scholarly journals Host Protective Immune Responses against Influenza A Virus Infection

Viruses ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 504 ◽  
Author(s):  
Hi Eun Jung ◽  
Heung Kyu Lee
Keyword(s):  
Immune Responses ◽  
Influenza A ◽  
Current Knowledge ◽  
Influenza Viruses ◽  
Health Concern ◽  
Genetic Mutations ◽  
Public Health Concern ◽  
Influenza A Viruses ◽  
Influenza A Virus Infection ◽  
Influenza Outbreaks

Influenza viruses cause infectious respiratory disease characterized by fever, myalgia, and congestion, ranging in severity from mild to life-threating. Although enormous efforts have aimed to prevent and treat influenza infections, seasonal and pandemic influenza outbreaks remain a major public health concern. This is largely because influenza viruses rapidly undergo genetic mutations that restrict the long-lasting efficacy of vaccine-induced immune responses and therapeutic regimens. In this review, we discuss the virological features of influenza A viruses and provide an overview of current knowledge of the innate sensing of invading influenza viruses and the protective immune responses in the host.

scholarly journals Broadly Reactive H2 Hemagglutinin Vaccines Elicit Cross-Reactive Antibodies in Ferrets Preimmune to Seasonal Influenza A Viruses

mSphere ◽  
2021 ◽  
Vol 6 (2) ◽  
Author(s):  
Z. Beau Reneer ◽  
Amanda L. Skarlupka ◽  
Parker J. Jamieson ◽  
Ted M. Ross
Keyword(s):  
Influenza Virus ◽  
Immune Responses ◽  
Recombinant Proteins ◽  
Human Population ◽  
Influenza A ◽  
Seasonal Influenza ◽  
Influenza Viruses ◽  
Wild Type ◽  
Influenza A Viruses ◽  
Global Pandemic

ABSTRACT Influenza vaccines have traditionally been tested in naive mice and ferrets. However, humans are first exposed to influenza viruses within the first few years of their lives. Therefore, there is a pressing need to test influenza virus vaccines in animal models that have been previously exposed to influenza viruses before being vaccinated. In this study, previously described H2 computationally optimized broadly reactive antigen (COBRA) hemagglutinin (HA) vaccines (Z1 and Z5) were tested in influenza virus “preimmune” ferret models. Ferrets were infected with historical, seasonal influenza viruses to establish preimmunity. These preimmune ferrets were then vaccinated with either COBRA H2 HA recombinant proteins or wild-type H2 HA recombinant proteins in a prime-boost regimen. A set of naive preimmune or nonpreimmune ferrets were also vaccinated to control for the effects of the multiple different preimmunities. All of the ferrets were then challenged with a swine H2N3 influenza virus. Ferrets with preexisting immune responses influenced recombinant H2 HA-elicited antibodies following vaccination, as measured by hemagglutination inhibition (HAI) and classical neutralization assays. Having both H3N2 and H1N1 immunological memory regardless of the order of exposure significantly decreased viral nasal wash titers and completely protected all ferrets from both morbidity and mortality, including the mock-vaccinated ferrets in the group. While the vast majority of the preimmune ferrets were protected from both morbidity and mortality across all of the different preimmunities, the Z1 COBRA HA-vaccinated ferrets had significantly higher antibody titers and recognized the highest number of H2 influenza viruses in a classical neutralization assay compared to the other H2 HA vaccines. IMPORTANCE H1N1 and H3N2 influenza viruses have cocirculated in the human population since 1977. Nearly every human alive today has antibodies and memory B and T cells against these two subtypes of influenza viruses. H2N2 influenza viruses caused the 1957 global pandemic and people born after 1968 have never been exposed to H2 influenza viruses. It is quite likely that a future H2 influenza virus could transmit within the human population and start a new global pandemic, since the majority of people alive today are immunologically naive to viruses of this subtype. Therefore, an effective vaccine for H2 influenza viruses should be tested in an animal model with previous exposure to influenza viruses that have circulated in humans. Ferrets were infected with historical influenza A viruses to more accurately mimic the immune responses in people who have preexisting immune responses to seasonal influenza viruses. In this study, preimmune ferrets were vaccinated with wild-type (WT) and COBRA H2 recombinant HA proteins in order to examine the effects that preexisting immunity to seasonal human influenza viruses have on the elicitation of broadly cross-reactive antibodies from heterologous vaccination.

