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1.
Virus Genes ; 56(2): 150-167, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32076918

RESUMO

The viruses historically implicated or currently considered as candidates for misuse in bioterrorist events are poxviruses, filoviruses, bunyaviruses, orthomyxoviruses, paramyxoviruses and a number of arboviruses causing encephalitis, including alpha- and flaviviruses. All these viruses are of concern for public health services when they occur in natural outbreaks or emerge in unvaccinated populations. Recent events and intelligence reports point to a growing risk of dangerous biological agents being used for nefarious purposes. Public health responses effective in natural outbreaks of infectious disease may not be sufficient to deal with the severe consequences of a deliberate release of such agents. One important aspect of countermeasures against viral biothreat agents are the antiviral treatment options available for use in post-exposure prophylaxis. These issues were adressed by the organizers of the 16th Medical Biodefense Conference, held in Munich in 2018, in a special session on the development of drugs to treat infections with viruses currently perceived as a threat to societies or associated with a potential for misuse as biothreat agents. This review will outline the state-of-the-art methods in antivirals research discussed and provide an overview of antiviral compounds in the pipeline that are already approved for use or still under development.


Assuntos
Antivirais/uso terapêutico , Arbovirus/efeitos dos fármacos , Bioterrorismo/prevenção & controle , Viroses/tratamento farmacológico , Arbovirus/patogenicidade , Filoviridae/efeitos dos fármacos , Filoviridae/patogenicidade , Humanos , Orthobunyavirus/efeitos dos fármacos , Orthobunyavirus/patogenicidade , Orthomyxoviridae/efeitos dos fármacos , Orthomyxoviridae/patogenicidade , Paramyxovirinae/efeitos dos fármacos , Paramyxovirinae/patogenicidade , Poxviridae/efeitos dos fármacos , Poxviridae/patogenicidade , Viroses/virologia
2.
Proc Natl Acad Sci U S A ; 117(9): 4931-4941, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32075920

RESUMO

Paramyxoviruses are enveloped, nonsegmented, negative-strand RNA viruses that cause a wide spectrum of human and animal diseases. The viral genome, packaged by the nucleoprotein (N), serves as a template for the polymerase complex, composed of the large protein (L) and the homo-tetrameric phosphoprotein (P). The ∼250-kDa L possesses all enzymatic activities necessary for its function but requires P in vivo. Structural information is available for individual P domains from different paramyxoviruses, but how P interacts with L and how that affects the activity of L is largely unknown due to the lack of high-resolution structures of this complex in this viral family. In this study we determined the structure of the L-P complex from parainfluenza virus 5 (PIV5) at 4.3-Šresolution using cryoelectron microscopy, as well as the oligomerization domain (OD) of P at 1.4-Šresolution using X-ray crystallography. P-OD associates with the RNA-dependent RNA polymerase domain of L and protrudes away from it, while the X domain of one chain of P is bound near the L nucleotide entry site. The methyltransferase (MTase) domain and the C-terminal domain (CTD) of L adopt a unique conformation, positioning the MTase active site immediately above the poly-ribonucleotidyltransferase domain and near the likely exit site for the product RNA 5' end. Our study reveals a potential mechanism that mononegavirus polymerases may employ to switch between transcription and genome replication. This knowledge will assist in the design and development of antivirals against paramyxoviruses.


Assuntos
Metiltransferases/química , Metiltransferases/metabolismo , Paramyxovirinae/enzimologia , Proteínas Virais/química , Proteínas Virais/metabolismo , Domínio Catalítico , Microscopia Crioeletrônica , Cristalografia por Raios X , Genoma Viral , Metiltransferases/genética , Modelos Moleculares , Nucleoproteínas/química , Vírus da Parainfluenza 5/química , Paramyxovirinae/genética , Fosfoproteínas/química , Ligação Proteica , Conformação Proteica , Domínios Proteicos
3.
J Virol ; 94(6)2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-31896588

RESUMO

Influenza viruses are highly infectious and are the leading cause of human respiratory diseases and may trigger severe epidemics and occasional pandemics. Although antiviral drugs against influenza viruses have been developed, there is an urgent need to design new strategies to develop influenza virus inhibitors due to the increasing resistance of viruses toward currently available drugs. In this study, we examined the antiviral activity of natural compounds against the following influenza virus strains: A/WSN/33 (H1N1), A/Udorn/72 (H3N2), and B/Lee/40. Papaverine (a nonnarcotic alkaloid that has been used for the treatment of heart disease, impotency, and psychosis) was found to be an effective inhibitor of multiple strains of influenza virus. Kinetic studies demonstrated that papaverine inhibited influenza virus infection at a late stage in the virus life cycle. An alteration in influenza virus morphology and viral ribonucleoprotein (vRNP) localization was observed as an effect of papaverine treatment. Papaverine is a well-known phosphodiesterase inhibitor and also modifies the mitogen-activated protein kinase (MAPK) pathway by downregulating the phosphorylation of MEK and extracellular signal-regulated kinase (ERK). Thus, the modulation of host cell signaling pathways by papaverine may be associated with the nuclear retention of vRNPs and the reduction of influenza virus titers. Interestingly, papaverine also inhibited paramyxoviruses parainfluenza virus 5 (PIV5), human parainfluenza virus 3 (HPIV3), and respiratory syncytial virus (RSV) infections. We propose that papaverine can be a potential candidate to be used as an antiviral agent against a broad range of influenza viruses and paramyxoviruses.IMPORTANCE Influenza viruses are important human pathogens that are the causative agents of epidemics and pandemics. Despite the availability of an annual vaccine, a large number of cases occur every year globally. Here, we report that papaverine, a vasodilator, shows inhibitory action against various strains of influenza virus as well as the paramyxoviruses PIV5, HPIV3, and RSV. A significant effect of papaverine on the influenza virus morphology was observed. Papaverine treatment of influenza-virus-infected cells resulted in the inhibition of virus at a later time in the virus life cycle through the suppression of nuclear export of vRNP and also interfered with the host cellular cAMP and MEK/ERK cascade pathways. This study explores the use of papaverine as an effective inhibitor of both influenza viruses as well as paramyxoviruses.


