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1.
Artigo em Inglês | MEDLINE | ID: mdl-33715290

RESUMO

BACKGROUND: Coronavirus disease (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first detected in Japan in January 2020 and has spread throughout the country. Previous studies have reported that viral interference among influenza virus, rhinovirus, and other respiratory viruses can affect viral infections at the host and population level. METHODS: To investigate the impact of COVID-19 on influenza and other respiratory virus infections, we analyzed clinical specimens collected from 2244 patients in Japan with respiratory diseases between January 2018 and September 2020. RESULTS: The frequency of influenza and other respiratory viruses (coxsackievirus A and B; echovirus; enterovirus; human coronavirus 229E, HKU1, NL63, and OC43; human metapneumovirus; human parainfluenza virus 1, 2, 3, and 4; human parechovirus; human respiratory syncytial virus; human adenovirus; human bocavirus; human parvovirus B19; herpes simplex virus type 1; and varicella-zoster virus) was appreciably reduced among all patients during the COVID-19 pandemic except for that of rhinovirus in children younger than 10 years, which was appreciably increased. COVID-19 has not spread among this age group, suggesting an increased risk of rhinovirus infection in children. CONCLUSIONS: Rhinovirus infections should be continuously monitored to understand their increased risk during the COVID-19 pandemic and viral interference with SARS-CoV-2.

2.
Mod Rheumatol Case Rep ; : 1-6, 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33719867

RESUMO

Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection of the central nervous system caused by reactivation of JC virus (JCV). Typical PML shows confluent, bilateral but asymmetric, subcortical lesions in the supratentorial white matter on magnetic resonance imaging (MRI). We report here a 50-year-old woman with systemic lupus erythematosus complicated with lymphoma who developed PML with atypical brain MRI findings limited to the infratentorial area at presentation. She presented with numbness on the right side of the face, including her tongue, clumsiness of the right hand, and gait disturbance, after completion of remission induction therapy for lymphoma, including rituximab. Brain MRI demonstrated a solitary lesion limited to the cerebellum and brainstem, but a definitive diagnosis could not be made from cerebrospinal fluid study or tentative histologic evaluation of brain biopsy specimens. Despite methylprednisolone pulse therapy, her neurological deficits progressively worsened. One month later, in-depth analysis of her cerebrospinal fluid and brain biopsy specimens confirmed the presence of JCV. Eventually, the localised unilateral crescent-shaped cerebellar lesions on MRI expanded to the contralateral cerebellum, middle cerebellar hemisphere, pons, and midbrain and finally developed multifocal invasion into the white matter of the cerebral hemispheres. Our case suggests that PML could first present with a solitary infratentorial lesion in immunocompromised patients.

3.
Anal Chem ; 92(23): 15388-15393, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33205942

RESUMO

Glass nanopipettes are widely used for various applications in nanosciences. In most of the applications, it is important to characterize their geometrical parameters, such as the aperture size and the inner cone angle at the tip region. For nanopipettes with sub-10 nm aperture and thin wall thickness, transmission electron microscopy (TEM) must be most instrumental in their precise geometrical measurement. However, this measurement has remained a challenge because heat generated by electron beam irradiation would largely deform sub-10 nm nanopipettes. Here, we provide methods for preparing TEM specimens that do not cause deformation of such tiny nanopipettes.

4.
Pathogens ; 9(9)2020 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-32887429

RESUMO

Influenza A(H1N1)pdm09 viruses carrying a dual neuraminidase (NA) substitution were isolated from immunocompromised patients after administration of one or more NA inhibitors. These mutant viruses possessed an H275Y/I223R, H275Y/I223K, or H275Y/G147R substitution in their NA and showed enhanced cross-resistance to oseltamivir and peramivir and reduced susceptibility to zanamivir compared to single H275Y mutant viruses. Baloxavir could be a treatment option against the multidrug-resistant viruses because these dual H275Y mutant viruses showed susceptibility to this drug. The G147R substitution appears to stabilize the NA structure, with the fitness of the H275Y/G147R mutant virus being similar or somewhat better than that of the wild-type virus. Since the multidrug-resistant viruses may be able to transmit between humans, surveillance of these viruses must continue to improve clinical management and to protect public health.

