Avian Influenza H6 Viruses Productively Infect and Cause Illness in Mice and Ferrets

ABSTRACT Influenza pandemic preparedness has focused on influenza virus H5 and H7 subtypes. However, it is not possible to predict with certainty which subtype of avian influenza virus will cause the next pandemic, and it is prudent to include other avian influenza virus subtypes in pandemic preparedness efforts. An H6 influenza virus was identified as a potential progenitor of the H5N1 viruses that emerged in Hong Kong in 1997. This virus continues to circulate in the bird population in Asia, and other H6 viruses are prevalent in birds in North America and Asia. The high rate of reassortment observed in influenza viruses and the prevalence of H6 viruses in birds suggest that this subtype may pose a pandemic risk. Very little is known about the replicative capacity, immunogenicity, and correlates of protective immunity for low-pathogenicity H6 influenza viruses in mammals. We evaluated the antigenic and genetic relatedness of 14 H6 influenza viruses and their abilities to replicate and induce a cross-reactive immune response in two animal models: mice and ferrets. The different H6 viruses replicated to different levels in the respiratory tracts of mice and ferrets, causing varied degrees of morbidity and mortality in these two models. H6 virus infection induced similar patterns of neutralizing antibody responses in mice and ferrets; however, species-specific differences in the cross-reactivity of the antibody responses were observed. Overall, cross-reactivity of neutralizing antibodies in H6 virus-infected mice did not correlate well with protection against heterologous wild-type H6 viruses. However, we have identified an H6 virus that induces protective immunity against viruses in the North American and Eurasian lineages.

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Potency of an Inactivated Influenza Vaccine against a Challenge with A/Swine/Missouri/A01727926/2015 (H4N6) in Mice for Pandemic Preparedness

Vaccines ◽

10.3390/vaccines8040768 ◽

2020 ◽

Vol 8 (4) ◽

pp. 768

Author(s):

Hirotaka Hayashi ◽

Norikazu Isoda ◽

Enkhbold Bazarragchaa ◽

Naoki Nomura ◽

Keita Matsuno ◽

...

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Neutralizing Antibodies ◽

Influenza Pandemic ◽

Influenza Virus Infection ◽

Cross Reactivity ◽

Influenza Viruses ◽

Pandemic Preparedness ◽

Antigenic Relation ◽

High Immunogenicity

H4 influenza viruses have been isolated from birds across the world. In recent years, an H4 influenza virus infection has been confirmed in pigs. Pigs play an important role in the transmission of influenza viruses to human hosts. Therefore, it is important to develop a new vaccine in the case of an H4 influenza virus infection in humans, considering that this virus has a different antigenicity from seasonal human influenza viruses. In this study, after selecting vaccine candidate strains based on their antigenic relation to one of the pig isolates, A/swine/Missouri/A01727926/2015 (H4N6) (MO/15), an inactivated whole-particle vaccine was prepared from A/swan/Hokkaido/481102/2017 (H4N6). This vaccine showed high immunogenicity in mice, and the antibody induced by the vaccine showed high cross-reactivity to the MO/15 virus. This vaccine induced sufficient neutralizing antibodies and mitigated the effects of an MO/15 infection in a mouse model. This study is the first to suggest that an inactivated whole-particle vaccine prepared from an influenza virus isolated from wild birds is an effective countermeasure in case of a future influenza pandemic caused by the H4 influenza virus.

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Seroepizootiological investigations of animals from Obedska bara locality for presence of Avian influenza virus

Veterinarski glasnik ◽

10.2298/vetgl1006307d ◽

2010 ◽

Vol 64 (5-6) ◽

pp. 307-317

Author(s):

Bosiljka Djuricic ◽

Ana Samokovlija ◽

Zivka Ilic ◽

Dragan Bacic ◽

Sonja Radojicic ◽

...