Assuntos
Antivirais/farmacologia , Reposicionamento de Medicamentos , Infecções por Orthomyxoviridae , Orthomyxoviridae/metabolismo , Papaverina/farmacologia , Infecções por Paramyxoviridae , Paramyxovirinae/metabolismo , Animais , Cães , Avaliação Pré-Clínica de Medicamentos , Células HEK293 , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células Madin Darby de Rim Canino , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/metabolismo , Infecções por Orthomyxoviridae/patologia , Infecções por Paramyxoviridae/metabolismo , Infecções por Paramyxoviridae/patologia
4.
Viruses ; 11(12)2019 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-31847282

RESUMO

Bats are known reservoirs of a wide variety of viruses that rarely result in overt clinical disease in the bat host. However, anthropogenic influences on the landscape and climate can change species assemblages and interactions, as well as undermine host-resilience. The cumulative result is a disturbance of bat-pathogen dynamics, which facilitate spillover events to sympatric species, and may threaten bat communities already facing synergistic stressors through ecological change. Therefore, characterisation of viral pathogens in bat communities provides important basal information to monitor and predict the emergence of diseases relevant to conservation and public health. This study used targeted molecular techniques, serological assays and next generation sequencing to characterise adenoviruses, coronaviruses and paramyxoviruses from 11 species of insectivorous bats within the South West Botanical Province of Western Australia. Phylogenetic analysis indicated complex ecological interactions including virus-host associations, cross-species infections, and multiple viral strains circulating concurrently within selected bat populations. Additionally, we describe the entire coding sequences for five alphacoronaviruses (representing four putative new species), and one novel adenovirus. Results indicate that viral burden (both prevalence and richness) is not homogeneous among species, with Chalinolobus gouldii identified as a key epidemiological element within the studied communities.


Assuntos
Biodiversidade , Quirópteros/virologia , Adenoviridae/classificação , Adenoviridae/genética , Adenoviridae/imunologia , Adenoviridae/isolamento & purificação , Animais , Quirópteros/classificação , Coronavirus/classificação , Coronavirus/genética , Coronavirus/imunologia , Coronavirus/isolamento & purificação , Fezes/virologia , Comportamento Alimentar , Genoma Viral/genética , Paramyxovirinae/classificação , Paramyxovirinae/genética , Paramyxovirinae/imunologia , Paramyxovirinae/isolamento & purificação , Filogenia , Análise de Sequência , Estudos Soroepidemiológicos , Especificidade da Espécie , Proteínas Virais/genética , Proteínas Virais/imunologia , Austrália Ocidental/epidemiologia
5.
Eur J Clin Microbiol Infect Dis ; 38(12): 2355-2364, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31489496

RESUMO

To investigate the features of paramyxovirus respiratory syncytial virus (RSV), parainfluenza virus (PIV), and human metapneumovirus (HMPV) infection and determine the effect of meteorological conditions in Guangzhou, a subtropical region of southern China. We collected 11,398 respiratory samples from hospitalized pediatric patients with acute respiratory illness between July 2009 and June 2016 in Guangzhou. The samples were tested simultaneously for 18 respiratory pathogens using real-time PCR. Local meteorological data were also collected for correlation analysis. Of 11,398 patients tested, 5606 (49.2%) patients tested positive for one or more pathogens; RSV, PIV, and HMPV were the first, sixth, and ninth most frequently detected pathogens, in 1690 (14.8%), 502 (4.4%), and 321 (2.8%) patients, respectively. A total 17.9% (4605/5606) of patients with positive results had coinfection with other pathogens. Significant differences were found in the prevalence of RSV, PIV, and HMPV among all age groups (p < 0.001). RSV and HMPV had similar seasonal patterns, with two prevalence peaks every year. PIV appeared alternatively with RSV and HMPV. Multiple linear regression models were established for RSV, PIV, and HMPV prevalence and meteorological factors (p < 0.05). RSV and PIV incidence was negatively correlated with monthly mean relative humidity; RSV and HMPV incidence was negatively correlated with sunshine duration; PIV incidence was positively correlated with mean temperature. We described the features of paramyxovirus infection in a subtropical region of China and highlighted the correlation with meteorological factors. These findings will assist public health authorities and clinicians in improving strategies for controlling paramyxovirus infection.