scholarly journals Structural and Molecular Characterization of the Hemagglutinin from the Fifth-Epidemic-Wave A(H7N9) Influenza Viruses

2018 ◽  
Vol 92 (16) ◽  
Author(s):  
Hua Yang ◽  
Paul J. Carney ◽  
Jessie C. Chang ◽  
Zhu Guo ◽  
James Stevens
Keyword(s):  
Public Health ◽  
Avian Influenza ◽  
Influenza A ◽  
Human Infection ◽  
Influenza Viruses ◽  
Surface Proteins ◽  
Health Concern ◽  
Public Health Concern ◽  
H7n9 Influenza ◽  
Epidemic Wave

ABSTRACTThe avian influenza A(H7N9) virus continues to cause human infections in China and is a major ongoing public health concern. Five epidemic waves of A(H7N9) infection have occurred since 2013, and the recent fifth epidemic wave saw the emergence of two distinct lineages with elevated numbers of human infection cases and broader geographic distribution of viral diseases compared to the first four epidemic waves. Moreover, highly pathogenic avian influenza (HPAI) A(H7N9) viruses were also isolated during the fifth epidemic wave. Here, we present a detailed structural and biochemical analysis of the surface hemagglutinin (HA) antigen from viruses isolated during this recent epidemic wave. Results highlight that, compared to the 2013 virus HAs, the fifth-wave virus HAs remained a weak binder to human glycan receptor analogs. We also studied three mutations, V177K-K184T-G219S, that were recently reported to switch a 2013 A(H7N9) HA to human-type receptor specificity. Our results indicate that these mutations could also switch the H7 HA receptor preference to a predominantly human binding specificity for both fifth-wave H7 HAs analyzed in this study.IMPORTANCEThe A(H7N9) viruses circulating in China are of great public health concern. Here, we report a molecular and structural study of the major surface proteins from several recent A(H7N9) influenza viruses. Our results improve the understanding of these evolving viruses and provide important information on their receptor preference that is central to ongoing pandemic risk assessment.

scholarly journals Influenza Viruses and mRNA Splicing: Doing More with Less

mBio ◽  
2014 ◽  
Vol 5 (3) ◽  
Author(s):  
Julia Dubois ◽  
Olivier Terrier ◽  
Manuel Rosa-Calatrava
Keyword(s):  
Influenza A ◽  
Current Knowledge ◽  
Influenza Viruses ◽  
Splicing Regulation ◽  
Influenza A Viruses ◽  
Sequence Alignments ◽  
Cellular Expression ◽  
Replication Stage ◽  
Regulation Mechanisms ◽  
Splicing Machinery

ABSTRACTDuring their nuclear replication stage, influenza viruses hijack the host splicing machinery to process some of their RNA segments, the M and NS segments. In this review, we provide an overview of the current knowledge gathered on this interplay between influenza viruses and the cellular spliceosome, with a particular focus on influenza A viruses (IAV). These viruses have developed accurate regulation mechanisms to reassign the host spliceosome to alter host cellular expression and enable an optimal expression of specific spliced viral products throughout infection. Moreover, IAV segments undergoing splicing display high levels of similarity with human consensus splice sites and their viral transcripts show noteworthy secondary structures. Sequence alignments and consensus analyses, along with recently published studies, suggest both conservation and evolution of viral splice site sequences and structure for improved adaptation to the host. Altogether, these results emphasize the ability of IAV to be well adapted to the host’s splicing machinery, and further investigations may contribute to a better understanding of splicing regulation with regard to viral replication, host range, and pathogenesis.

scholarly journals Antiviral Susceptibility of Variant Influenza A(H3N2)v Viruses Isolated in the United States from 2011 to 2013

2014 ◽  
Vol 58 (4) ◽  
pp. 2045-2051 ◽  
Author(s):  
K. Sleeman ◽  
V. P. Mishin ◽  
Z. Guo ◽  
R. J. Garten ◽  
A. Balish ◽  
...  
Keyword(s):  
United States ◽  
Influenza A ◽  
Untreated Patient ◽  
Continuous Monitoring ◽  
The United States ◽  
Antiviral Drugs ◽  
Influenza Viruses ◽  
Health Concern ◽  
Public Health Concern ◽  
M Gene