5.
Elife ; 92020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32876050

RESUMO

Seasonal influenza virus A/H3N2 is a major cause of death globally. Vaccination remains the most effective preventative. Rapid mutation of hemagglutinin allows viruses to escape adaptive immunity. This antigenic drift necessitates regular vaccine updates. Effective vaccine strains need to represent H3N2 populations circulating one year after strain selection. Experts select strains based on experimental measurements of antigenic drift and predictions made by models from hemagglutinin sequences. We developed a novel influenza forecasting framework that integrates phenotypic measures of antigenic drift and functional constraint with previously published sequence-only fitness estimates. Forecasts informed by phenotypic measures of antigenic drift consistently outperformed previous sequence-only estimates, while sequence-only estimates of functional constraint surpassed more comprehensive experimentally-informed estimates. Importantly, the best models integrated estimates of both functional constraint and either antigenic drift phenotypes or recent population growth.

6.
Antiviral Res ; 180: 104828, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32574689

RESUMO

Human-to-human transmission of PA I38 mutant influenza A(H3N2) viruses with reduced baloxavir susceptibility has been reported in Japan. In December 2019, we detected a PA E23K mutant A(H1N1)pdm09 virus from a child without baloxavir treatment. The PA E23K mutant virus exhibited reduced baloxavir susceptibility but remained susceptible to neuraminidase inhibitors. Epidemiological data suggest possible transmission of this PA E23K mutant virus among humans, although its growth capability relative to that of the wild-type virus was reduced. Therefore, baloxavir susceptibility monitoring of influenza viruses is essential.

8.
PLoS One ; 15(3): e0229601, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32130243

RESUMO

A community outbreak of human influenza A(H1N1)pdm09 virus strains was observed in Myanmar in 2017. We investigated the circulation patterns, antigenicity, and drug resistance of 2017 influenza A(H1N1)pdm09 viruses from Myanmar and characterized the full genome of influenza virus strains in Myanmar from in-patients and out-patients to assess the pathogenicity of the viruses. Nasopharyngeal swabs were collected from out-patients and in-patients with acute respiratory tract infections in Yangon and Pyinmana City in Myanmar during January-December 2017. A total of 215 out-patients and 18 in-patients infected with A(H1N1)pdm09 were detected by virus isolation and real-time RT-PCR. Among the positive patients, 90.6% were less than 14 years old. Hemagglutination inhibition (HI) antibody titers against A(H1N1)pdm09 viruses in Myanmar were similar to the recommended Japanese influenza vaccine strain for 2017-2018 seasons (A/Singapore/GP1908/2015) and WHO recommended 2017 southern hemisphere vaccine component (A/Michigan/45/2015). Phylogenetic analysis of the hemagglutinin sequence showed that the Myanmar strains belonged to the genetic subclade 6B.1, possessing mutations of S162N and S164T at potential antigenic sites. However, the amino acid mutation at position 222, which may enhance the severity of disease and mortality, was not found. One case with no prior history of oseltamivir treatment possessed H275Y mutated virus in neuraminidase (NA), which confers resistance to oseltamivir and peramivir with elevated IC50 values. The full genome sequence of Myanmar strains showed no difference between samples from in-patients and out-patients, suggesting no additional viral mutations associated with patient severity. Several amino acid changes were observed in PB2, PB1, and M2 of Myanmar strains when compared to the vaccine strain and other Asian strains. However, no mutations associated with pathogenicity were found in the Myanmar strains, suggesting that viral factors cannot explain the underlying reasons of the massive outbreak in Myanmar. This study reported the first detection of an oseltamivir-resistant influenza virus in Myanmar, highlighting the importance of continuous antiviral monitoring and genetic characterization of the influenza virus in Myanmar.


