scholarly journals Cross-reactive immunity drives global oscillation and opposed alternation patterns of seasonal influenza A viruses

2017 ◽  
Author(s):  
Lorenzo Gatti ◽  
Jitao David Zhang ◽  
Maria Anisimova ◽  
Martin Schutten ◽  
Ab Osterhaus ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Influenza Pandemic ◽  
Host Immunity ◽  
Temperate Climate ◽  
Prospective Clinical Study ◽  
Human Pathogens ◽  
Extrinsic Factors ◽  
Influenza Seasonality ◽  
Alternation Pattern

AbstractSeveral human pathogens exhibit distinct patterns of seasonality and circulate as pairs of discrete strains. For instance, the activity of the two co-circulating influenza A virus subtypes oscillates and peaks during winter seasons of the world’s temperate climate zones. These periods of increased activity are usually caused by a single dominant subtype. Alternation of dominant strains in successive influenza seasons makes epidemic forecasting a major challenge. From the start of the 2009 influenza pandemic we enrolled influenza A virus infected patients (n = 2,980) in a global prospective clinical study. Complete hemagglutinin (HA) sequences were obtained from 1,078 A/H1N1 and 1,033 A/H3N2 viruses and were linked to patient data. We then used phylodynamics to construct high resolution spatio-temporal phylogenetic HA trees and estimated global influenza A effective reproductive numbers (R) over time (2009-2013). We demonstrate that R, a parameter to define host immunity, oscillates around R = 1 with a clear opposed alternation pattern between phases of the A/H1N1 and A/H3N2 subtypes. Moreover, we find a similar alternation pattern for the number of global virus migration events between the sampled geographical locations. Both observations suggest a between-strain competition for susceptible hosts on a global level. Extrinsic factors that affect person-to-person transmission are a major driver of influenza seasonality, which forces influenza epidemics to coincide with winter seasons. The data presented here indicate that also cross-reactive host immunity is a key intrinsic driver of global influenza seasonality, which determines the outcome of competition between influenza A virus strains at the onset of each epidemic season.Significance statementAnnual influenza epidemics coincide with winter seasons in many parts of the world. Environmental factors, such as air humidity variation or temperature change, are commonly believed to drive these seasonality patterns. Interestingly, three out of the four latest pandemics (1918, 1968 and 2009) did not spread in winter initially, but during summer. This questions to what extent other factors could also impact virus spread among humans. We demonstrate that cross-reactive host immunity is a key factor. It drives the well-known seasonal patterns of virus activity oscillation and alternation of the dominant influenza virus subtype in successive seasons. Furthermore, this factor may also explain the efficient spread of pandemic viruses during summer when cross-reactive host immunity is relatively low.

scholarly journals Avian Influenza A Virus Pandemic Preparedness and Vaccine Development

Vaccines ◽  
2018 ◽  
Vol 6 (3) ◽  
pp. 46 ◽  
Author(s):  
Rory de Vries ◽  
Sander Herfst ◽  
Mathilde Richard
Keyword(s):  
Avian Influenza ◽  
Influenza A Virus ◽  
Influenza A ◽  
Vaccine Development ◽  
Influenza Pandemic ◽  
Broad Host Range ◽  
Influenza A Viruses ◽  
Vaccination Strategies ◽  
Pandemic Virus ◽  
Wide Range

Influenza A viruses can infect a wide range of hosts, creating opportunities for zoonotic transmission, i.e., transmission from animals to humans, and placing the human population at constant risk of potential pandemics. In the last hundred years, four influenza A virus pandemics have had a devastating effect, especially the 1918 influenza pandemic that took the lives of at least 40 million people. There is a constant risk that currently circulating avian influenza A viruses (e.g., H5N1, H7N9) will cause a new pandemic. Vaccines are the cornerstone in preparing for and combating potential pandemics. Despite exceptional advances in the design and development of (pre-)pandemic vaccines, there are still serious challenges to overcome, mainly caused by intrinsic characteristics of influenza A viruses: Rapid evolution and a broad host range combined with maintenance in animal reservoirs, making it near impossible to predict the nature and source of the next pandemic virus. Here, recent advances in the development of vaccination strategies to prepare against a pandemic virus coming from the avian reservoir will be discussed. Furthermore, remaining challenges will be addressed, setting the agenda for future research in the development of new vaccination strategies against potentially pandemic influenza A viruses.

scholarly journals Multiple Anti-Interferon Actions of the Influenza A Virus NS1 Protein

