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1.
Rev Soc Bras Med Trop ; 53: e20190511, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32578703

RESUMO

INTRODUCTION: The Amazon tropical rainforest has the most dense and diverse ecosystem worldwide. A few studies have addressed rodent-borne diseases as potential hazards to humans in this region. METHODS: A retrospective survey was conducted using enzyme-linked immunosorbent assay for detecting mammarenavirus and orthohantavirus antibodies in 206 samples collected from rural settlers of the Brazilian Western Amazonian region. RESULTS: Six (2.91%) individuals in the age group of 16 to 36 years were found to possess antibodies against mammarenavirus. CONCLUSION: Evidence of previous exposure to mammarenavirus in the rural population points to its silent circulation in this region.


Assuntos
Anticorpos Antivirais/sangue , Infecções por Arenaviridae/epidemiologia , Arenaviridae/imunologia , Reservatórios de Doenças/veterinária , Hepatite Viral Humana/epidemiologia , Orthohepadnavirus/imunologia , Roedores/virologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Arenaviridae/classificação , Infecções por Arenaviridae/diagnóstico , Infecções por Arenaviridae/transmissão , Brasil/epidemiologia , Criança , Pré-Escolar , Feminino , Hepatite Viral Humana/diagnóstico , Hepatite Viral Humana/transmissão , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Orthohepadnavirus/classificação , Estudos Retrospectivos , Roedores/classificação , População Rural , Fatores Socioeconômicos , Adulto Jovem
2.
PLoS One ; 15(3): e0229667, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32119716

RESUMO

Inclusion body disease (IBD) is caused by reptarenaviruses and constitutes one of the most notorious viral diseases in snakes. Although central nervous system disease and various other clinical signs have been attributed to IBD in boid and pythonid snakes, studies that unambiguously reveal the clinical course of natural IBD and reptarenavirus infection are scarce. In the present study, the prevalence of IBD and reptarenaviruses in captive snake collections and the correlation of IBD and reptarenavirus infection with the clinical status of the sampled snakes were investigated. In three IBD positive collections, long-term follow-up during a three- to seven-year period was performed. A total of 292 snakes (178 boas and 114 pythons) from 40 collections in Belgium were sampled. In each snake, blood and buffy coat smears were evaluated for the presence of IBD inclusion bodies (IB) and whole blood was tested for reptarenavirus RNA by RT-PCR. Of all tested snakes, 16.5% (48/292) were positive for IBD of which all were boa constrictors (34.0%; 48/141) and 17.1% (50/292) were reptarenavirus RT-PCR positive. The presence of IB could not be demonstrated in any of the tested pythons, while 5.3% (6/114) were reptarenavirus positive. In contrast to pythons, the presence of IB in peripheral blood cells in boa constrictors is strongly correlated with reptarenavirus detection by RT-PCR (P<0.0001). Although boa constrictors often show persistent subclinical infection, long-term follow-up indicated that a considerable number (22.2%; 6/27) of IBD/reptarenavirus positive boas eventually develop IBD associated comorbidities.


Assuntos
Boidae/metabolismo , Infecções por Citomegalovirus/epidemiologia , Corpos de Inclusão/metabolismo , Animais , Animais de Zoológico , Arenaviridae/patogenicidade , Bélgica/epidemiologia , Comorbidade , Estudos Transversais , Corpos de Inclusão/fisiologia , Corpos de Inclusão Viral/genética , Prevalência , RNA Viral/genética , Serpentes/genética
3.
Artigo em Inglês | MEDLINE | ID: mdl-31859843

RESUMO

During the Brazilian slavery period, many African migrants were brought to the American continent. Historically, some of these migrants escaped from the Brazilian gold mines and farms to which they had been brought and settled in remote valleys and this was the main mode of resistance to the slavery system. These runaway-slave descendant communities are called quilombos, a group with distinct ethnic identity, specific behavioral habits, including geographic isolation and conservative practices. The objective of this study was to investigate the prevalence of rodent-borne viruses in two Afro-descendent communities from Mato Grosso do Sul State, Midwestern Brazil. A total of 319 individuals from rural and urban quilombola communities were enrolled. Twelve (3.76%) had anti-rodent-borne virus IgG antibodies. Seven (2.19%) were anti-mammarenavirus reactive and nine (2.82%) had anti-orthohantavirus antibodies. The literature includes limited data on the health status of quilombola communities, but all the studies emphasize the disparity of attention of local healthcare personnel to these communities compared to the general population. The findings of this study highlight the vulnerability and the precarious health conditions of quilombola groups, especially those living in rural areas and thus, point to the need of preventive measures to improve access to healthcare for this ethnic group.