Assuntos
Epidemias , Vírus da Influenza A Subtipo H1N1 , Influenza Humana/epidemiologia , Adolescente , Adulto , Substituição de Aminoácidos , Antígenos Virais , Antivirais/farmacologia , Criança , Pré-Escolar , Farmacorresistência Viral/genética , Feminino , Genoma Viral , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Humanos , Lactente , Vírus da Influenza A Subtipo H1N1/classificação , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana/tratamento farmacológico , Influenza Humana/virologia , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Mianmar/epidemiologia , Oseltamivir/farmacologia , Filogenia , Adulto Jovem
9.
Influenza Other Respir Viruses ; 14(4): 436-443, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32064779

RESUMO

BACKGROUND: The novel cap-dependent endonuclease inhibitor baloxavir marboxil was approved in February 2018 for the treatment of influenza virus infection in Japan. In vitro studies have revealed that an I38T substitution in the polymerase acidic subunit (PA) is associated with reduced susceptibility of influenza viruses to baloxavir. OBJECTIVES: Development of a rapid and simple method for monitoring influenza A(H1N1)pdm09, A(H3N2), and B viruses possessing the I38T substitution in PA. METHODS: Three assays were developed based on RNase H2-dependent PCR (rhPCR) and named A/H1pdm PA_I38T rhPCR, A/H3 PA_I38T rhPCR, and B PA_I38T rhPCR. The assays were evaluated using cDNAs synthesized from in vitro-transcribed PA gene RNA controls, RNAs purified from viruses isolated in the 2017/2018 and 2018/2019 influenza seasons, and RNAs purified from clinical specimens collected in the 2018/2019 influenza season. RESULTS: The assays developed in this study accurately discriminated PA I38 and PA T38 with high sensitivity. CONCLUSIONS: Our assays should be considered a powerful tool for monitoring the emergence of baloxavir-resistant influenza viruses.

10.
Anal Chem ; 91(21): 14080-14084, 2019 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-31589026

RESUMO

Typically, utilization of small nanopipettes results in either high sensitivity or spatial resolution in modern nanoscience and nanotechnology. However, filling a nanopipette with a sub-10-nm pore diameter remains a significant challenge. Here, we introduce a thermally driven approach to filling sub-10-nm pipettes with batch production, regardless of their shape. A temperature gradient is applied to transport water vapor from the backside of nanopipettes to the tip region until bubbles are completely removed from this region. The electrical contact and pore size for filling nanopipettes are confirmed by current-voltage and transmission electron microscopy (TEM) measurements, respectively. In addition, we quantitatively compare the pore size between the TEM characterization and estimation on the basis of pore radius and conductance. The validity of this method provides a foundation for highly sensitive detection of single molecules and high spatial resolution imaging of nanostructures.

11.
J Gen Virol ; 100(10): 1345-1349, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31424377

RESUMO

Long-term culture of the human lung adenocarcinoma cell line A549 promotes the differentiation of these cells toward an alveolar type II cell phenotype. Here, we evaluated the susceptibility of long-term cultured A549 cells to human influenza viruses. A549 cells were cultured continuously for 25 days (D25-A549) or 1 day (D1-A549) in Ham's F12K medium. Six human influenza A viruses grew much faster in D25-A549 cells than in D1-A549 cells; however, two influenza B viruses replicated poorly in both cell types. Two avian influenza viruses replicated efficiently in both cell types, with similar titres. Expression levels of human virus receptors were higher in D25-A549 cells than in D1-A549 cells. D25-A549 cells thus more efficiently support the replication of human influenza A viruses compared with D1-A549 cells. Our data suggest that long-term cultured A549 cells will be useful for influenza A virus research.