Assuntos
Infecções por Paramyxoviridae/epidemiologia , Infecções por Paramyxoviridae/virologia , Paramyxoviridae/isolamento & purificação , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/virologia , Adolescente , Distribuição por Idade , Criança , Pré-Escolar , China/epidemiologia , Clima , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Metapneumovirus/isolamento & purificação , Conceitos Meteorológicos , Paramyxovirinae/isolamento & purificação , Prevalência , Vírus Sincicial Respiratório Humano/isolamento & purificação , Estações do Ano
6.
Emerg Microbes Infect ; 8(1): 1314-1323, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31495335

RESUMO

Within host-parasite communities, viral co-circulation and co-infections of hosts are the norm, yet studies of significant emerging zoonoses tend to focus on a single parasite species within the host. Using a multiplexed paramyxovirus bead-based PCR on urine samples from Australian flying foxes, we show that multi-viral shedding from flying fox populations is common. We detected up to nine bat paramyxoviruses shed synchronously. Multi-viral shedding infrequently coalesced into an extreme, brief and spatially restricted shedding pulse, coinciding with peak spillover of Hendra virus, an emerging fatal zoonotic pathogen of high interest. Such extreme pulses of multi-viral shedding could easily be missed during routine surveillance yet have potentially serious consequences for spillover of novel pathogens to humans and domestic animal hosts. We also detected co-occurrence patterns suggestive of the presence of interactions among viruses, such as facilitation and cross-immunity. We propose that multiple viruses may be interacting, influencing the shedding and spillover of zoonotic pathogens. Understanding these interactions in the context of broader scale drivers, such as habitat loss, may help predict shedding pulses of Hendra virus and other fatal zoonoses.


Assuntos
Coinfecção/veterinária , Transmissão de Doença Infecciosa , Infecções por Paramyxoviridae/veterinária , Paramyxovirinae/isolamento & purificação , Urina/virologia , Eliminação de Partículas Virais , Zoonoses/virologia , Animais , Quirópteros , Coinfecção/transmissão , Coinfecção/virologia , Infecções por Paramyxoviridae/transmissão , Infecções por Paramyxoviridae/virologia , Paramyxovirinae/classificação , Zoonoses/transmissão
7.
J Gen Virol ; 100(3): 403-413, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30688635

RESUMO

Bats are the reservoir hosts for multiple viruses with zoonotic potential, including coronaviruses, paramyxoviruses and filoviruses. Urine collected from Australian pteropid bats was assessed for the presence of paramyxoviruses. One of the viruses isolated was Teviot virus (TevPV), a novel rubulavirus previously isolated from pteropid bat urine throughout the east coast of Australia. Here, we further characterize TevPV through analysis of whole-genome sequencing, growth kinetics, antigenic relatedness and the experimental infection of ferrets and mice. TevPV is phylogenetically and antigenically most closely related to Tioman virus (TioPV). Unlike many other rubulaviruses, cell receptor attachment by TevPV does not appear to be sialic acid-dependent, with the receptor for host cell entry being unknown. The infection of ferrets and mice suggested that TevPV has a low pathogenic potential in mammals. Infected ferrets seroconverted by 10 days post-infection without clinical signs of disease. Furthermore, infected ferrets did not shed virus in any respiratory secretions, suggesting a low risk of onward transmission of TevPV. No productive infection was observed in the mouse infection study.


Assuntos
Quirópteros/virologia , Infecções por Paramyxoviridae/veterinária , Paramyxovirinae/isolamento & purificação , Animais , Austrália , Furões , Genoma Viral , Camundongos , Infecções por Paramyxoviridae/virologia , Paramyxovirinae/genética , Paramyxovirinae/patogenicidade , Paramyxovirinae/fisiologia , Filogenia , Virulência
8.
BMC Genomics ; 19(1): 617, 2018 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-30115009

RESUMO

BACKGROUND: In the past decade, many new paramyxoviruses that do not belong to any of the seven established genera in the family Paramyxoviridae have been discovered. Amongst them are J-virus (JPV), Beilong virus (BeiPV) and Tailam virus (TlmPV), three paramyxovirus species found in rodents. Based on their similarities, it has been suggested that these viruses should compose a new genus, tentatively called 'Jeilongvirus'. RESULTS: Here we present the complete genomes of three newly discovered paramyxoviruses, one found in a bank vole (Myodes glareolus) from Slovenia and two in a single, co-infected Rungwe brush-furred rat (Lophuromys machangui) from Mozambique, that represent three new, separate species within the putative genus 'Jeilongvirus'. The genome organization of these viruses is similar to other paramyxoviruses, but like JPV, BeiPV and TlmPV, they possess an additional open reading frame, encoding a transmembrane protein, that is located between the F and G genes. As is the case for all Jeilongviruses, the G genes of the viruses described here are unusually large, and their encoded proteins are characterized by a remarkable amino acid composition pattern that is not seen in other paramyxoviruses, but resembles certain motifs found in Orthopneumovirus G proteins. CONCLUSIONS: The phylogenetic clustering of JPV, BeiPV and TlmPV with the viruses described here, as well as their shared features that set them apart from other paramyxoviruses, provide additional support for the recognition of the genus 'Jeilongvirus'.