ABSTRACTSince 2011, outbreaks caused by influenza A(H3N2) variant [A(H3N2)v] viruses have become a public health concern in the United States. The A(H3N2)v viruses share the A(H1N1)pdm09 M gene containing the marker of M2 blocker resistance, S31N, but do not contain any known molecular markers associated with resistance to neuraminidase (NA) inhibitors (NAIs). Using a fluorescent NA inhibition (NI) assay, the susceptibilities of recovered A(H3N2)v viruses (n= 168) to FDA-approved (oseltamivir and zanamivir) and other (peramivir, laninamivir, and A-315675) NAIs were assessed. All A(H3N2)v viruses tested, with the exception of a single virus strain, A/Ohio/88/2012, isolated from an untreated patient, were susceptible to the NAIs tested. The A/Ohio/88/2012 virus contained two rare substitutions, S245N and S247P, in the NA and demonstrated reduced inhibition by oseltamivir (31-fold) and zanamivir (66-fold) in the NI assay. Using recombinant NA (recNA) proteins, S247P was shown to be responsible for the observed altered NAI susceptibility, in addition to an approximately 60% reduction in NA enzymatic activity. The S247P substitution has not been previously reported as a molecular marker of reduced susceptibility to the NAIs. Using cell culture assays, the investigational antiviral drugs nitazoxanide, favipiravir, and fludase were shown to inhibit the replication of A(H3N2)v viruses, including the virus with the S247P substitution in the NA. This report demonstrates the importance of continuous monitoring of susceptibility of zoonotic influenza viruses to available and investigational antiviral drugs.

scholarly journals Inhibition of host innate immune responses and pathogenicity of recombinant Newcastle disease viruses expressing NS1 genes of influenza A viruses

2010 ◽  
Vol 91 (8) ◽  
pp. 1996-2001 ◽  
Author(s):  
Shin-Hee Kim ◽  
Siba K. Samal
Keyword(s):  
Immune Responses ◽  
Newcastle Disease ◽  
Influenza A ◽  
Rna Binding ◽  
Mutational Analysis ◽  
Influenza Viruses ◽  
Innate Immune ◽  
Ns1 Protein ◽  
Innate Immune Responses ◽  
Influenza A Viruses

The NS1 protein has been associated with the virulence of influenza A viruses. To evaluate the role of the NS1 protein in pathogenicity of pandemic H5N1 avian influenza and H1N1 2009 influenza viruses, recombinant Newcastle disease viruses (rNDVs) expressing NS1 proteins were generated. Expression of the NS1 proteins resulted in inhibition of host innate immune responses (beta interferon and protein kinase R production). In addition, the NS1 proteins were localized predominantly in the nucleus of virus-infected cells. Consequently, expression of the NS1 protein contributed to an increase in pathogenicity of rNDV in chickens. In particular, mutational analysis of H5N1 NS1 protein indicated that both the RNA-binding and effector domains affect virus pathogenicity synergistically. Our study also demonstrated that expression of H1N1/09 NS1 resulted in enhanced replication of rNDV in human cells, indicating that function of the NS1 proteins can be host-species-specific.

Cross-protective immunity of the hemagglutinin stalk domain presented on the surface of Lactococcus lactis against divergent influenza viruses in mice

2020 ◽  
Author(s):  
Han Lei ◽  
Tong Gao ◽  
Qianhong Cen
Keyword(s):  
Immune Responses ◽  
Protective Immunity ◽  
Influenza A ◽  
Influenza Viruses ◽  
Cross Protection ◽  
Influenza A Viruses ◽  
Universal Vaccine ◽  
Influenza Hemagglutinin ◽  
Alternative Approach ◽  
Stalk Domain