Assuntos
Vírus da Influenza A/crescimento & desenvolvimento , Vírus da Influenza B/crescimento & desenvolvimento , Replicação Viral , Células A549 , Meios de Cultura/química , Meios de Cultura/metabolismo , Humanos , Vírus da Influenza A/fisiologia , Vírus da Influenza B/fisiologia , Influenza Humana/virologia , Fatores de Tempo , Cultura de Vírus
12.
Emerg Infect Dis ; 25(11): 2108-2111, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31436527

RESUMO

In 2019, influenza A(H3N2) viruses carrying an I38T substitution in the polymerase acidic gene, which confers reduced susceptibility to baloxavir, were detected in Japan in an infant without baloxavir exposure and a baloxavir-treated sibling. These viruses' whole-genome sequences were identical, indicating human-to-human transmission. Influenza virus isolates should be monitored for baloxavir susceptibility.


Assuntos
Antivirais/farmacologia , Suscetibilidade a Doenças , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Influenza Humana/transmissão , Influenza Humana/virologia , Oxazinas/farmacologia , Piridinas/farmacologia , Tiepinas/farmacologia , Triazinas/farmacologia , Adolescente , Adulto , Antivirais/uso terapêutico , Criança , Dibenzotiepinas , Humanos , Lactente , Vírus da Influenza A Subtipo H3N2/genética , Influenza Humana/tratamento farmacológico , Influenza Humana/epidemiologia , Japão/epidemiologia , Pessoa de Meia-Idade , Morfolinas , Mutação , Oxazinas/uso terapêutico , Piridinas/uso terapêutico , Piridonas , Tiepinas/uso terapêutico , Triazinas/uso terapêutico , Adulto Jovem
13.
Genes Environ ; 41: 11, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30988834

RESUMO

Background: Chloroethylnitrosourea (CENU) derivatives, such as nimustine (ACNU) and carmustine (BCNU), are employed in brain tumor chemotherapy due to their ability to cross the blood-brain barrier. They are thought to suppress tumor development through DNA chloroethylation, followed by the formation of interstrand cross-links (ICLs) that efficiently block replication and transcription. However, the alkylation of DNA and ICLs may trigger genotoxicity, leading to tumor formation as a side effect of the chemotherapeutic treatment. Although the involvement of O 6-alkylguanine-DNA alkyltransferase (AGT) in repairing chloroethylated guanine (O 6-chloroethylguanine) has been reported, the exact lesion responsible for the genotoxicity and the pathway responsible for repairing it remains unclear. Results: We examined the mutations induced by ACNU and BCNU using a series of Escherichia coli strains, CC101 to CC111, in which reverse mutations due to each episome from F'101 to F'106 and frameshift mutations due to each episome from F'107 to F'111 could be detected. The mutant frequency increased in E. coli CC102, which can detect a GC to AT mutation. To determine the pathway responsible for repairing the CENU-induced lesions, we compared the frequency of mutations induced by CENU in the wild-type strain to those in the ada, ogt (AGT-deficient) strain, uvrA (nucleotide excision repair (NER)-deficient) strain, mismatch repair (MMR)-deficient strains, and recA (recombination deficient) strain of E. coli CC102. The frequencies of mutations induced by ACNU and BCNU increased in the ada, ogt strain, demonstrating that O 6-chloroethylguanines were formed, and that a portion was repaired by AGT.Mutation induced by ACNU in NER-deficient strain showed a similar profile to that in AGT-deficient strain, suggesting that an NER and AGT play at the similar efficacy to protect E. coli from mutation induced by ACNU. O 6-Chloroethylguanine is reported to form ICLs if it is not repaired. We examined the survival rates and the frequencies of mutations induced by ACNU and BCNU in the uvrA strain, the recA strain, as well as a double-deficient strain of CC102. The mutation profile of the double-deficient strain was similar to that of the NER-deficient strain, suggesting that an NER protects E. coli from mutations but not recombination. In addition, cell death was more pronounced in the uvrA, recA double-deficient strain than in the single-deficient strains. Conclusion: These results suggest that the toxic lesions induced by CENU were repaired additively or synergistically by NER and recombination. In other words, lesions, such as ICLs, appear to be repaired by NER and recombination independently.