Assuntos
Genoma Viral , Proteínas de Membrana/genética , Paramyxovirinae/classificação , Paramyxovirinae/genética , Proteínas Virais/genética , Sequência de Aminoácidos , Animais , Clonagem Molecular , Paramyxoviridae/classificação , Paramyxoviridae/genética , Filogenia , Análise de Sequência de DNA
9.
PLoS One ; 13(2): e0191933, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29390028

RESUMO

In 2011, an unusually large number of independent Hendra virus outbreaks were recorded on horse properties in Queensland and New South Wales, Australia. Urine from bat colonies adjacent to the outbreak sites were sampled and screened for Hendra and other viruses. Several novel paramyxoviruses were also isolated at different locations. Here one of the novel viruses, named Hervey virus (HerPV), is fully characterized by genome sequencing, annotation, phylogeny and in vitro host range, and its serological cross-reactivity and neutralization patterns are examined. HerPV may have ecological and spatial and temporal patterns similar to Hendra virus and could serve as a sentinel virus for the surveillance of this highly pathogenic virus. The suitability of HerPV as potential sentinel virus is further assessed by determining the serological prevalence of HerPV antibodies in fruit-eating bats from Australia, Indonesia, Papua New Guinea, Tanzania and the Gulf of Guinea, indicating the presence of similar viruses in regions beyond the Australian border.


Assuntos
Quirópteros/virologia , Henipavirus/isolamento & purificação , Paramyxovirinae/isolamento & purificação , África/epidemiologia , Animais , Anticorpos Antivirais/imunologia , Austrália/epidemiologia , Linhagem Celular , Surtos de Doenças , Henipavirus/genética , Henipavirus/imunologia , Infecções por Henipavirus/epidemiologia , Infecções por Henipavirus/virologia , Sequenciamento de Nucleotídeos em Larga Escala , Indonésia/epidemiologia , Microscopia Confocal , Testes de Neutralização , Papua Nova Guiné/epidemiologia , Paramyxovirinae/genética , Paramyxovirinae/imunologia
10.
PLoS Pathog ; 14(2): e1006889, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29425244

RESUMO

Paramyxoviruses represent a family of RNA viruses causing significant human diseases. These include measles virus, the most infectious virus ever reported, in addition to parainfluenza virus, and other emerging viruses. Paramyxoviruses likely share common replication machinery but their mechanisms of RNA biosynthesis activities and details of their complex polymerase structures are unknown. Mechanistic and functional details of a paramyxovirus polymerase would have sweeping implications for understanding RNA virus replication and for the development of new antiviral medicines. To study paramyxovirus polymerase structure and function, we expressed an active recombinant Nipah virus (NiV) polymerase complex assembled from the multifunctional NiV L protein bound to its phosphoprotein cofactor. NiV is an emerging highly pathogenic virus that causes severe encephalitis and has been declared a global public health concern due to its high mortality rate. Using negative-stain electron microscopy, we demonstrated NiV polymerase forms ring-like particles resembling related RNA polymerases. We identified conserved sequence elements driving recognition of the 3'-terminal genomic promoter by NiV polymerase, and leading to initiation of RNA synthesis, primer extension, and transition to elongation mode. Polyadenylation resulting from NiV polymerase stuttering provides a mechanistic basis for transcription termination. It also suggests a divergent adaptation in promoter recognition between pneumo- and paramyxoviruses. The lack of available antiviral therapy for NiV prompted us to identify the triphosphate forms of R1479 and GS-5734, two clinically relevant nucleotide analogs, as substrates and inhibitors of NiV polymerase activity by delayed chain termination. Overall, these findings provide low-resolution structural details and the mechanism of an RNA polymerase from a previously uncharacterized virus family. This work illustrates important functional differences yet remarkable similarities between the polymerases of nonsegmented negative-strand RNA viruses.


Assuntos
RNA Polimerases Dirigidas por DNA/metabolismo , Vírus Nipah/genética , Fosfoproteínas/metabolismo , Elongação da Transcrição Genética , Iniciação da Transcrição Genética , Terminação da Transcrição Genética , Proteínas Virais/metabolismo , Sequência de Aminoácidos , RNA Polimerases Dirigidas por DNA/química , RNA Polimerases Dirigidas por DNA/genética , Vírus Nipah/enzimologia , Paramyxovirinae/enzimologia , Paramyxovirinae/genética , Paramyxovirinae/metabolismo , Fosfoproteínas/química , Fosfoproteínas/genética , RNA Viral/genética , RNA Viral/metabolismo , Proteínas Virais/química , Proteínas Virais/genética , Replicação Viral
11.
Viral Immunol ; 31(2): 133-141, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29323621

RESUMO

Human parainfluenza viruses (family Paramyxoviridae), human metapneumovirus, and respiratory syncytial virus (family Pneumoviridae) infect most infants and children within the first few years of life and are the etiologic agents for many serious acute respiratory illnesses. These virus infections are also associated with long-term diseases that impact quality of life, including asthma. Despite over a half-century of vaccine research, development, and clinical trials, no vaccine has been licensed to date for the paramyxoviruses or pneumoviruses for the youngest infants. In this study, we describe the recent reclassification of paramyxoviruses and pneumoviruses into distinct families by the International Committee on the Taxonomy of Viruses. We also discuss some past unsuccessful vaccine trials and some currently preferred vaccine strategies. Finally, we discuss hurdles that must be overcome to support successful respiratory virus vaccine development for the youngest children.