2007 ◽  
Vol 81 (13) ◽  
pp. 7011-7021 ◽  
Author(s):  
Georg Kochs ◽  
Adolfo García-Sastre ◽  
Luis Martínez-Sobrido
Keyword(s):  
Gene Expression ◽  
Influenza A Virus ◽  
Influenza A ◽  
Nonstructural Protein ◽  
Influenza Pandemic ◽  
Ns1 Protein ◽  
Cellular Genes ◽  
Cellular Mrnas ◽  
Cleavage And Polyadenylation ◽  
Specificity Factor

ABSTRACT The replication and pathogenicity of influenza A virus (FLUAV) are controlled in part by the alpha/beta interferon (IFN-α/β) system. This virus-host interplay is dependent on the production of IFN-α/β and on the capacity of the viral nonstructural protein NS1 to counteract the IFN system. Two different mechanisms have been described for NS1, namely, blocking the activation of IFN regulatory factor 3 (IRF3) and blocking posttranscriptional processing of cellular mRNAs. Here we directly compare the abilities of NS1 gene products from three different human FLUAV (H1N1) strains to counteract the antiviral host response. We found that A/PR/8/34 NS1 has a strong capacity to inhibit IRF3 and activation of the IFN-β promoter but is unable to suppress expression of other cellular genes. In contrast, the NS1 proteins of A/Tx/36/91 and of A/BM/1/18, the virus that caused the Spanish influenza pandemic, caused suppression of additional cellular gene expression. Thus, these NS1 proteins prevented the establishment of an IFN-induced antiviral state, allowing virus replication even in the presence of IFN. Interestingly, the block in gene expression was dependent on a newly described NS1 domain that is important for interaction with the cleavage and polyadenylation specificity factor (CPSF) component of the cellular pre-mRNA processing machinery but is not functional in A/PR/8/34 NS1. We identified the Phe-103 and Met-106 residues in NS1 as being critical for CPSF binding, together with the previously described C-terminal binding domain. Our results demonstrate the capacity of FLUAV NS1 to suppress the antiviral host defense at multiple levels and the existence of strain-specific differences that may modulate virus pathogenicity.

scholarly journals Influenza A virus co-opts ERI1 exonuclease bound to histone mRNA to promote viral transcription

2020 ◽  
Vol 48 (18) ◽  
pp. 10428-10440
Author(s):  
Marion Declercq ◽  
Elise Biquand ◽  
Marwah Karim ◽  
Natalia Pietrosemoli ◽  
Yves Jacob ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Rna Binding ◽  
Rna Stability ◽  
Screening Strategy ◽  
Virus Multiplication ◽  
Human Pathogens ◽  
Influenza A Viruses ◽  
Protein Protein Interaction ◽  
Multiplication Cycle

Abstract Cellular exonucleases involved in the processes that regulate RNA stability and quality control have been shown to restrict or to promote the multiplication cycle of numerous RNA viruses. Influenza A viruses are major human pathogens that are responsible for seasonal epidemics, but the interplay between viral proteins and cellular exonucleases has never been specifically studied. Here, using a stringent interactomics screening strategy and an siRNA-silencing approach, we identified eight cellular factors among a set of 75 cellular proteins carrying exo(ribo)nuclease activities or involved in RNA decay processes that support influenza A virus multiplication. We show that the exoribonuclease ERI1 interacts with the PB2, PB1 and NP components of the viral ribonucleoproteins and is required for viral mRNA transcription. More specifically, we demonstrate that the protein-protein interaction is RNA dependent and that both the RNA binding and exonuclease activities of ERI1 are required to promote influenza A virus transcription. Finally, we provide evidence that during infection, the SLBP protein and histone mRNAs co-purify with vRNPs alongside ERI1, indicating that ERI1 is most probably recruited when it is present in the histone pre-mRNA processing complex in the nucleus.

scholarly journals Protection against a Lethal Avian Influenza A Virus in a Mammalian System

1999 ◽  
Vol 73 (2) ◽  
pp. 1453-1459 ◽  
Author(s):  
Janice M. Riberdy ◽  
Kirsten J. Flynn ◽  
Juergen Stech ◽  
Robert G. Webster ◽  
John D. Altman ◽  
...  
Keyword(s):  
T Cell ◽  
Avian Influenza ◽  
Influenza A Virus ◽  
Influenza A ◽  
Influenza Pandemic ◽  
Immune Memory ◽  
H3n2 Virus ◽  
Influenza A Viruses ◽  
Cell Responses ◽  
Avian Influenza A Virus