Keyword(s):

Influenza Virus ◽

Hong Kong ◽

Avian Influenza ◽

Avian Influenza Virus ◽

Influenza A ◽

Migratory Birds ◽

Type A ◽

Influenza Viruses ◽

High Rate ◽

Virus Serotype

The disease caused by Influenza viruses has been well known for a very long time. In the recent period there has been noted an occurrence of pandemics caused by Influenza viruses type A with a high rate of mortality. The ongoing pandemic caused by avian influenza virus serotype H9N9 began in Hong Kong in 1992, and another pandemic caused by serotype H5N1 began in China (Hong Kong) in 1999. The world wide spreading of these viruses occurred due to migratory birds. Avian influenza was confirmed in Serbia in 2007. The goal of this study was to examine whether the avian influenza viruses type A circulate in the region of the Obedska bara marsh, which is a famous resort for many birds in Serbia, as well as many birds migrating from Europe to Africa and vice versa. The samples of blood sera of many animal species (123 samples from fowl, 64 samples from donkeys, 40 samples from horses) were tested by serologic reaction of inhibition of haemmaglutination (IHA) for the presence of antibodies to influenza A subtypes H5N1, H5N2, H5N3, H7N1 and H7N2. Also, the samples of blood sera of experimental chicken exposed to wild life in Obedska bara (sentinel species) were tested. Antibodies to subtypes H5N1, H5N2, H5N3, H7N1 and H7N2 were found in chicken from Dec, Boljevci, Petrovcic and Kupinovo villages but no antibodies were found in blood sera from hams from Dobanovci, Jakovo, Becmen and Surcin villages. From 23 samples from ducks antibodies were detected in 3 samples, and from 22 geese blood sera antibodies were found in 4 samples. From a total of 40 horse blood sera tested one was tested positive, and from 64 donkey sera 17 were positive for the presence of antibodies for avian influenza type A. In blood sera of experimental chicken antibodies were found by subtype H5N1 with corrections with H5N2 and H7N1.

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Infection of HLA-DR1 Transgenic Mice with a Human Isolate of Influenza A Virus (H1N1) Primes a Diverse CD4 T-Cell Repertoire That Includes CD4 T Cells with Heterosubtypic Cross-Reactivity to Avian (H5N1) Influenza Virus

Journal of Virology ◽

10.1128/jvi.00302-09 ◽

2009 ◽

Vol 83 (13) ◽

pp. 6566-6577 ◽

Cited By ~ 52

Author(s):

Katherine A. Richards ◽

Francisco A. Chaves ◽

Andrea J. Sant

Keyword(s):

T Cells ◽

Influenza Virus ◽

T Cell ◽

Avian Influenza ◽

Avian Influenza Virus ◽

Cd4 T Cells ◽

Cross Reactivity ◽

Cd4 T Cell ◽

Ns1 Protein ◽

Infected Cells

ABSTRACT The specificity of the CD4 T-cell immune response to influenza virus is influenced by the genetic complexity of the virus and periodic encounters with variant subtypes and strains. In order to understand what controls CD4 T-cell reactivity to influenza virus proteins and how the influenza virus-specific memory compartment is shaped over time, it is first necessary to understand the diversity of the primary CD4 T-cell response. In the study reported here, we have used an unbiased approach to evaluate the peptide specificity of CD4 T cells elicited after live influenza virus infection. We have focused on four viral proteins that have distinct intracellular distributions in infected cells, hemagglutinin (HA), neuraminidase (NA), nucleoprotein, and the NS1 protein, which is expressed in infected cells but excluded from virion particles. Our studies revealed an extensive diversity of influenza virus-specific CD4 T cells that includes T cells for each viral protein and for the unexpected immunogenicity of the NS1 protein. Due to the recent concern about pandemic avian influenza virus and because CD4 T cells specific for HA and NA may be particularly useful for promoting the production of neutralizing antibody to influenza virus, we have also evaluated the ability of HA- and NA-specific CD4 T cells elicited by a circulating H1N1 strain to cross-react with related sequences found in an avian H5N1 virus and find substantial cross-reactivity, suggesting that seasonal vaccines may help promote protection against avian influenza virus.

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Swine ANP32A Supports Avian Influenza Virus Polymerase

Journal of Virology ◽

10.1128/jvi.00132-20 ◽

2020 ◽

Vol 94 (12) ◽

Cited By ~ 2

Author(s):

Thomas P. Peacock ◽

Olivia C. Swann ◽

Hamish A. Salvesen ◽

Ecco Staller ◽

P. Brian Leung ◽

...

