Pigs are considered as important hosts or “mixing vessels” for the generation of pandemic influenza viruses. Systematic surveillance of influenza viruses in pigs is essential for early warning and ...preparedness for the next potential pandemic. Here, we report on an influenza virus surveillance of pigs from 2011 to 2018 in China, and identify a recently emerged genotype 4 (G4) reassortant Eurasian avian-like (EA) H1N1 virus, which bears 2009 pandemic (pdm/09) and triple-reassortant (TR)-derived internal genes and has been predominant in swine populations since 2016. Similar to pdm/09 virus, G4 viruses bind to human-type receptors, produce much higher progeny virus in human airway epithelial cells, and show efficient infectivity and aerosol transmission in ferrets. Moreover, low antigenic cross-reactivity of human influenza vaccine strains with G4 reassortant EA H1N1 virus indicates that preexisting population immunity does not provide protection against G4 viruses. Further serological surveillance among occupational exposure population showed that 10.4% (35/338) of swine workers were positive for G4 EA H1N1 virus, especially for participants 18 y to 35 y old, who had 20.5% (9/44) seropositive rates, indicating that the predominant G4 EA H1N1 virus has acquired increased human infectivity. Such infectivity greatly enhances the opportunity for virus adaptation in humans and raises concerns for the possible generation of pandemic viruses.
Since its identification in April 2009, an A(H1N1) virus containing a unique combination of gene segments from both North American and Eurasian swine lineages has continued to circulate in humans. ...The lack of similarity between the 2009 A(H1N1) virus and its nearest relatives indicates that its gene segments have been circulating undetected for an extended period. Its low genetic diversity suggests that the introduction into humans was a single event or multiple events of similar viruses. Molecular markers predictive of adaptation to humans are not currently present in 2009 A(H1N1) viruses, suggesting that previously unrecognized molecular determinants could be responsible for the transmission among humans. Antigenically the viruses are homogeneous and similar to North American swine A(H1N1) viruses but distinct from seasonal human A(H1N1).
The mechanism of resistance to favipiravir in influenza Goldhill, Daniel H.; te Velthuis, Aartjan J. W.; Fletcher, Robert A. ...
Proceedings of the National Academy of Sciences - PNAS,
11/2018, Letnik:
115, Številka:
45
Journal Article
Recenzirano
Odprti dostop
Favipiravir is a broad-spectrum antiviral that has shown promise in treatment of influenza virus infections. While emergence of resistance has been observed for many antiinfluenza drugs, to date, ...clinical trials and laboratory studies of favipiravir have not yielded resistant viruses. Here we show evolution of resistance to favipiravir in the pandemic H1N1 influenza A virus in a laboratory setting. We found that two mutations were required for robust resistance to favipiravir. We demonstrate that a K229R mutation in motif F of the PB1 subunit of the influenza virus RNA-dependent RNA polymerase (RdRP) confers resistance to favipiravir in vitro and in cell culture. This mutation has a cost to viral fitness, but fitness can be restored by a P653L mutation in the PA subunit of the polymerase. K229R also conferred favipiravir resistance to RNA polymerases of other influenza A virus strains, and its location within a highly conserved structural feature of the RdRP suggests that other RNA virusesmight also acquire resistance through mutations in motif F. The mutations identified here could be used to screen influenza virus-infected patients treated with favipiravir for the emergence of resistance.
A brief history of bird flu Lycett, Samantha J; Duchatel, Florian; Digard, Paul
Philosophical transactions of the Royal Society of London. Series B. Biological sciences,
06/2019, Letnik:
374, Številka:
1775
Journal Article
Recenzirano
Odprti dostop
In 1918, a strain of influenza A virus caused a human pandemic resulting in the deaths of 50 million people. A century later, with the advent of sequencing technology and corresponding phylogenetic ...methods, we know much more about the origins, evolution and epidemiology of influenza epidemics. Here we review the history of avian influenza viruses through the lens of their genetic makeup: from their relationship to human pandemic viruses, starting with the 1918 H1N1 strain, through to the highly pathogenic epidemics in birds and zoonoses up to 2018. We describe the genesis of novel influenza A virus strains by reassortment and evolution in wild and domestic bird populations, as well as the role of wild bird migration in their long-range spread. The emergence of highly pathogenic avian influenza viruses, and the zoonotic incursions of avian H5 and H7 viruses into humans over the last couple of decades are also described. The threat of a new avian influenza virus causing a human pandemic is still present today, although control in domestic avian populations can minimize the risk to human health. This article is part of the theme issue 'Modelling infectious disease outbreaks in humans, animals and plants: approaches and important themes'. This issue is linked with the subsequent theme issue 'Modelling infectious disease outbreaks in humans, animals and plants: epidemic forecasting and control'.