Assuntos
Descoberta de Drogas/tendências , Infecções por Paramyxoviridae/prevenção & controle , Paramyxovirinae/imunologia , Pneumovirinae/imunologia , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vacinas Virais/imunologia , Vacinas Virais/isolamento & purificação , Animais , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos , Infecções por Paramyxoviridae/epidemiologia , Paramyxovirinae/classificação , Pneumovirinae/classificação , Infecções por Vírus Respiratório Sincicial/epidemiologia
12.
PLoS Pathog ; 14(1): e1006877, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29381763

RESUMO

The interferon (IFN) system represents the first line of defense against a wide range of viruses. Virus infection rapidly triggers the transcriptional induction of IFN-ß and IFN Stimulated Genes (ISGs), whose protein products act as viral restriction factors by interfering with specific stages of virus life cycle, such as entry, transcription, translation, genome replication, assembly and egress. Here, we report a new mode of action of an ISG, IFN-induced TDRD7 (tudor domain containing 7) inhibited paramyxovirus replication by inhibiting autophagy. TDRD7 was identified as an antiviral gene by a high throughput screen of an ISG shRNA library for blocking IFN's protective effect against Sendai virus (SeV) replication. The antiviral activity of TDRD7 against SeV, human parainfluenza virus 3 and respiratory syncytial virus was confirmed by its genetic ablation or ectopic expression in several types of mouse and human cells. TDRD7's antiviral action was mediated by its ability to inhibit autophagy, a cellular catabolic process which was robustly induced by SeV infection and required for its replication. Mechanistic investigation revealed that TDRD7 interfered with the activation of AMP-dependent kinase (AMPK), an enzyme required for initiating autophagy. AMPK activity was required for efficient replication of several paramyxoviruses, as demonstrated by its genetic ablation or inhibition of its activity by TDRD7 or chemical inhibitors. Therefore, our study has identified a new antiviral ISG with a new mode of action.


Assuntos
Antivirais/farmacologia , Autofagia , Interferons/farmacologia , Paramyxovirinae/fisiologia , Ribonucleoproteínas/fisiologia , Replicação Viral/efeitos dos fármacos , Animais , Autofagia/genética , Autofagia/imunologia , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Células HeLa , Humanos , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/genética , Camundongos , Camundongos Endogâmicos C57BL , Ribonucleoproteínas/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Replicação Viral/genética
13.
J Emerg Med ; 54(2): 207-214, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29110978

RESUMO

BACKGROUND: Mumps is a Paramyxoviridae virus. This disease was rampant prior to introduction of the measles, mumps, and rubella vaccine, resulting in decreased incidence. This disease has demonstrated several outbreaks. OBJECTIVE: This review provides a focused evaluation of mumps, an update on outbreaks, management recommendations, and ways to decrease transmission. DISCUSSION: Clusters of mumps outbreaks continue to occur. The virus is a paramyxovirus, a single-stranded RNA virus. The vaccine can provide lifelong immunity if administered properly, though prior to 1967 and introduction of the vaccine, the virus was common. In the past decade, there have been several notable outbreaks. Humans are the only known hosts, with disease spread through exposure to droplets and saliva. Factors affecting transmission include age, compromised immunity, time of year, travel, and vaccination status. Upper respiratory symptoms, fever, and headache are common, with unilateral or bilateral parotitis, and the virus may spread to other systems. Diagnosis is clinical, though polymerase chain reaction and immunoglobulin testing are available. This review provides several recommendations for vaccine in pregnancy, patients living in close quarters, health care personnel, and those immunocompromised. Treatment is generally supportive, with emphasis on proper isolation to prevent widespread outbreaks. Although reporting regulations and procedures vary by state, mumps is reportable in most states. CONCLUSIONS: Mumps is an easily spread virus. Although vaccination is the most effective way to prevent transmission, early recognition of the disease is crucial. As an emergency physician, it is important to recognize the clinical presentation, recommended testing, treatment, and isolation procedures.


Assuntos
Surtos de Doenças/prevenção & controle , Caxumba/terapia , Caxumba/virologia , Febre/etiologia , Humanos , Vacina contra Sarampo-Caxumba-Rubéola/efeitos adversos , Vacina contra Sarampo-Caxumba-Rubéola/uso terapêutico , Meningite/complicações , Meningite/etiologia , Caxumba/epidemiologia , Rigidez Muscular/etiologia , Paramyxovirinae/patogenicidade , Vacinação/métodos , Vacinação/tendências
14.
J Virol ; 92(5)2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29237836