Assuntos
Anticorpos Antivirais/sangue , Infecções por Arenaviridae/epidemiologia , Arenaviridae/imunologia , Infecções por Hantavirus/epidemiologia , Hantavirus/imunologia , Imunoglobulina G/sangue , Adolescente , Adulto , Grupo com Ancestrais do Continente Africano , Idoso , Idoso de 80 Anos ou mais , Animais , Infecções por Arenaviridae/diagnóstico , Brasil/epidemiologia , Criança , Pré-Escolar , Feminino , Infecções por Hantavirus/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Roedores/virologia , Estudos Soroepidemiológicos , Fatores Socioeconômicos , Adulto Jovem
5.
PLoS One ; 14(9): e0221863, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31498825

RESUMO

Boid Inclusion Body Disease (BIBD) is a potentially fatal disease reported in captive boid snakes worldwide that is caused by reptarenavirus infection. Although the detection of intracytoplasmic inclusion bodies (IB) in blood cells serves as the gold standard for the ante mortem diagnosis of BIBD, the mechanisms underlying IB formation and the pathogenesis of BIBD are unknown. Knowledge on the reptile immune system is sparse compared to the mammalian counterpart, and in particular the response towards reptarenavirus infection is practically unknown. Herein, we investigated a breeding collection of 70 Boa constrictor snakes for BIBD, reptarenavirus viraemia, anti-reptarenavirus IgM and IgY antibodies, and population parameters. Using NGS and RT-PCR on pooled blood samples of snakes with and without BIBD, we could identify three different reptarenavirus S segments in the collection. The examination of individual samples by RT-PCR indicated that the presence of University of Giessen virus (UGV)-like S segment strongly correlates with IB formation. We could also demonstrate a negative correlation between BIBD and the presence of anti-UGV NP IgY antibodies. Further evidence of an association between antibody response and BIBD is the finding that the level of anti-reptarenavirus antibodies measured by ELISA was lower in snakes with BIBD. Furthermore, female snakes had a significantly lower body weight when they had BIBD. Taken together our findings suggest that the detection of the UGV-/S6-like S segment and the presence of anti-reptarenavirus IgY antibodies might serve as a prognostic tool for predicting the development of BIBD.


Assuntos
Anticorpos Antivirais/imunologia , Infecções por Arenaviridae/imunologia , Arenaviridae/fisiologia , Corpos de Inclusão Viral/fisiologia , Serpentes/imunologia , Serpentes/virologia , Animais , Anticorpos Antivirais/sangue , Arenaviridae/genética , Arenaviridae/imunologia , Infecções por Arenaviridae/sangue , Infecções por Arenaviridae/diagnóstico , Feminino , Masculino , Serpentes/sangue
6.
J Gen Virol ; 100(8): 1200-1201, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31192784

RESUMO

Members of the family Arenaviridae produce enveloped virions containing genomes consisting of two or three single-stranded RNA segments totalling about 10.5 kb. Arenaviruses can infect mammals, including humans and other primates, snakes, and fish. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Arenaviridae, which is available at www.ictv.global/report/arenaviridae.


Assuntos
Infecções por Arenaviridae/veterinária , Infecções por Arenaviridae/virologia , Arenaviridae/classificação , Arenaviridae/genética , Animais , Arenaviridae/isolamento & purificação , Arenaviridae/ultraestrutura , Peixes , Genoma Viral , Humanos , Filogenia , RNA Viral/genética , Répteis , Proteínas Virais/genética
7.
Mem Inst Oswaldo Cruz ; 114: e180586, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31141019

RESUMO

Here, we report the complete genome sequence of the Aporé virus (Bunyavirales: Arenaviridae), obtained from a wild rodent Oligoryzomys mattogrossae captured in Mato Grosso do Sul state, Brazil. The genome of this virus showed strong similarity to highly pathogenic mammarenavirus from South America.