Antigenic drift of the hemagglutinin (HA) and neuraminidase (NA) proteins of the influenza virus cause a decrease in vaccine efficacy. Since the information about the evolution of these viruses in ...Saudi is deficient so we investigated the genetic diversity of circulating H1N1 viruses. Nasopharyngeal aspirates/swabs collected from 149 patients hospitalized with flu‐like symptoms during 2014 and 2015 were analyzed. Viral RNA extraction was followed by a reverse transcription‐polymerase chain reaction and genetic sequencing. We analyzed complete gene sequences of HA and NA from 80 positive isolates. Phylogenetic analysis of HA and NA genes of 80 isolates showed similar topologies and co‐circulation of clades 6b. Genetic diversity was observed among circulating viruses belonging to clade 6B.1A. The amino acid residues in the HA epitope domain were under purifying selection. Amino acid changes at key antigenic sites, such as position S101N, S179N (antigenic site‐Sa), I233T (antigenic site‐Sb) in the head domain might have resulted in antigenic drift and emergence of variant viruses. For NA protein, 36% isolates showed the presence of amino acid changes such as V13I (n = 29), I314M (n = 29) and 12% had I34V (n = 10). However, H257Y mutation responsible for resistance to neuraminidase inhibitors was missing. The presence of amino acid changes at key antigenic sites and their topologies with structural mapping of residues under purifying selection highlights the importance of antigenic drift and warrants further characterization of recently circulating viruses in view of vaccine effectiveness. The co‐circulation of several clades and the predominance of clade 6B.1 suggest multiple introductions in Saudi.
Highlights
The presence of amino acid changes at key antigenic sites.
The topologies with structural mapping of residues under purifying selection highlights the importance of antigenic drift.
The co‐circulation of several clades and the predominance of clade 6B.1 suggest multiple introductions in Saudi.
Background
The effect of corticosteroids on influenza A(H1N1)pdm09 viral pneumonia patients remains controversial, and the impact of dosage has never been studied.
Methods
Using data of hospitalized ...adolescent and adult patients with influenza A(H1N1)pdm09 viral pneumonia, prospectively collected from 407 hospitals in mainland China, the effects of low‐to‐moderate‐dose (25‐150 mg d−1) and high‐dose (>150 mg d−1) corticosteroids on 30‐day mortality, 60‐day mortality, and nosocomial infection were assessed with multivariate Cox regression and propensity score‐matched case–control analysis.
Results
In total, 2141 patients (median age: 34 years; morality rate: 15.9%) were included. Among them, 1160 (54.2%) had PaO2/FiO2<300 mm Hg on admission, and 1055 (49.3%) received corticosteroids therapy. Corticosteroids, without consideration of dose, did not influence either 30‐day or 60‐day mortality. Further analysis revealed that, as compared with the no‐corticosteroid group, low‐to‐moderate‐dose corticosteroids were related to reduced 30‐day mortality (adjusted hazard ratio aHR 0.64 95% CI 0.43‐0.96, P=.033). In the subgroup analysis among patients with PaO2/FiO2<300 mm Hg, low‐to‐moderate‐dose corticosteroid treatment significantly reduced both 30‐day mortality (aHR 0.49 95% CI 0.32‐0.77) and 60‐day mortality (aHR 0.51 95% CI 0.33‐0.78), while high‐dose corticosteroid therapy yielded no difference. For patients with PaO2/FiO2 ≥300 mm Hg, corticosteroids (irrespective of dose) showed no benefit and even increased 60‐day mortality (aHR 3.02 95% CI 1.06‐8.58). Results were similar in the propensity model analysis.
Conclusions
Low‐to‐moderate‐dose corticosteroids might reduce mortality of influenza A(H1N1)pdm09 viral pneumonia patients with PaO2/FiO2<300 mm Hg. Mild patients with PaO2/FiO2 ≥300 mm Hg could not benefit from corticosteroid therapy.
Abstract A recently emerged novel influenza A H1N1 virus continues to spread globally. The virus contains a novel constellation of gene segments, the nearest known precursors being viruses found in ...swine and it likely arose through reassortment of two or more viruses of swine origin. H1N1, H1N2 and H3N2 subtype swine influenza viruses have occasionally infected humans before but such zoonotic transmission events did not lead to sustained human-to-human transmission in the manner this swine-origin influenza virus (S-OIV) has done. Its transmission among humans appears to be higher than that observed with seasonal influenza. Children and young adults appear to those most affected and also those who appear to maintain transmission. Clinical disease generally appears mild but complications leading to hospitalization can occur, especially in those with underlying lung or cardiac disease, diabetes or those on immunosuppresive therapies. There are concerns that the virus may reassort with existing human influenza virus giving rise to more transmissible or more pathogenic viruses. The virus appears to retain the potential to transmit back to swine and thus continued reassortment with swine viruses is a cause for concern.