Keyword(s):

Influenza Virus ◽

Avian Influenza ◽

Avian Influenza Virus ◽

Virus Replication ◽

Mammalian Species ◽

Gene Mutations ◽

Influenza Viruses ◽

Avian Influenza Viruses ◽

2009 H1n1 ◽

Mixing Vessels

ABSTRACT Avian influenza viruses occasionally infect and adapt to mammals, including humans. Swine are often described as “mixing vessels,” being susceptible to both avian- and human-origin viruses, which allows the emergence of novel reassortants, such as the precursor to the 2009 H1N1 pandemic. ANP32 proteins are host factors that act as influenza virus polymerase cofactors. In this study, we describe how swine ANP32A, uniquely among the mammalian ANP32 proteins tested, supports the activity of avian-origin influenza virus polymerases and avian influenza virus replication. We further show that after the swine-origin influenza virus emerged in humans and caused the 2009 pandemic, it evolved polymerase gene mutations that enabled it to more efficiently use human ANP32 proteins. We map the enhanced proviral activity of swine ANP32A to a pair of amino acids, 106 and 156, in the leucine-rich repeat and central domains and show these mutations enhance binding to influenza virus trimeric polymerase. These findings help elucidate the molecular basis for the mixing vessel trait of swine and further our understanding of the evolution and ecology of viruses in this host. IMPORTANCE Avian influenza viruses can jump from wild birds and poultry into mammalian species such as humans or swine, but they only continue to transmit if they accumulate mammalian adapting mutations. Pigs appear uniquely susceptible to both avian and human strains of influenza and are often described as virus “mixing vessels.” In this study, we describe how a host factor responsible for regulating virus replication, ANP32A, is different between swine and humans. Swine ANP32A allows a greater range of influenza viruses, specifically those from birds, to replicate. It does this by binding the virus polymerase more tightly than the human version of the protein. This work helps to explain the unique properties of swine as mixing vessels.

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Specific Antibody Responses and Generation of Antigenic Variants in Chickens Immunized against a Virulent Avian Influenza Virus

Avian Diseases ◽

10.2307/1591337 ◽

1990 ◽

Vol 34 (1) ◽

pp. 80 ◽

Cited By ~ 7

Author(s):

Virginia S. Hinshaw ◽

Martha G. Sheerar ◽

Diane Larsen

Keyword(s):

Influenza Virus ◽

Avian Influenza ◽

Avian Influenza Virus ◽

Specific Antibody ◽

Antibody Responses

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Knockout of IRF7 Highlights its Modulator Function of Host Response Against Avian Influenza Virus and the Involvement of MAPK and TOR Signaling Pathways in Chicken

Genes ◽

10.3390/genes11040385 ◽

2020 ◽

Vol 11 (4) ◽

pp. 385

Author(s):

Tae Hyun Kim ◽

Colin Kern ◽

Huaijun Zhou

Keyword(s):

Influenza Virus ◽

Avian Influenza ◽

Avian Influenza Virus ◽

Signaling Pathways ◽

Cell Lines ◽

Host Response ◽

Antiviral Response ◽

Influenza Viruses ◽

Interferon Response ◽

Type I

Interferon regulatory factor 7 (IRF7) is known as the master transcription factor of the type I interferon response in mammalian species along with IRF3. Yet birds only have IRF7, while they are missing IRF3, with a smaller repertoire of immune-related genes, which leads to a distinctive immune response in chickens compared to in mammals. In order to understand the functional role of IRF7 in the regulation of the antiviral response against avian influenza virus in chickens, we generated IRF7-/- chicken embryonic fibroblast (DF-1) cell lines and respective controls (IRF7wt) by utilizing the CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) system. IRF7 knockout resulted in increased viral titers of low pathogenic avian influenza viruses. Further RNA-sequencing performed on H6N2-infected IRF7-/- and IRF7wt cell lines revealed that the deletion of IRF7 resulted in the significant down-regulation of antiviral effectors and the differential expression of genes in the MAPK (mitogen-activated protein kinase) and mTOR (mechanistic target of rapamycin) signaling pathways. Dynamic gene expression profiling of the host response between the wildtype and IRF7 knockout revealed potential signaling pathways involving AP1 (activator protein 1), NF-κB (nuclear factor kappa B) and inflammatory cytokines that may complement chicken IRF7. Our findings in this study provide novel insights that have not been reported previously, and lay a solid foundation for enhancing our understanding of the host antiviral response against the avian influenza virus in chickens.