Abstract Background Most of the current approaches to influenza vaccine design focus on antibodies against influenza hemagglutinin (HA). However, these influenza vaccines typically provide strain-specific protection against mostly homologous subtypes. There is an urgent need to develop a universal vaccine that confers cross-protection against influenza viruses. Of note, the HA stalk domain (HAs) is a new target for such an influenza vaccine.Results Recombinant L.lactis/pNZ8150-pgsA-HAs constructed in which pgsA was used as an anchor protein and investigated the immunogenicity of HAs, in the mouse model by oral administration without the use of a mucosal adjuvant. Mice were orally vaccinated with L.lactis/pNZ8150-pgsA-HAs, and then produced significant humoral and mucosal immune responses. Importantly, L.lactis/pNZ8150-pgsA-HAs provided significant cross-protection against H5N1, H3N2 or H1N1 virus infection.Conclusions Our data support the hypothesis that HAs presented on the surface of L. lactis can provide cross-protective immunity against influenza A viruses. Taken together, these findings suggest that L.lactis/pNZ8150-pgsA-HAs can be considered an alternative approach to developing a novel universal vaccine during an influenza A pandemic.

scholarly journals Deep Sequencing of H7N9 Influenza A Viruses from 16 Infected Patients from 2013 to 2015 in Shanghai Reveals Genetic Diversity and Antigenic Drift

mSphere ◽  
2018 ◽  
Vol 3 (5) ◽  
Author(s):  
Yong-Li Xiao ◽  
Lili Ren ◽  
Xi Zhang ◽  
Li Qi ◽  
John C. Kash ◽  
...  
Keyword(s):  
Avian Influenza ◽  
Deep Sequencing ◽  
Influenza A ◽  
Influenza Viruses ◽  
Antigenic Drift ◽  
Health Concern ◽  
Nucleotide Polymorphisms ◽  
Influenza A Viruses ◽  
Avian Influenza Viruses ◽  
H7n9 Influenza

ABSTRACTInfluenza A virus (IAV) infections are a major public health concern, including annual epidemics, epizootic outbreaks, and pandemics. A significant IAV epizootic outbreak was the H7N9 avian influenza A outbreak in China, which was first detected in 2013 and which has spread over 5 waves from 2013 to 2017, causing human infections in many different Chinese provinces. Here, RNA from primary clinical throat swab samples from 20 H7N9-infected local patients with different clinical outcomes, who were admitted and treated at one hospital in Shanghai, China, from April 2013 to April 2015, was analyzed. Whole-transcriptome amplification, with positive enrichment of IAV RNA, was performed, all 20 samples were subjected to deep sequencing, and data from 16 samples were analyzed in detail. Many single-nucleotide polymorphisms, including ones not previously reported, and many nonsynonymous changes that could affect hemagglutinin head and stalk antibody binding epitopes were observed. Minor populations representing viral quasispecies, including nonsynonymous hemagglutinin changes shared by antigenically variant H7N9 clades identified in the most recent wave of H7N9 infections in 2016 to 2017, were also identified.IMPORTANCEH7N9 subtype avian influenza viruses caused infections in over 1,400 humans from 2013 to 2017 and resulted in almost 600 deaths. It is important to understand how avian influenza viruses infect and cause disease in humans and to assess their potential for efficient person-to-person transmission. In this study, we used deep sequencing of primary clinical material to assess the evolution and potential for human adaptation of H7N9 influenza viruses.

scholarly journals The Microminipig as an Animal Model for Influenza A Virus Infection

2016 ◽  
Vol 91 (2) ◽  
Author(s):  
Kiyoko Iwatsuki-Horimoto ◽  
Noriko Nakajima ◽  
Masatoshi Shibata ◽  
Kenta Takahashi ◽  
Yuko Sato ◽  
...  
Keyword(s):  
Animal Model ◽  
Virus Infection ◽  
Influenza A Virus ◽  
Experimental Animal ◽  
Influenza A ◽  
Influenza Viruses ◽  
Experimental Animal Model ◽  
Influenza A Viruses ◽  
Miniature Pigs ◽  
Influenza A Virus Infection