Influenza viruses typically cause the most severe disease in children and elderly individuals. However, H1N1 viruses disproportionately affected middle-aged adults during the 2013–2014 influenza ...season. Although H1N1 viruses recently acquired several mutations in the hemagglutinin (HA) glycoprotein, classic serological tests used by surveillance laboratories indicate that these mutations do not change antigenic properties of the virus. Here, we show that one of these mutations is located in a region of HA targeted by antibodies elicited in many middle-aged adults. We find that over 42% of individuals born between 1965 and 1979 possess antibodies that recognize this region of HA. Our findings offer a possible antigenic explanation of why middle-aged adults were highly susceptible to H1N1 viruses during the 2013–2014 influenza season. Our data further suggest that a drifted H1N1 strain should be included in future influenza vaccines to potentially reduce morbidity and mortality in this age group.
Significance Influenza viruses typically cause a higher disease burden in children and the elderly, who have weaker immune systems. During the 2013–2014 influenza season, H1N1 viruses caused an unusually high level of disease in middle-aged adults. Here, we show that recent H1N1 strains possess a mutation that allows viruses to avoid immune responses elicited in middle-aged adults. We show that current vaccine strains elicit immune responses that are predicted to be less effective in some middle-aged adults. We suggest that new viral strains should be incorporated into seasonal influenza vaccines so that proper immunity is elicited in all humans, regardless of age and pre-exposure histories.
Abstract
Background
Coronavirus disease 2019 (COVID-19) is an emerging serious global health problem. Gastrointestinal symptoms are common in COVID-19 patients, and severe acute respiratory syndrome ...coronavirus 2 RNA has been detected in stool specimens. However, the relationship between the gut microbiome and disease remains to be established.
Methods
We conducted a cross-sectional study of 30 patients with COVID-19, 24 patients with influenza A(H1N1), and 30 matched healthy controls (HCs) to identify differences in the gut microbiota by 16S ribosomal RNA gene V3–V4 region sequencing.
Results
Compared with HCs, COVID-19 patients had significantly reduced bacterial diversity; a significantly higher relative abundance of opportunistic pathogens, such as Streptococcus, Rothia, Veillonella, and Actinomyces; and a lower relative abundance of beneficial symbionts. Five biomarkers showed high accuracy for distinguishing COVID-19 patients from HCs with an area under the curve (AUC) up to 0.89. Patients with H1N1 displayed lower diversity and different overall microbial composition compared with COVID-19 patients. Seven biomarkers were selected to distinguish the 2 cohorts (AUC = 0.94).
Conclusions
The gut microbial signature of patients with COVID-19 was different from that of H1N1 patients and HCs. Our study suggests the potential value of the gut microbiota as a diagnostic biomarker and therapeutic target for COVID-19, but further validation is needed.
In this cross-sectional study, we identified specific signatures of the fecal microbiota in COVID-19 patients, H1N1 patients, and healthy controls in a Chinese population by high-throughput 16S rRNA gene sequencing, to provide a theoretical basis for intestinal microbial intervention.
The coronavirus disease 2019 (COVID-19) pandemic, caused by the SARS-CoV-2 virus, has highlighted the need for antiviral approaches that can target emerging viruses with no effective vaccines or ...pharmaceuticals. Here, we demonstrate a CRISPR-Cas13-based strategy, PAC-MAN (prophylactic antiviral CRISPR in human cells), for viral inhibition that can effectively degrade RNA from SARS-CoV-2 sequences and live influenza A virus (IAV) in human lung epithelial cells. We designed and screened CRISPR RNAs (crRNAs) targeting conserved viral regions and identified functional crRNAs targeting SARS-CoV-2. This approach effectively reduced H1N1 IAV load in respiratory epithelial cells. Our bioinformatic analysis showed that a group of only six crRNAs can target more than 90% of all coronaviruses. With the development of a safe and effective system for respiratory tract delivery, PAC-MAN has the potential to become an important pan-coronavirus inhibition strategy.
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•PAC-MAN is a CRISPR-based strategy for RNA-guided viral RNA inhibition and degradation•Cas13d PAC-MAC is effective at targeting and cleaving SARS-CoV-2 sequences•Cas13d PAC-MAC can reduce H1N1 IAV load in respiratory epithelial cells•A group of six crRNAs can target more than 90% of all coronaviruses
A CRISPR-based strategy is developed to target conserved sequences across coronaviruses and other pathogenic viruses.
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