Assuntos
Arenaviridae/genética , Genoma Viral/genética , Roedores/virologia , Animais , Arenaviridae/isolamento & purificação , Sequência de Bases , Brasil , Filogenia
8.
Aust Vet J ; 97(4): 93-102, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30919443

RESUMO

BACKGROUND: Inclusion body disease (IBD) is a disease of snakes with a global distribution and has recently been shown to be caused by reptarenaviruses. Testing for this group of viruses in asymptomatic snakes allows the association between infection and disease to be further elucidated. METHODS: A reptarenavirus was detected by RT-PCR in a reticulated python (Malayopython reticulatus) from an Australian zoological collection that was open-mouth breathing and had erythematous oral mucosa. Another 27 pythons, 4 elapids, 2 colubrids and 2 boas from this collection were then screened. From these animals, swabs, whole blood and/or tissue were tested for reptarenaviruses by RT-PCR. Additionally, blood films from 10 snakes were examined by light microscopy for the presence of inclusion bodies. The majority of samples were collected over a 484-day period. RESULTS: A total of 8 animals were RT-PCR-positive (8/36 = 22.2%): 6 were pythons, 1 was a corn snake (Pantherophis guttatus) and 1 was a Madagascar tree boa (Sanzinia madagascariensis). From them, 57 samples were collected, but only one from each animal was RT-PCR-positive (8/57 = 14.0%). From all 36 animals in this study, 8/182 samples were RT-PCR-positive (4.4%). Inclusion bodies were not recognised in any of the blood films. Only the reticulated python showed signs of illness, which improved without any further intervention. All other RT-PCR-positive snakes were apparently healthy throughout the duration of the study. CONCLUSION: This study showed a weak association between the presence of reptarenaviruses and disease. Testing serially collected swab and whole-blood samples increased the number of animals in which reptarenaviruses were detected.


Assuntos
Infecções por Arenaviridae/veterinária , Arenaviridae/isolamento & purificação , Serpentes/virologia , Animais , Animais de Zoológico/virologia , Infecções por Arenaviridae/epidemiologia , Austrália , Feminino , Masculino , Reação em Cadeia da Polimerase Via Transcriptase Reversa/veterinária
9.
PLoS Negl Trop Dis ; 13(2): e0007049, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30768614

RESUMO

BACKGROUND: Mammarenaviruses are associated with human hemorrhagic fever diseases in Africa and America. Recently, a rodent mammarenavirus, Wenzhou virus (WENV) and related viruses, have been reported in China, Cambodia, and Thailand. Moreover, in Cambodia, these viruses were suspected to be associated with human disease. In China, Yunnan Province is famous for its abundant animal and plant diversity and is adjacent to several South-eastern Asia countries. Therefore, it is necessary to know whether WENV-related viruses, or other mammarenaviruses, are prevalent in this province. METHODOLOGY/PRINCIPAL FINDINGS: Small mammals were trapped, euthanized, and sampled. Mammarenavirus RNA was detected using a nested reverse transcription polymerase chain reaction (RT-PCR) and quantified by real-time RT-PCR. A total of 1040 small mammals belonging to 13 genera and 26 species were trapped in Yunnan Province. WENV-related mammarenaviruses were detected in 41 rodent liver samples, mainly in brown rats (Rattus norvegicus) and oriental house rats (R. tanezumi).Viral nucleocapsid protein was detected in liver sections by indirect immunofluorescence assay. Full-length-genomes were amplified by RT-PCR and used for phylogenetic analysis with the MEGA package. Recombination analysis was performed using the SimPlot and Recombination Detection Program. CONCLUSIONS/SIGNIFICANCE: WENV related viruses circulated in small mammals in Yunnan Province. Whole genome sequence analysis of five selected viral strains showed that these viruses are closely related to WENVs discovered in Asia and form an independent branch in the phylogenetic tree in the WENV clade. Paying attention to investigate the influence of these viruses to public health is essential in the epidemic regions.