ABSTRACT Pigs are considered a mixing vessel for the generation of novel pandemic influenza A viruses through reassortment because of their susceptibility to both avian and human influenza viruses. However, experiments to understand reassortment in pigs in detail have been limited because experiments with regular-sized pigs are difficult to perform. Miniature pigs have been used as an experimental animal model, but they are still large and require relatively large cages for housing. The microminipig is one of the smallest miniature pigs used for experiments. Introduced in 2010, microminipigs weigh around 10 kg at an early stage of maturity (6 to 7 months old) and are easy to handle. To evaluate the microminipig as an animal model for influenza A virus infection, we compared the receptor distribution of 10-week-old male pigs (Yorkshire Large White) and microminipigs. We found that both animals have SAα2,3Gal and SAα2,6Gal in their respiratory tracts, with similar distributions of both receptor types. We further found that the sensitivity of microminipigs to influenza A viruses was the same as that of larger miniature pigs. Our findings indicate that the microminipig could serve as a novel model animal for influenza A virus infection. IMPORTANCE The microminipig is one of the smallest miniature pigs in the world and is used as an experimental animal model for life science research. In this study, we evaluated the microminipig as a novel animal model for influenza A virus infection. The distribution of influenza virus receptors in the respiratory tract of the microminipig was similar to that of the pig, and the sensitivity of microminipigs to influenza A viruses was the same as that of miniature pigs. Our findings suggest that microminipigs represent a novel animal model for influenza A virus infection.

scholarly journals Broadly Reactive H2 Hemagglutinin Vaccines Elicit Cross-Reactive Antibodies in Ferrets Pre-Immune to Seasonal Influenza A Viruses

2021 ◽  
Author(s):  
Z. Beau Reneer ◽  
Amanda S. Skarlupka ◽  
Parker J. Jamieson ◽  
Ted M. Ross
Keyword(s):  
Influenza Virus ◽  
Immune Responses ◽  
Recombinant Proteins ◽  
Human Population ◽  
Influenza A ◽  
Seasonal Influenza ◽  
Influenza Viruses ◽  
Morbidity And Mortality ◽  
Influenza A Viruses ◽  
Global Pandemic

AbstractInfluenza vaccines have traditionally been tested in naïve mice and ferrets. However, humans are first exposed to influenza viruses within the first few years of their lives. Therefore, there is a pressing need to test influenza virus vaccines in animal models that have been previously exposed to influenza viruses before being vaccinated. In this manuscript, previously described H2 computationally optimized broadly reactive antigen (COBRA) HA vaccines (Z1, Z5) were tested in influenza virus ‘pre-immune’ ferret models. Ferrets were infected with historical, seasonal influenza viruses to establish pre-immunity. These pre-immune ferrets were then vaccinated with either COBRA H2 HA recombinant proteins or WT H2 HA recombinant proteins in a prime-boost regimen. A set of naïve pre-immune or non pre-immune ferrets were also vaccinated to control of the effects of the multiple different pre-immunities. All of the ferrets were then challenged with a swine H2N3 influenza virus. Ferrets with pre-existing immune responses influenced recombinant H2 HA elicited antibodies following vaccination as measured by HAI and classical neutralization assays. Having both H3N2 and H1N1 immunological memory regardless of the order of exposure significantly decreased viral nasal wash titers and completely protected all ferrets from both morbidity and mortality, including the mock vaccinated ferrets in the group. While the vast majority of the pre-immune ferrets were protected from both morbidity and mortality across all of the different pre-immunities, the Z1 COBRA HA vaccinated ferrets had significantly higher antibody titers and recognized the highest number H2 influenza viruses in a classical neutralization assay compared to the other H2 HA vaccines.ImportanceH1N1 and H3N2 influenza viruses have co-circulated in the human population since 1977. Nearly every human alive today has antibodies and memory B and T cells against these two subtypes of influenza viruses. H2N2 influenza viruses caused the 1957 global pandemic and people born after 1968 have never been exposed to H2 influenza viruses. It is quite likely that a future H2 influenza virus could transmit within the human population and start a new global pandemic, since the majority of people alive today are immunologically naïve to viruses of this subtype. Therefore, an effective vaccine for H2 influenza viruses should be tested in an animal model with previous exposure to influenza viruses that have circulated in humans. Ferrets were infected with historical influenza A viruses to more accurately mimic the immune responses in people who have pre-existing immune responses to seasonal influenza viruses. In this study, pre-immune ferrets were vaccinated with WT and COBRA H2 recombinant HA proteins in order to examine the effects of pre-existing immunity to seasonal human influenza viruses have on the elicitation of broadly cross-reactive antibodies from heterologous vaccination.

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