ABSTRACT The question of how best to protect the human population against a potential influenza pandemic has been raised by the recent outbreak caused by an avian H5N1 virus in Hong Kong. The likely strategy would be to vaccinate with a less virulent, laboratory-adapted H5N1 strain isolated previously from birds. Little attention has been given, however, to dissecting the consequences of sequential exposure to serologically related influenza A viruses using contemporary immunology techniques. Such experiments with the H5N1 viruses are limited by the potential risk to humans. An extremely virulent H3N8 avian influenza A virus has been used to infect both immunoglobulin-expressing (Ig+/+) and Ig−/− mice primed previously with a laboratory-adapted H3N2 virus. The cross-reactive antibody response was very protective, while the recall of CD8+ T-cell memory in the Ig−/− mice provided some small measure of resistance to a low-dose H3N8 challenge. The H3N8 virus also replicated in the respiratory tracts of the H3N2-primed Ig+/+ mice, generating secondary CD8+ and CD4+ T-cell responses that may contribute to recovery. The results indicate that the various components of immune memory operate together to provide optimal protection, and they support the idea that related viruses of nonhuman origin can be used as vaccines.

scholarly journals Global dynamic spatiotemporal pattern of seasonal influenza since 2009 influenza pandemic

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Zhi-Wei Xu ◽  
Zhong-Jie Li ◽  
Wen-Biao Hu
Keyword(s):  
South Africa ◽  
Influenza A ◽  
Seasonal Influenza ◽  
Influenza Pandemic ◽  
Influenza Viruses ◽  
Sub Saharan Africa ◽  
Spatiotemporal Pattern ◽  
Influenza B ◽  
2009 Influenza Pandemic ◽  
Influenza Seasonality

Abstract Background Understanding the global spatiotemporal pattern of seasonal influenza is essential for influenza control and prevention. Available data on the updated global spatiotemporal pattern of seasonal influenza are scarce. This study aimed to assess the spatiotemporal pattern of seasonal influenza after the 2009 influenza pandemic. Methods Weekly influenza surveillance data in 86 countries from 2010 to 2017 were obtained from FluNet. First, the proportion of influenza A in total influenza viruses (PA) was calculated. Second, weekly numbers of influenza positive virus (A and B) were divided by the total number of samples processed to get weekly positive rates of influenza A (RWA) and influenza B (RWB). Third, the average positive rates of influenza A (RA) and influenza B (RB) for each country were calculated by averaging RWA, and RWB of 52 weeks. A Kruskal-Wallis test was conducted to examine if the year-to-year change in PA in all countries were significant, and a universal kriging method with linear semivariogram model was used to extrapolate RA and RB in all countries. Results PA ranged from 0.43 in Zambia to 0.98 in Belarus, and PA in countries with higher income was greater than those countries with lower income. The spatial patterns of high RB were the highest in sub-Saharan Africa, Asia-Pacific region and South America. RWA peaked in early weeks in temperate countries, and the peak of RWB occurred a bit later. There were some temperate countries with non-distinct influenza seasonality (e.g., Mauritius and Maldives) and some tropical/subtropical countries with distinct influenza seasonality (e.g., Chile and South Africa). Conclusions Influenza seasonality is not predictable in some temperate countries, and it is distinct in Chile, Argentina and South Africa, implying that the optimal timing for influenza vaccination needs to be chosen with caution in these unpredictable countries.

scholarly journals A multiplex real-time PCR assay for detection of oseltamivir-resistant strains of influenza virus

2014 ◽  
Vol 9 (6) ◽  
pp. 628-633
Author(s):  
Dawid Nidzworski ◽  
Joanna Dobkowska ◽  
Marcin Hołysz ◽  
Beata Gromadzka ◽  
Bogusław Szewczyk
Keyword(s):  
Real Time ◽  
Influenza A Virus ◽  
Real Time Pcr ◽  
Influenza A ◽  
Influenza Pandemic ◽  
Neuraminidase Inhibitor ◽  
Influenza Viruses ◽  
Antigenic Drift ◽  
Influenza A Viruses ◽  
Oseltamivir Resistance