Assuntos
Arenaviridae/isolamento & purificação , Roedores/virologia , Animais , Arenaviridae/genética , China , Genoma Viral , Filogenia , Reação em Cadeia da Polimerase
10.
Arch Virol ; 164(3): 927-941, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30663021

RESUMO

In October 2018, the order Bunyavirales was amended by inclusion of the family Arenaviridae, abolishment of three families, creation of three new families, 19 new genera, and 14 new species, and renaming of three genera and 22 species. This article presents the updated taxonomy of the order Bunyavirales as now accepted by the International Committee on Taxonomy of Viruses (ICTV).


Assuntos
Arenaviridae/classificação , Animais , Arenaviridae/genética , Arenaviridae/isolamento & purificação , Infecções por Arenaviridae/virologia , Humanos , Filogenia
11.
Clin Microbiol Infect ; 21S: e17-e27, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24690109

RESUMO

Viral haemorrhagic fever can be caused by one of a diverse group of viruses that come from four different families of RNA viruses. Disease severity can vary from mild self-limiting febrile illness to severe disease characterized by high fever, high-level viraemia, increased vascular permeability that can progress to shock, multi-organ failure and death. Despite the urgent need, effective treatments and preventative vaccines are currently lacking for the majority of these viruses. A number of factors preclude the effective study of these diseases in humans including the high virulence of the agents involved, the sporadic nature of outbreaks of these viruses, which are typically in geographically isolated areas with underserviced diagnostic capabilities, and the requirements for high level bio-containment. As a result, animal models that accurately mimic human disease are essential for advancing our understanding of the pathogenesis of viral haemorrhagic fevers. Moreover, animal models for viral haemorrhagic fevers are necessary to test vaccines and therapeutic intervention strategies. Here, we present an overview of the animal models that have been established for each of the haemorrhagic fever viruses and identify which aspects of human disease are modelled. Furthermore, we discuss how experimental design considerations, such as choice of species and virus strain as well as route and dose of inoculation, have an influence on animal model development. We also bring attention to some of the pitfalls that need to be avoided when extrapolating results from animal models.


Assuntos
Modelos Animais de Doenças , Febres Hemorrágicas Virais/patologia , Febres Hemorrágicas Virais/virologia , Animais , Arenaviridae/classificação , Arenaviridae/patogenicidade , Bunyaviridae/classificação , Bunyaviridae/patogenicidade , Filoviridae/classificação , Filoviridae/patogenicidade , Flaviviridae/classificação , Flaviviridae/patogenicidade , Febres Hemorrágicas Virais/fisiopatologia , Humanos
12.
PLoS Pathog ; 14(11): e1007415, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30427944

RESUMO

The family Arenaviridae comprises three genera, Mammarenavirus, Reptarenavirus and the most recently added Hartmanivirus. Arenaviruses have a bisegmented genome with ambisense coding strategy. For mammarenaviruses and reptarenaviruses the L segment encodes the Z protein (ZP) and the RNA-dependent RNA polymerase, and the S segment encodes the glycoprotein precursor and the nucleoprotein. Herein we report the full length genome and characterization of Haartman Institute snake virus-1 (HISV-1), the putative type species of hartmaniviruses. The L segment of HISV-1 lacks an open-reading frame for ZP, and our analysis of purified HISV-1 particles by SDS-PAGE and electron microscopy further support the lack of ZP. Since we originally identified HISV-1 in co-infection with a reptarenavirus, one could hypothesize that co-infecting reptarenavirus provides the ZP to complement HISV-1. However, we observed that co-infection does not markedly affect the amount of hartmanivirus or reptarenavirus RNA released from infected cells in vitro, indicating that HISV-1 does not benefit from reptarenavirus ZP. Furthermore, we succeeded in generating a pure HISV-1 isolate showing the virus to replicate without ZP. Immunofluorescence and ultrastructural studies demonstrate that, unlike reptarenaviruses, HISV-1 does not produce the intracellular inclusion bodies typical for the reptarenavirus-induced boid inclusion body disease (BIBD). While we observed HISV-1 to be slightly cytopathic for cultured boid cells, the histological and immunohistological investigation of HISV-positive snakes showed no evidence of a pathological effect. The histological analyses also revealed that hartmaniviruses, unlike reptarenaviruses, have a limited tissue tropism. By nucleic acid sequencing, de novo genome assembly, and phylogenetic analyses we identified additional four hartmanivirus species. Finally, we screened 71 individuals from a collection of snakes with BIBD by RT-PCR and found 44 to carry hartmaniviruses. These findings suggest that harmaniviruses are common in captive snake populations, but their relevance and pathogenic potential needs yet to be revealed.