RESUMO

Parainfluenza virus 5 (PIV5) belongs to the family Paramyxoviridae, which consists of enveloped viruses with a nonsegmented negative-strand RNA genome encapsidated by the nucleoprotein (N). Paramyxovirus replication is regulated by the phosphoprotein (P) through protein-protein interactions with N and the RNA polymerase (L). The chaperone activity of P is essential to maintain the unassembled RNA-free form of N in order to prevent nonspecific RNA binding and premature N oligomerization. Here, we determined the crystal structure of unassembled PIV5 N in complex with a P peptide (N0P) derived from the N terminus of P (P50) at 2.65 Å. The PIV5 N0P consists of two domains: an N-terminal domain (NTD) and a C-terminal domain (CTD) separated by a hinge region. The cleft at the hinge region of RNA-bound PIV5 N was previously shown to be an RNA binding site. The N0P structure shows that the P peptide binds to the CTD of N and extends toward the RNA binding site to inhibit N oligomerization and, hence, RNA binding. Binding of P peptide also keeps the PIV5 N in the open form. A molecular dynamics (MD) analysis of both the open and closed forms of N shows the flexibility of the CTD and the preference of the N protein to be in an open conformation. The gradual opening of the hinge region, to release the RNA, was also observed. Together, these results advance our knowledge of the conformational swapping of N required for the highly regulated paramyxovirus replication.IMPORTANCE Paramyxovirus replication is regulated by the interaction of P with N and L proteins. Here, we report the crystal structure of unassembled parainfluenza virus 5 (PIV5) N chaperoned with P peptide. Our results provide a detailed understanding of the binding of P to N. The conformational switching of N between closed and open forms during its initial interaction with P, as well as during RNA release, was analyzed. Our data also show the plasticity of the CTD and the importance of domain movement for conformational switching. The results improve our understanding of the mechanism of interchanging N conformations for RNA replication and release.


Assuntos
Nucleoproteínas/química , Vírus da Parainfluenza 5/química , Paramyxovirinae/química , Peptídeos/química , Fosfoproteínas/química , Sítios de Ligação , Cristalografia por Raios X , Modelos Moleculares , Nucleoproteínas/metabolismo , Peptídeos/metabolismo , Fosfoproteínas/metabolismo , Ligação Proteica , Conformação Proteica , Dobramento de Proteína , Domínios e Motivos de Interação entre Proteínas , RNA Viral/química , RNA Viral/metabolismo , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/metabolismo , Proteínas Virais/química , Proteínas Virais/metabolismo , Replicação Viral
15.
J Virol ; 92(5)2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29237838

RESUMO

One of the first defenses against infecting pathogens is the innate immune system activated by cellular recognition of pathogen-associated molecular patterns (PAMPs). Although virus-derived RNA species, especially copyback (cb)-type defective interfering (DI) genomes, have been shown to serve as real PAMPs, which strongly induce interferon-beta (IFN-ß) during mononegavirus infection, the mechanisms underlying DI generation remain unclear. Here, for the first time, we identified a single amino acid substitution causing production of cbDI genomes by successful isolation of two distinct types of viral clones with cbDI-producing and cbDI-nonproducing phenotypes from the stock Sendai virus (SeV) strain Cantell, which has been widely used in a number of studies on antiviral innate immunity as a representative IFN-ß-inducing virus. IFN-ß induction was totally dependent on the presence of a significant amount of cbDI genome-containing viral particles (DI particles) in the viral stock, but not on deficiency of the IFN-antagonistic viral accessory proteins C and V. Comparison of the isolates indicated that a single amino acid substitution found within the N protein of the cbDI-producing clone was enough to cause the emergence of DI genomes. The mutated N protein of the cbDI-producing clone resulted in a lower density of nucleocapsids than that of the DI-nonproducing clone, probably causing both production of the DI genomes and their formation of a stem-loop structure, which serves as an ideal ligand for RIG-I. These results suggested that the integrity of mononegaviral nucleocapsids might be a critical factor in avoiding the undesirable recognition of infection by host cells.IMPORTANCE The type I interferon (IFN) system is a pivotal defense against infecting RNA viruses that is activated by sensing viral RNA species. RIG-I is a major sensor for infection with most mononegaviruses, and copyback (cb)-type defective interfering (DI) genomes have been shown to serve as strong RIG-I ligands in real infections. However, the mechanism underlying production of cbDI genomes remains unclear, although DI genomes emerge as the result of an error during viral replication with high doses of viruses. Sendai virus has been extensively studied and is unique in that its interaction with innate immunity reveals opposing characteristics, such as high-level IFN-ß induction and strong inhibition of type I IFN pathways. Our findings provide novel insights into the mechanism of production of mononegaviral cbDI genomes, as well as virus-host interactions during innate immunity.


