-1 protease (S1P) is implicated in the proteolytic processing of the viral envelope glycoprotein precursor (GPC) of arenaviruses, a step strictly required for production of infectious progeny. The small molecule SKI-1/S1P inhibitor PF-429242 was shown to have anti-viral activity against Old World arenaviruses. Here we extended these studies and show that PF-429242 also inhibits GPC processing and productive infection of New World arenaviruses, making PF-429242 a broadly active anti-arenaviral drug. In combination therapy, PF-429242 potentiated the anti-viral activity of ribavirin, indicating a synergism between the two drugs. A hallmark of arenaviruses is their ability to establish persistent infection in vitro and in vivo. Notably, PF-429242 was able to efficiently and rapidly clear persistent infection by arenaviruses. Interruption of drug treatment did not result in re-emergence of infection, indicating that PF-429242 treatment leads to virus extinction. [Mh] Termos MeSH primário: Infecções por Arenaviridae/tratamento farmacológico Infecções por Arenaviridae/enzimologia Arenavirus do Velho Mundo/efeitos dos fármacos Inibidores Enzimáticos/farmacologia Pró-Proteína Convertases/antagonistas & inibidores Pirrolidinas/farmacologia [Mh] Termos MeSH secundário: Sequência de Aminoácidos Infecções por Arenaviridae/virologia Arenavirus do Velho Mundo/metabolismo Sequência de Bases Linhagem Celular Seres Humanos Dados de Sequência Molecular Pró-Proteína Convertases/genética Pró-Proteína Convertases/metabolismo Serina Endopeptidases/genética Serina Endopeptidases/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Enzyme Inhibitors); 0 (PF-429242); 0 (Pyrrolidines); EC 3.4.21.- (Proprotein Convertases); EC 3.4.21.- (Serine Endopeptidases); EC 3.4.21.112 (membrane-bound transcription factor peptidase, site 1) [Em] Mês de entrada: 1202 [Cu] Atualização por classe: 161125 [Lr] Data última revisão: 161125 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 111214 [St] Status: MEDLINE [do] DOI: 10.1016/j.virol.2011.11.008

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