Assuntos
Arenavirus/classificação , Arenavirus/genética , Animais , Arenaviridae/genética , Infecções por Arenaviridae/virologia , Sequência de Bases , Boidae/virologia , Linhagem Celular , Corpos de Inclusão Viral/patologia , Filogenia , RNA Replicase/genética , RNA Viral/genética , Proteínas Virais/genética
13.
PLoS Pathog ; 14(11): e1007430, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30419076

RESUMO

Lassa virus (LASV) is responsible for a viral hemorrhagic fever in humans and the death of 3,000 to 5,000 people every year. The immune response to LASV is poorly understood, but type I interferon (IFN-I) and T-cell responses appear to be critical for the host. We studied the response of myeloid dendritic cells (mDC) to LASV, as mDCs are involved in both IFN-I production and T-cell activation. We compared the response of primary human mDCs to LASV and Mopeia virus (MOPV), which is similar to LASV, but non-pathogenic. We showed that mDCs produced substantial amounts of IFN-I in response to both LASV and MOPV. However, only MOPV-infected mDCs were able to activate T cells. More surprisingly, coculture with T cells completely inhibited the activation of LASV-infected mDCs. These differences between LASV and MOPV were mostly due to the LASV nucleoprotein, which has major immunosuppressive properties, but the glycoprotein was also involved. Overall, these results suggest that mDCs may be important for the global response to LASV and play a role in the outcome of Lassa fever.


Assuntos
Células Dendríticas/imunologia , Vírus Lassa/imunologia , Células Mieloides/imunologia , Antivirais , Arenaviridae/imunologia , Células Dendríticas/virologia , Voluntários Saudáveis , Febres Hemorrágicas Virais/virologia , Humanos , Interferon Tipo I , Interferon-alfa/metabolismo , Interferon beta/metabolismo , Febre Lassa/virologia , Vírus Lassa/patogenicidade , Ativação Linfocitária/imunologia , Ativação Linfocitária/fisiologia , Células Mieloides/virologia , Nucleoproteínas/metabolismo , Cultura Primária de Células , Linfócitos T/imunologia
14.
Infect Genet Evol ; 64: 212-218, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29966765

RESUMO

Reptarenaviruses, a genus of snake-infecting viruses belonging to the family Arenaviridae, have bi-segmented genomes. The long (L) segment encodes the Z and L (RNA polymerase) proteins, whereas the short (S) segment codes for the glycoprotein precursor (GPC) and for the nucleoprotein (NP). Presently, reptarenaviruses have only been described in captive snakes. In these animals, mixed infections are common and most infected reptiles harbor multiple S and/or L segment genotypes. Within single animals, L segments are more genetically diverse than S segments and one S segment genotype (S6) was detected in the majority of snakes. Whether the unbalanced L to S segment ratio is due to stochastic events, to distinct replication/packaging efficiencies, or to differential selective pressure is presently unknown. We addressed these open questions by analyzing the ancient and recent evolutionary history of reptarenavirus genomes. Results indicated that purifying selection shaped the bulk of reptarenavirus coding sequences, although selective constraint was stronger for NP and L compared to GPC. During the divergence of reptarenavirus genomes, episodic positive selection contributed to the evolution of the viral polymerase, an observation that parallels those on mammarenaviruses. Population genetics analyses indicated that the most common S and L segment genotypes (including S6) display markedly negative Tajima's D values, but not low nucleotide diversity, suggesting recent population expansion. In conclusion, our data indicate that the selective pressures were stronger for the L segment than for the S segment, at least during reptarenavirus genotype divergence. More recently, the population sizes of some L and S segment genotypes expanded, suggesting that they out-competed the other genotypes, which show D values consistent with constant or decreasing population size. Competition among segments may have driven the disappearance of some S segment genotypes from wild and/or captive snake populations, eventually leading to the observed L to S imbalance.