Assuntos
Substituição de Aminoácidos/imunologia , Vírus Defeituosos/genética , Interferon beta/metabolismo , Nucleoproteínas/imunologia , Paramyxovirinae/genética , Paramyxovirinae/imunologia , Vírus Sendai/genética , Substituição de Aminoácidos/genética , Animais , Linhagem Celular , Proteína DEAD-box 58 , Vírus Defeituosos/imunologia , Feminino , Regulação da Expressão Gênica , Genoma Viral , Células HeLa , Interações Hospedeiro-Parasita/genética , Interações Hospedeiro-Parasita/imunologia , Humanos , Imunidade Inata , Fator Regulador 3 de Interferon/análise , Interferon Tipo I/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Nucleocapsídeo/metabolismo , Nucleoproteínas/genética , Infecções por Paramyxoviridae/imunologia , Infecções por Paramyxoviridae/virologia , Padrões Moleculares Associados a Patógenos/imunologia , Padrões Moleculares Associados a Patógenos/metabolismo , RNA Viral/genética , Vírus Sendai/imunologia , Replicação Viral
16.
Molecules ; 22(7)2017 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-28714870

RESUMO

A set of lipopeptides was recently reported for their broad-spectrum antiviral activity against viruses belonging to the Paramyxoviridae family, including human parainfluenza virus type 3 and Nipah virus. Among them, the peptide with a 24-unit PEG linker connecting it to a cholesterol moiety (VG-PEG24-Chol) was found to be the best membrane fusion inhibitory peptide. Here, we evaluated the interaction of the same set of peptides with biomembrane model systems and isolated human peripheral blood mononuclear cells (PBMC). VG-PEG24-Chol showed the highest insertion rate and it was among the peptides that induced a larger change on the surface pressure of cholesterol rich membranes. This peptide also displayed a high affinity towards PBMC membranes. These data provide new information about the dynamics of peptide-membrane interactions of a specific group of antiviral peptides, known for their potential as multipotent paramyxovirus antivirals.


Assuntos
Antivirais/química , Membrana Celular/química , Lipopeptídeos/química , Polietilenoglicóis/química , Antivirais/metabolismo , Antivirais/farmacologia , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Colesterol/química , Humanos , Leucócitos Mononucleares/química , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/virologia , Bicamadas Lipídicas/química , Bicamadas Lipídicas/metabolismo , Lipopeptídeos/metabolismo , Lipopeptídeos/farmacologia , Lipossomos/química , Paramyxovirinae/química , Relação Estrutura-Atividade
17.
Appl Environ Microbiol ; 83(18)2017 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-28710271

RESUMO

Several infectious disease outbreaks with high mortality in humans have been attributed to viruses that are thought to have evolved from bat viruses. In this study from Luxembourg, the genetic diversity and epidemiology of paramyxoviruses and coronaviruses shed by the bat species Rhinolophus ferrumequinum and Myotis emarginatus were evaluated. Feces collection (n = 624) was performed longitudinally in a mixed-species colony in 2015 and 2016. In addition, feces (n = 254) were collected cross-sectionally from six Myotis emarginatus colonies in 2016. By use of degenerate primers in a nested format, overall prevalences of 1.1% (10/878) and 4.9% (43/878) were determined for paramyxoviruses and coronaviruses. Sequences of the partial RNA-dependent RNA polymerase and spike glycoprotein genes of coronaviruses, as well as sequences of the partial L gene of paramyxoviruses, were obtained. Novel paramyxovirus and Alphacoronavirus strains were identified in different Myotis emarginatus colonies, and severe acute respiratory syndrome (SARS)-related Betacoronavirus strains were shed by Rhinolophus ferrumequinum Logistic regression revealed that the level of Alphacoronavirus shedding was highest in July (odds ratio, 2.8; P < 0.01), probably due to periparturient stress. Phylogenetic analyses point to close virus-host coevolution, and the high genetic similarity of the study strains suggests that the Myotis emarginatus colonies in Luxembourg are socially connected. Most interestingly, we show that bats also host Betacoronavirus1 strains. The high similarity of the spike gene sequences of these viruses with mammalian Betacoronavirus 1 strains may be of concern. Both the SARS-related and Betacoronavirus 1 strains detected in bats in Luxembourg may cross the species barrier after a host adaptation process.IMPORTANCE Bats are a natural reservoir of a number of zoonotic pathogens. Several severe outbreaks in humans (e.g., a Nipah virus outbreak in Malaysia in 1998, and the almost global spread of severe acute respiratory syndrome in 2003) have been caused by bat-borne viruses that were transmitted to humans mostly after virus adaptation (e.g., in intermediate animal hosts). Despite the indigenousness of bat species that host viruses with suspected zoonotic potential and despite the zoonotic transmission of European bat 1 lyssavirus in Luxembourg, knowledge about the diversity and epidemiology of bat viruses remains limited in this country. Moreover, in contrast to other European countries, bat viruses are currently not included in the national surveillance activities of this land-locked country. We suggest that this gap in disease surveillance should be addressed, since we show here that synanthropic bats host viruses that may be able to cross the species barrier.


Assuntos
Alphacoronavirus/isolamento & purificação , Quirópteros/virologia , Paramyxovirinae/isolamento & purificação , Vírus da SARS/isolamento & purificação , Alphacoronavirus/classificação , Alphacoronavirus/genética , Animais , Quirópteros/classificação , Evolução Molecular , Variação Genética , Genoma Viral , Humanos , Luxemburgo , Paramyxovirinae/classificação , Paramyxovirinae/genética , Filogenia , Vírus da SARS/classificação , Vírus da SARS/genética
18.
Adv Virus Res ; 98: 1-55, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28433050

RESUMO

The risk of spillover of enzootic paramyxoviruses and the susceptibility of recipient human and domestic animal populations are defined by a broad collection of ecological and molecular factors that interact in ways that are not yet fully understood. Nipah and Hendra viruses were the first highly lethal zoonotic paramyxoviruses discovered in modern times, but other paramyxoviruses from multiple genera are present in bats and other reservoirs that have unknown potential to spillover into humans. We outline our current understanding of paramyxovirus reservoir hosts and the ecological factors that may drive spillover, and we explore the molecular barriers to spillover that emergent paramyxoviruses may encounter. By outlining what is known about enzootic paramyxovirus receptor usage, mechanisms of innate immune evasion, and other host-specific interactions, we highlight the breadth of unexplored avenues that may be important in understanding paramyxovirus emergence.