AbstractInfluenza is a contagious disease of humans and animals caused by viruses belonging to the Orthomyxoviridae family. The influenza A virus genome consists of negative sense, single-stranded, segmented RNA. Influenza viruses are classified into subtypes based on two surface antigens known as hemagglutinin (H) and neuraminidase (N). The main problem with influenza A viruses infecting humans is drug resistance, which is caused by antigenic changes. A few antiviral drugs are available, but the most popular is the neuraminidase inhibitor — oseltamivir. The resistance against this drug has probably developed through antigenic drift by a point mutation in one amino acid at position 275 (H275Y). In order to prevent a possible influenza pandemic it is necessary to develop fast diagnostic tests. The aim of this project was to develop a new test for detection of influenza A virus and determination of oseltamivir resistance/sensitivity in humans. Detection and differentiation of oseltamivir resistance/sensitivity of influenza A virus was based on real-time PCR. This test contains two TaqMan probes, which work at different wavelengths. Application of techniques like multiplex real-time PCR has greatly enhanced the capability for surveillance and characterization of influenza viruses. After its potential validation, this test can be used for diagnosis before treatment.

scholarly journals H1N1 influenza – pandemic, 2009

2009 ◽  
Vol 150 (50) ◽  
pp. 2265-2273 ◽  
Author(s):  
János Osztovits ◽  
Csaba Balázs ◽  
János Fehér
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
H1n1 Virus ◽  
Influenza Pandemic ◽  
H1n1 Influenza ◽  
Virus H1n1 ◽  
H1n1 Influenza Pandemic

2009 márciusában egy új, addig csak sertésekben kimutatott influenza A-vírus H1N1-szubtípusa okozott emberi megbetegedéseket Mexikóban, majd három hónap alatt a föld minden régiójában elterjedt. Bár a mortalitás aránya alapján az új H1N1-fertőzések nem súlyosabbak a szezonális influenzajárványoknál, a gyors és globális terjedés miatt az Egészségügyi Világszervezet (WHO) 2009. július 11-én világméretű járványnak (pandémiának) nyilvánította a H1N1-fertőzést. 2009. október elejéig közel 400 000 igazolt H1N1-vírus-fertőzést és 5000 halálesetet ismerünk a világ minden tájáról. A fertőzés terjedésének üteme világszerte mérsékelten növekvő tendenciát mutat, bár Európában és Észak-Amerikában az őszi-téli időjárás várhatóan kedvezni fog a gyorsuló terjedésnek. A betegség az esetek többségében enyhe tünetekkel zajlik, láz, köhögés, torokfájás, izomfájdalmak jelentkezhetnek, melyek 3–7 nap alatt spontán elmúlnak. Ekkor az otthon maradás javasolt, a fertőzés továbbadásának elkerülése céljából. Orvoshoz kell fordulni a fokozott kockázatú betegeknek, és szövődmény kialakulásának gyanújakor. Ez esetben szóba jön az antivirális kezelés, illetve más gyógyszeres vagy szükség esetén intenzív terápia is. A H1N1-pandémia elleni védekezés legfontosabb eleme a megelőzés, amely egyrészt a higiénés előírások ismeretét és betartását jelenti, különösen közösségekben, másrészt a védőoltás mérlegelését. A rendelkezésre álló tudományos igényű tanulmányok nagy esetszámú és sokéves tapasztalatokról számolnak be a jelenleg is alkalmazott influenza-védőoltásokkal kapcsolatban. Néhány speciális csoport esetében (várandós anyák az első trimeszterben, 6 hónaposnál fiatalabb gyermekek) az influenzavakcina adása – tapasztalatok hiánya miatt – nem javasolt, de a népesség túlnyomó többsége számára a védőoltás ellen jelentős érv nem ismert. Az influenza elleni védőoltás hatására esetlegesen jelentkező szövődmények enyhék, ezek kockázata nagyságrendekkel kisebb az influenzafertőzés okozta szövődmények és mortalitás rizikójánál.

scholarly journals The PB2-E627K Mutation Attenuates Viruses Containing the 2009 H1N1 Influenza Pandemic Polymerase

mBio ◽  
2010 ◽  
Vol 1 (1) ◽  
Author(s):  
Brett W. Jagger ◽  
Matthew J. Memoli ◽  
Zong-Mei Sheng ◽  
Li Qi ◽  
Rachel J. Hrabal ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
H1n1 Virus ◽  
Influenza Pandemic ◽  
Influenza Infection ◽  
H1n1 Influenza ◽  
Influenza Viruses ◽  
Pandemic Virus ◽  
2009 H1n1 ◽  
Animal Reservoirs