Assuntos
Arenaviridae/genética , Genes Virais , Genoma Viral , Genótipo , Seleção Genética , Arenaviridae/classificação , Variação Genética , Modelos Moleculares , Fases de Leitura Aberta , Filogenia , Conformação Proteica , Relação Estrutura-Atividade , Proteínas Virais/química , Proteínas Virais/genética
15.
J Virol ; 92(16)2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-29899092

RESUMO

Lassa virus (LASV) belongs to the Mammarenavirus genus (family Arenaviridae) and causes severe hemorrhagic fever in humans. At present, there are no Food and Drug Administration (FDA)-approved drugs or vaccines specific for LASV. Here, high-throughput screening of an FDA-approved drug library was performed against LASV entry by using pseudotype virus bearing LASV envelope glycoprotein (GPC). Two hit compounds, lacidipine and phenothrin, were identified as LASV entry inhibitors in the micromolar range. A mechanistic study revealed that both compounds inhibited LASV entry by blocking low-pH-induced membrane fusion. Accordingly, lacidipine showed virucidal effects on the pseudotype virus of LASV. Adaptive mutant analyses demonstrated that replacement of T40, located in the ectodomain of the stable-signal peptide (SSP), with lysine (K) conferred LASV resistance to lacidipine. Furthermore, lacidipine showed antiviral activity against LASV, the closely related Mopeia virus (MOPV), and the New World arenavirus Guanarito virus (GTOV). Drug-resistant variants indicated that V36M in the ectodomain of the SSP mutant and V436A in the transmembrane domain of the GP2 mutant conferred GTOV resistance to lacidipine, suggesting the interface between SSP and GP2 is the target of lacidipine. This study shows that lacidipine is a candidate for LASV therapy, reinforcing the notion that the SSP-GP2 interface provides an entry-targeted platform for arenavirus inhibitor design.IMPORTANCE Currently, there is no approved therapy to treat Lassa fever; therefore, repurposing of approved drugs will accelerate the development of a therapeutic stratagem. In this study, we screened an FDA-approved library of drugs and identified two compounds, lacidipine and phenothrin, which inhibited Lassa virus entry by blocking low-pH-induced membrane fusion. Additionally, both compounds extended their inhibition against the entry of Guanarito virus, and the viral targets were identified as the SSP-GP2 interface.


Assuntos
Antivirais/farmacologia , Di-Hidropiridinas/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Ensaios de Triagem em Larga Escala/métodos , Vírus Lassa/efeitos dos fármacos , Piretrinas/farmacologia , Internalização do Vírus/efeitos dos fármacos , Arenaviridae/efeitos dos fármacos , Arenavirus do Novo Mundo/efeitos dos fármacos , Análise Mutacional de DNA , Farmacorresistência Viral , Vírus Lassa/fisiologia
16.
Arch Virol ; 163(8): 2295-2310, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29680923

RESUMO

In 2018, the family Arenaviridae was expanded by inclusion of 1 new genus and 5 novel species. At the same time, the recently established order Bunyavirales was expanded by 3 species. This article presents the updated taxonomy of the family Arenaviridae and the order Bunyavirales as now accepted by the International Committee on Taxonomy of Viruses (ICTV) and summarizes additional taxonomic proposals that may affect the order in the near future.