Assuntos
Resistência à Doença/genética , Infecções por Paramyxoviridae/epidemiologia , Paramyxovirinae/patogenicidade , Filogenia , Zoonoses/epidemiologia , Animais , Gatos , Quirópteros/virologia , Suscetibilidade a Doenças/imunologia , Vetores de Doenças , Cães , Interações Hospedeiro-Patógeno , Humanos , Infecções por Paramyxoviridae/imunologia , Infecções por Paramyxoviridae/transmissão , Infecções por Paramyxoviridae/veterinária , Paramyxovirinae/classificação , Paramyxovirinae/genética , Roedores/virologia , Zoonoses/imunologia , Zoonoses/transmissão , Zoonoses/virologia
19.
Calcif Tissue Int ; 101(2): 141-147, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28361207

RESUMO

Paget's disease of bone (PDB) is a common skeletal disorder characterised by focal abnormalities of increased and disorganised bone turnover. Genetic factors play a central role in the pathogenesis of PDB but environmental factors also contribute. Measles virus (MV), respiratory syncytial virus (RSV) and canine distemper virus (CDV) have all been implicated as potential disease triggers but the data are conflicting. Since chronic paramyxovirus infection with measles is known to be accompanied by increased production of antiviral antibodies, we have analysed circulating concentrations of antibodies to MV, CDV, and RSV as well as mumps, rubella and varicella zoster virus (VZV) in 463 patients with PDB and 220 aged and gender-matched controls. We also studied the relation between viral antibody concentrations and various markers of disease severity and extent in 460 PDB patients. A high proportion of cases and controls tested positive for antiviral antibodies but there was no significant difference in circulating antibody concentrations between PDB cases and controls for MV, CDV, RSV, rubella or VZV. However, mumps virus antibody levels were significantly higher in the PDB cases (mean ± SD = 3.1 ± 0.84 vs. 2.62 ± 0.86. p < 0.001). There was no association between disease severity and circulating antibody concentrations to any of the viruses. In conclusion, we found no evidence to suggest that PDB is associated with abnormalities of immune response to measles or other paramyxoviruses, although there was evidence of a greater antibody response to mumps. The results do not support that hypothesis that PDB is associated with a persistent infection with measles or other paramyxoviruses.


Assuntos
Formação de Anticorpos/imunologia , Osso e Ossos/virologia , Osteíte Deformante/virologia , Paramyxovirinae , Idoso , Idoso de 80 Anos ou mais , Osso e Ossos/patologia , Feminino , Humanos , Hibridização In Situ/métodos , Masculino , Pessoa de Meia-Idade , Osteíte Deformante/diagnóstico , Osteíte Deformante/imunologia , Osteoclastos/patologia , Osteoclastos/virologia
20.
Virol J ; 14(1): 19, 2017 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-28159006

RESUMO

BACKGROUND: The four types of human parainfluenza viruses (PIV) are important causes of community-acquired pneumonia, particularly in children; however, limited information exists about the incidence of PIV in critically ill patients. The aim of this study is to describe the spectrum, incidence and clinical features of PIV-associated infections diagnosed during the hospital stay of patients admitted to pediatric intensive care unit (PICU) and intensive care unit (ICU) of 5 medical centers across Kuwait. METHODS: This was a population-based, retrospective study from 2013 to 2015. Specimens were analyzed by molecular methods. This analysis was performed using the database of Virology Unit, Mubarak Al-Kabeer Hospital. Data from 1510 admitted patients with suspected respiratory viral infections was extracted. RESULTS: The database contained a total of 39 (2.6%) patients infected with PIV (53.8% male and 46.2% females) and 20 (51.3%) were under 1 year of age. The most frequently isolated type was type 3 (28, 71.8%) followed by type 1 (9, 23.1%). At admission the most common clinical diagnosis was pneumonia in 12 patients (30.8%, p < 0.05) followed by bronchiolitis in 10 patients (25.6%). CONCLUSION: PIV plays an important yet unrecognized role in the outcomes of PIUC and ICU patients. Our results contribute to the limited epidemiologic data of PIV in PIUC and ICU in this region.


Assuntos
Estado Terminal , Hospitalização , Infecções por Paramyxoviridae/epidemiologia , Paramyxovirinae/classificação , Paramyxovirinae/isolamento & purificação , Pneumonia Viral/epidemiologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Hospitais , Humanos , Incidência , Lactente , Recém-Nascido , Kuweit/epidemiologia , Masculino , Pessoa de Meia-Idade , Infecções por Paramyxoviridae/patologia , Infecções por Paramyxoviridae/virologia , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Estudos Retrospectivos , Adulto Jovem
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