14.
Euro Surveill ; 24(12)2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30914078

RESUMO

In January 2019, two influenza A(H3N2) viruses carrying an I38T substitution in the polymerase acidic subunit (PA), which confers reduced susceptibility to baloxavir, were detected from epidemiologically unrelated hospitalised children in Japan. The viruses exhibited reduced susceptibility to baloxavir but were susceptible to neuraminidase inhibitors. Only one of the two children had been treated with baloxavir. An epidemiological analysis suggests possible transmission of the PA I38T mutant A(H3N2) virus among humans.


Assuntos
Antivirais/farmacologia , Farmacorresistência Viral/genética , Vírus da Influenza A Subtipo H3N2/genética , Influenza Humana/tratamento farmacológico , Oxazinas/farmacologia , Piridinas/farmacologia , Tiepinas/farmacologia , Triazinas/farmacologia , Adolescente , Adulto , Antivirais/uso terapêutico , Criança , Dibenzotiepinas , Inibidores Enzimáticos/farmacologia , Humanos , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/isolamento & purificação , Influenza Humana/diagnóstico , Pacientes Internados , Japão , Pessoa de Meia-Idade , Morfolinas , Oxazinas/uso terapêutico , Reação em Cadeia da Polimerase , Piridinas/uso terapêutico , Piridonas , Tiepinas/uso terapêutico , Resultado do Tratamento , Triazinas/uso terapêutico , Adulto Jovem
15.
J Med Case Rep ; 13(1): 74, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30890184

RESUMO

BACKGROUND: Segmental arterial mediolysis is a rare nonarteriosclerotic and noninflammatory vascular disease that may cause intraperitoneal bleeding. Scleroderma renal crisis is a rare complication of systemic sclerosis, leading to severe hypertension and renal dysfunction. To the best of our knowledge, this is the first reported case of a patient with concurrent systemic sclerosis with scleroderma renal crisis and pathologically confirmed segmental arterial mediolysis. CASE PRESENTATION: We report a case of a 68-year-old Chinese woman diagnosed with systemic sclerosis who was found to have coexisting segmental arterial mediolysis. She presented with back pain, and massive intraperitoneal bleeding was detected by computed tomography. She underwent laparotomy, and the bleeding was found to originate from the gastroepiploic artery. The pathological examination demonstrated gastroepiploic arterial dissection caused by segmental arterial mediolysis. After surgery, she developed severe hypertension with hyperreninemia and progressive renal dysfunction. Given the risk factors of corticosteroid administration and the presence of anti-ribonucleic acid polymerase III antibody, she was diagnosed with scleroderma renal crisis. The patient was proved to have a very rare case of coexisting scleroderma renal crisis and segmental arterial mediolysis. CONCLUSIONS: There is no known etiological connection between segmental arterial mediolysis and systemic sclerosis or scleroderma renal crisis, but it is possible that coexisting segmental arterial mediolysis and scleroderma renal crisis may have interacted to trigger the development of the other in our patient.


Assuntos
Lesão Renal Aguda/etiologia , Aneurisma Dissecante/complicações , Aneurisma Roto/etiologia , Escleroderma Sistêmico/complicações , Idoso , Feminino , Artéria Gastroepiploica , Hemorragia Gastrointestinal/etiologia , Humanos , Cavidade Peritoneal/irrigação sanguínea
16.
Euro Surveill ; 24(6)2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30755292