Assuntos
Arenaviridae/classificação , Animais , Arenaviridae/genética , Arenaviridae/isolamento & purificação , Infecções por Arenaviridae/veterinária , Infecções por Arenaviridae/virologia , Humanos , Filogenia
17.
Genome Biol Evol ; 10(3): 863-874, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29608723

RESUMO

The Mammarenavirus genus includes several pathogenic species of rodent-borne viruses. Old World (OW) mammarenaviruses infect rodents in the Murinae subfamily and are mainly transmitted in Africa and Asia; New World (NW) mammarenaviruses are found in rodents of the Cricetidae subfamily in the Americas. We applied a selection-informed method to estimate that OW and NW mammarenaviruses diverged less than ∼45,000 years ago (ya). By incorporating phylogeographic inference, we show that NW mammarenaviruses emerged in the Latin America-Caribbean region ∼41,400-3,300 ya, whereas OW mammarenaviruses originated ∼23,100-1,880 ya, most likely in Southern Africa. Cophylogenetic analysis indicated that cospeciation did not contribute significantly to mammarenavirus-host associations. Finally, we show that extremely strong selective pressure on the viral polymerase accompanied the speciation of NW viruses. These data suggest that the evolutionary history of mammarenaviruses was not driven by codivergence with their hosts. The viral polymerase should be regarded as a major determinant of mammarenavirus adaptation.


Assuntos
Arenaviridae/genética , Interações Hospedeiro-Patógeno/genética , Murinae/virologia , Filogeografia , Aclimatação/genética , África , Animais , Arenaviridae/patogenicidade , América Latina , Murinae/genética
18.
J Virol ; 92(12)2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29593043

RESUMO

Several Old World and New World arenaviruses are responsible for severe endemic and epidemic hemorrhagic fevers, whereas other members of the Arenaviridae family are nonpathogenic. To date, no approved vaccines, antivirals, or specific treatments are available, except for Junín virus. However, protection of nonhuman primates against Lassa fever virus (LASV) is possible through the inoculation of the closely related but nonpathogenic Mopeia virus (MOPV) before challenge with LASV. We reasoned that this virus, modified by using reverse genetics, would represent the basis for the generation of a vaccine platform against LASV and other pathogenic arenaviruses. After showing evidence of exoribonuclease (ExoN) activity in NP of MOPV, we found that this activity was essential for multiplication in antigen-presenting cells. The introduction of multiple mutations in the ExoN site of MOPV NP generated a hyperattenuated strain (MOPVExoN6b) that is (i) genetically stable over passages, (ii) has increased immunogenic properties compared to those of MOPV, and (iii) still promotes a strong type I interferon (IFN) response. MOPVExoN6b was further modified to harbor the envelope glycoproteins of heterologous pathogenic arenaviruses, such as LASV or Lujo, Machupo, Guanarito, Chapare, or Sabia virus in order to broaden specific antigenicity while preserving the hyperattenuated characteristics of the parental strain. Our MOPV-based vaccine candidate for LASV, MOPEVACLASV, was used in a one-shot immunization assay in nonhuman primates and fully protected them from a lethal challenge with LASV. Thus, our hyperattenuated strain of MOPV constitutes a promising new live-attenuated vaccine platform to immunize against several, if not all, pathogenic arenaviruses.IMPORTANCE Arenaviruses are emerging pathogens transmitted to humans by rodents and responsible for endemic and epidemic hemorrhagic fevers of global concern. Nonspecific symptoms associated with the onset of infection make these viruses difficult to distinguish from other endemic pathogens. Moreover, the unavailability of rapid diagnosis in the field delays the identification of the virus and early care for treatment and favors spreading. The vaccination of exposed populations would be of great help to decrease morbidity and human-to-human transmission. Using reverse genetics, we generated a vaccine platform for pathogenic arenaviruses based on a modified and hyperattenuated strain of the nonpathogenic Mopeia virus and showed that the Lassa virus candidate fully protected nonhuman primates from a lethal challenge. These results showed that a rationally designed recombinant MOPV-based vaccine is safe, immunogenic, and efficacious in nonhuman primates.