ABSTRACTThe swine-origin H1N1 influenza A virus emerged in early 2009 and caused the first influenza pandemic in 41 years. The virus has spread efficiently to both the Northern and the Southern Hemispheres and has been associated with over 16,000 deaths. Given the virus’s recent zoonotic origin, there is concern that the virus could acquire signature mutations associated with the enhanced pathogenicity of previous pandemic viruses or H5N1 viruses with pandemic potential. We tested the hypothesis that mutations in the polymerase PB2 gene at residues 627 and 701 would enhance virulence but found that influenza viruses containing these mutations in the context of the pandemic virus polymerase complex are attenuated in cell culture and mice.IMPORTANCEInfluenza A virus (IAV) evolution is characterized by host-specific lineages, and IAVs derived in whole or in part from animal reservoirs have caused pandemics in humans. Because IAVs are known to acquire host-adaptive genome mutations, and since the PB2 gene of the 2009 H1N1 virus is of recent avian derivation, there exists concern that the pathogenicity of the 2009 H1N1 influenza A pandemic virus could be potentiated by acquisition of the host-adaptive PB2-E627K or -D701N mutations, which have been shown to enhance the virulence of other influenza viruses. We present data from a mouse model of influenza infection showing that such mutations do not increase the virulence of viruses containing the 2009 H1N1 viral polymerase.

scholarly journals Influenza A Virus Reassortment Is Limited by Anatomical Compartmentalization following Coinfection via Distinct Routes

2017 ◽  
Vol 92 (5) ◽  
Author(s):  
Mathilde Richard ◽  
Sander Herfst ◽  
Hui Tao ◽  
Nathan T. Jacobs ◽  
Anice C. Lowen
Keyword(s):  
Respiratory Tract ◽  
Influenza A Virus ◽  
Lower Respiratory Tract ◽  
Influenza A ◽  
Upper Respiratory Tract ◽  
Extrinsic Factors ◽  
Genetic Incompatibility ◽  
Viral Spread ◽  
Virus Reassortment ◽  
The Impact

ABSTRACTExchange of gene segments through reassortment is a major feature of influenza A virus evolution and frequently contributes to the emergence of novel epidemic, pandemic, and zoonotic strains. It has long been evident that viral diversification through reassortment is constrained by genetic incompatibility between divergent parental viruses. In contrast, the role of virus-extrinsic factors in determining the likelihood of reassortment has remained unclear. To evaluate the impact of such factors in the absence of confounding effects of segment mismatch, we previously reported an approach in which reassortment between wild-type (wt) and genetically tagged variant (var) viruses of the same strain is measured. Here, using wt/var systems in the A/Netherlands/602/2009 (pH1N1) and A/Panama/2007/99 (H3N2) strain backgrounds, we tested whether inoculation of parental viruses into distinct sites within the respiratory tract limits their reassortment. Using a ferret (Mustella putorius furo) model, either matched parental viruses were coinoculated intranasally or one virus was instilled intranasally whereas the second was instilled intratracheally. Dual intranasal inoculation resulted in robust reassortment for wt/var viruses of both strain backgrounds. In contrast, when infections were initiated simultaneously at distinct sites, strong compartmentalization of viral replication was observed and minimal reassortment was detected. The observed lack of viral spread between upper and lower respiratory tract tissues may be attributable to localized exclusion of superinfection within the host, mediated by innate immune responses. Our findings indicate that dual infections in nature are more likely to result in reassortment if viruses are seeded into similar anatomical locations and have matched tissue tropisms.IMPORTANCEGenetic exchange between influenza A viruses (IAVs) through reassortment can facilitate the emergence of antigenically drifted seasonal strains and plays a prominent role in the development of pandemics. Typical human influenza infections are concentrated in the upper respiratory tract; however, lower respiratory tract (LRT) infection is an important feature of severe cases, which are more common in the very young, the elderly, and individuals with underlying conditions. In addition to host factors, viral characteristics and mode of transmission can also increase the likelihood of LRT infection: certain zoonotic IAVs are thought to favor the LRT, and transmission via small droplets allows direct seeding into lower respiratory tract tissues. To gauge the likelihood of reassortment in coinfected hosts, we assessed the extent to which initiation of infection at distinct respiratory tract sites impacts reassortment frequency. Our results reveal that spatially distinct inoculations result in anatomical compartmentalization of infection, which in turn strongly limits reassortment.

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