RESUMO

BACKGROUND: Influenza A(H3N2) virus rapidly evolves to evade human immune responses, resulting in changes in the antigenicity of haemagglutinin (HA). Therefore, continuous genetic and antigenic analyses of A(H3N2) virus are necessary to detect antigenic mutants as quickly as possible. AIM: We attempted to phylogenetically and antigenically capture the epidemic trend of A(H3N2) virus infection in Yokohama, Japan during the 2016/17 and 2017/18 influenza seasons. METHODS: We determined the HA sequences of A(H3N2) viruses detected in Yokohama, Japan during the 2016/17 and 2017/18 influenza seasons to identify amino acid substitutions and the loss or gain of potential N-glycosylation sites in HA, both of which potentially affect the antigenicity of HA. We also examined the antigenicity of isolates using ferret antisera obtained from experimentally infected ferrets. RESULTS: Influenza A(H3N2) viruses belonging to six clades (clades 3C.2A1, 3C.2A1a, 3C.2A1b, 3C.2A2, 3C.2A3 and 3C.2A4) were detected during the 2016/17 influenza season, whereas viruses belonging to two clades (clades 3C.2A1b and 3C.2A2) dominated during the 2017/18 influenza season. The isolates in clades 3C.2A1a and 3C.2A3 lost one N-linked glycosylation site in HA relative to other clades. Antigenic analysis revealed antigenic differences among clades, especially clade 3C.2A2 and 3C.2A4 viruses, which showed distinct antigenic differences from each other and from other clades in the antigenic map. CONCLUSION: Multiple clades, some of which differed antigenically from others, co-circulated in Yokohama, Japan during the 2016/17 and 2017/18 influenza seasons.


Assuntos
Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Vírus da Influenza A Subtipo H3N2/genética , Vírus da Influenza A Subtipo H3N2/isolamento & purificação , Influenza Humana/diagnóstico , RNA Viral/genética , Epidemias , Variação Genética , Hemaglutininas/genética , Humanos , Influenza Humana/epidemiologia , Japão/epidemiologia , Dados de Sequência Molecular , Filogenia , RNA Viral/isolamento & purificação , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estações do Ano , Análise de Sequência de DNA
17.
Euro Surveill ; 24(3)2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30670142

RESUMO

The novel cap-dependent endonuclease inhibitor baloxavir marboxil was approved for the treatment of influenza virus infection in Japan in February 2018. Two influenza A(H3N2) viruses carrying an I38T substitution in the polymerase acidic subunit (PA) were detected in baloxavir-treated children in December 2018. This mutation is known to confer reduced susceptibility to baloxavir, and the two mutant viruses exhibited 76- and 120-fold reduced susceptibility to baloxavir.


Assuntos
Antivirais/uso terapêutico , Endonucleases/antagonistas & inibidores , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/genética , Influenza Humana/tratamento farmacológico , Oxazinas/uso terapêutico , Piridinas/uso terapêutico , Tiepinas/uso terapêutico , Triazinas/uso terapêutico , Substituição de Aminoácidos/genética , Antivirais/administração & dosagem , Dibenzotiepinas , Farmacorresistência Viral/efeitos dos fármacos , Farmacorresistência Viral/genética , Endonucleases/genética , Humanos , Vírus da Influenza A Subtipo H3N2/isolamento & purificação , Influenza Humana/diagnóstico , Japão , Testes de Sensibilidade Microbiana , Morfolinas , Piridonas , Resultado do Tratamento
18.
Rev Sci Instrum ; 90(12): 123704, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31893861

RESUMO

Scanning ion conductance microscopy (SICM) can image the surface topography of specimens in ionic solutions without mechanical probe-sample contact. This unique capability is advantageous for imaging fragile biological samples but its highest possible imaging rate is far lower than the level desired in biological studies. Here, we present the development of high-speed SICM. The fast imaging capability is attained by a fast Z-scanner with active vibration control and pipette probes with enhanced ion conductance. By the former, the delay of probe Z-positioning is minimized to sub-10 µs, while its maximum stroke is secured at 6 µm. The enhanced ion conductance lowers a noise floor in ion current detection, increasing the detection bandwidth up to 100 kHz. Thus, temporal resolution 100-fold higher than that of conventional systems is achieved, together with spatial resolution around 20 nm.