Assuntos
Arenaviridae/imunologia , Febres Hemorrágicas Virais/imunologia , Febre Lassa/imunologia , Vírus Lassa/imunologia , Doenças dos Macacos/imunologia , Doenças dos Macacos/prevenção & controle , Vacinas Atenuadas/imunologia , Vacinas Virais/imunologia , Animais , Arenaviridae/genética , Linhagem Celular , Chlorocebus aethiops , Cricetinae , Exorribonucleases/metabolismo , Células HEK293 , Febres Hemorrágicas Virais/patologia , Febres Hemorrágicas Virais/transmissão , Febres Hemorrágicas Virais/virologia , Humanos , Interferon Tipo I/imunologia , Febre Lassa/prevenção & controle , Febre Lassa/virologia , Macaca fascicularis , Doenças dos Macacos/virologia , Vacinação , Células Vero
19.
Virology ; 518: 34-44, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29453057

RESUMO

Mammarenaviruses bud out of infected cells via the recruitment of the endosomal sorting complex required for transport through late domain motifs localized into their Z protein. Here, we demonstrated that mammarenaviruses lacking this protein can be rescued and are replicative, despite a 3-log reduction in virion production, in BHK-21 cells, but not in five other cell lines. Mutations of putative late domain motifs identified into the viral nucleoprotein resulted in the almost complete abolition of infectious virion production by Z-deleted mammarenaviruses. This result strongly suggested that the nucleoprotein may compensate for the deletion of Z. These observations were primarily obtained using the Lymphocytic choriomeningitis virus, and further confirmed using the Old World Lassa and New World Machupo viruses, responsible of human hemorrhagic fevers. Z-deleted viruses should prove very useful tools to investigate the biology of Mammarenaviruses.


Assuntos
Arenaviridae/genética , Regulação Viral da Expressão Gênica/fisiologia , Replicação Viral/genética , Replicação Viral/fisiologia , Animais , Linhagem Celular , Chlorocebus aethiops , Cricetinae , Células Vero , Proteínas Virais/genética , Proteínas Virais/metabolismo
20.
PLoS Pathog ; 14(2): e1006892, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29462184

RESUMO

Several mammalian arenaviruses (mammarenaviruses) cause hemorrhagic fevers in humans and pose serious public health concerns in their endemic regions. Additionally, mounting evidence indicates that the worldwide-distributed, prototypic mammarenavirus, lymphocytic choriomeningitis virus (LCMV), is a neglected human pathogen of clinical significance. Concerns about human-pathogenic mammarenaviruses are exacerbated by of the lack of licensed vaccines, and current anti-mammarenavirus therapy is limited to off-label use of ribavirin that is only partially effective. Detailed understanding of virus/host-cell interactions may facilitate the development of novel anti-mammarenavirus strategies by targeting components of the host-cell machinery that are required for efficient virus multiplication. Here we document the generation of a recombinant LCMV encoding a nucleoprotein (NP) containing an affinity tag (rLCMV/Strep-NP) and its use to capture the NP-interactome in infected cells. Our proteomic approach combined with genetics and pharmacological validation assays identified ATPase Na+/K+ transporting subunit alpha 1 (ATP1A1) and prohibitin (PHB) as pro-viral factors. Cell-based assays revealed that ATP1A1 and PHB are involved in different steps of the virus life cycle. Accordingly, we observed a synergistic inhibitory effect on LCMV multiplication with a combination of ATP1A1 and PHB inhibitors. We show that ATP1A1 inhibitors suppress multiplication of Lassa virus and Candid#1, a live-attenuated vaccine strain of Junín virus, suggesting that the requirement of ATP1A1 in virus multiplication is conserved among genetically distantly related mammarenaviruses. Our findings suggest that clinically approved inhibitors of ATP1A1, like digoxin, could be repurposed to treat infections by mammarenaviruses pathogenic for humans.


Assuntos
Coriomeningite Linfocítica/metabolismo , Vírus da Coriomeningite Linfocítica/metabolismo , Nucleoproteínas/metabolismo , Mapas de Interação de Proteínas , Proteoma/análise , Proteínas Repressoras/fisiologia , ATPase Trocadora de Sódio-Potássio/fisiologia , Células A549 , Animais , Arenaviridae/fisiologia , Células Cultivadas , Chlorocebus aethiops , Cricetinae , Células HEK293 , Interações Hospedeiro-Patógeno , Humanos , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/fisiologia , Camundongos , Ligação Proteica , Proteínas Repressoras/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Células Vero
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