19.
Arch Virol ; 164(2): 535-545, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30539262

RESUMO

Human infection by low-pathogenic avian influenza viruses of the H7N9 subtype was first reported in March 2013 in China. Subsequently, these viruses caused five outbreaks through September 2017. In the fifth outbreak, H7N9 virus possessing a multiple basic amino acid insertion in the cleavage site of hemagglutinin emerged and caused 4% of all human infections in that period. To date, H7N9 highly pathogenic avian influenza viruses (HPAIVs) have been isolated from poultry, mostly chickens, as well as the environment. To evaluate the relative infectivity of these viruses in poultry, chickens and ducks were subjected to experimental infection with two H7N9 HPAIVs isolated from humans, namely A/Guangdong/17SF003/2016 and A/Taiwan/1/2017. When chickens were inoculated with the HPAIVs at a dose of 106 50% egg infectious dose (EID50), all chickens died within 2-5 days after inoculation, and the viruses replicated in most of the internal organs examined. The 50% lethal doses of A/Guangdong/17SF003/2016 and A/Taiwan/1/2017 in chickens were calculated as 103.3 and 104.7 EID50, respectively. Conversely, none of the ducks inoculated with either virus displayed any clinical signs, and less-efficient virus replication and less shedding were observed in ducks compared to chickens. These findings indicate that chickens, but not ducks, are highly permissive hosts for emerging H7N9 HPAIVs.


Assuntos
Subtipo H7N9 do Vírus da Influenza A/patogenicidade , Influenza Aviária/virologia , Influenza Humana/virologia , Doenças das Aves Domésticas/virologia , Sequência de Aminoácidos , Animais , Galinhas , Patos , Humanos , Subtipo H7N9 do Vírus da Influenza A/classificação , Subtipo H7N9 do Vírus da Influenza A/genética , Subtipo H7N9 do Vírus da Influenza A/isolamento & purificação , Filogenia , Homologia de Sequência de Aminoácidos , Proteínas Virais/química , Proteínas Virais/genética , Virulência
20.
mBio ; 9(6)2018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30563907

RESUMO

The positions of host factors required for viral replication within a human protein-protein interaction (PPI) network can be exploited to identify drug targets that are robust to drug-mediated selective pressure. Host factors can physically interact with viral proteins, be a component of virus-regulated pathways (where proteins do not interact with viral proteins), or be required for viral replication but unregulated by viruses. Here, we demonstrate a method of combining human PPI networks with virus-host PPI data to improve antiviral drug discovery for influenza viruses by identifying target host proteins. Analysis shows that influenza virus proteins physically interact with host proteins in network positions significant for information flow, even after the removal of known abundance-degree bias within PPI data. We have isolated a subnetwork of the human PPI network that connects virus-interacting host proteins to host factors that are important for influenza virus replication without physically interacting with viral proteins. The subnetwork is enriched for signaling and immune processes distinct from those associated with virus-interacting proteins. Selecting proteins based on subnetwork topology, we performed an siRNA screen to determine whether the subnetwork was enriched for virus replication host factors and whether network position within the subnetwork offers an advantage in prioritization of drug targets to control influenza virus replication. We found that the subnetwork is highly enriched for target host proteins-more so than the set of host factors that physically interact with viral proteins. Our findings demonstrate that network positions are a powerful predictor to guide antiviral drug candidate prioritization.IMPORTANCE Integrating virus-host interactions with host protein-protein interactions, we have created a method using these established network practices to identify host factors (i.e., proteins) that are likely candidates for antiviral drug targeting. We demonstrate that interaction cascades between host proteins that directly interact with viral proteins and host factors that are important to influenza virus replication are enriched for signaling and immune processes. Additionally, we show that host proteins that interact with viral proteins are in network locations of power. Finally, we demonstrate a new network methodology to predict novel host factors and validate predictions with an siRNA screen. Our results show that integrating virus-host proteins interactions is useful in the identification of antiviral drug target candidates.


Assuntos
Interações Hospedeiro-Patógeno/genética , Orthomyxoviridae/fisiologia , Mapas de Interação de Proteínas , Replicação Viral , Linhagem Celular , Sistemas de Liberação de Medicamentos , Descoberta de Drogas , Humanos , Influenza Humana/tratamento farmacológico , Influenza Humana/virologia , Ligação Proteica , Transporte Proteico , RNA Interferente Pequeno , Proteínas Virais/metabolismo
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