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A review of H5Nx avian influenza viruses

Therapeutic Advances in Vaccines and Immunotherapy ◽

10.1177/2515135518821625 ◽

2019 ◽

Vol 7 ◽

pp. 251513551882162 ◽

Cited By ~ 9

Author(s):

Ivette A. Nuñez ◽

Ted M. Ross

Keyword(s):

Influenza Virus ◽

Avian Influenza ◽

Avian Influenza Virus ◽

Highly Pathogenic Avian Influenza ◽

Influenza Viruses ◽

Avian Influenza Viruses ◽

Highly Pathogenic ◽

Bird Populations ◽

Pathogenic Avian Influenza ◽

Pathogenic Avian Influenza Virus

Highly pathogenic avian influenza viruses (HPAIVs), originating from the A/goose/Guangdong/1/1996 H5 subtype, naturally circulate in wild-bird populations, particularly waterfowl, and often spill over to infect domestic poultry. Occasionally, humans are infected with HPAVI H5N1 resulting in high mortality, but no sustained human-to-human transmission. In this review, the replication cycle, pathogenicity, evolution, spread, and transmission of HPAIVs of H5Nx subtypes, along with the host immune responses to Highly Pathogenic Avian Influenza Virus (HPAIV) infection and potential vaccination, are discussed. In addition, the potential mechanisms for Highly Pathogenic Avian Influenza Virus (HPAIV) H5 Reassorted Viruses H5N1, H5N2, H5N6, H5N8 (H5Nx) viruses to transmit, infect, and adapt to the human host are reviewed.

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Contributions of the Avian Influenza Virus HA, NA, and M2 Surface Proteins to the Induction of Neutralizing Antibodies and Protective Immunity

Journal of Virology ◽

10.1128/jvi.02135-09 ◽

2009 ◽

Vol 84 (5) ◽

pp. 2408-2420 ◽

Cited By ~ 46

Author(s):

Baibaswata Nayak ◽

Sachin Kumar ◽

Joshua M. DiNapoli ◽

Anandan Paldurai ◽

Daniel R. Perez ◽

...

Keyword(s):

Influenza Virus ◽

Avian Influenza ◽

Avian Influenza Virus ◽

Neutralizing Antibodies ◽

Protective Immunity ◽

Reverse Genetics ◽

Severe Disease ◽

Serum Antibody ◽

Surface Proteins ◽

Serum Antibodies

ABSTRACT Highly pathogenic avian influenza virus (HPAIV) subtype H5N1 causes severe disease and mortality in poultry. Increased transmission of H5N1 HPAIV from birds to humans is a serious threat to public health. We evaluated the individual contributions of each of the three HPAIV surface proteins, namely, the hemagglutinin (HA), the neuraminidase (NA), and the M2 proteins, to the induction of HPAIV-neutralizing serum antibodies and protective immunity in chickens. Using reverse genetics, three recombinant Newcastle disease viruses (rNDVs) were engineered, each expressing the HA, NA, or M2 protein of H5N1 HPAIV. Chickens were immunized with NDVs expressing a single antigen (HA, NA, and M2), two antigens (HA+NA, HA+M2, and NA+M2), or three antigens (HA+NA+M2). Immunization with HA or NA induced high titers of HPAIV-neutralizing serum antibodies, with the response to HA being greater, thus identifying HA and NA as independent neutralization antigens. M2 did not induce a detectable neutralizing serum antibody response, and inclusion of M2 with HA or NA reduced the magnitude of the response. Immunization with HA alone or in combination with NA induced complete protection against HPAIV challenge. Immunization with NA alone or in combination with M2 did not prevent death following challenge, but extended the time period before death. Immunization with M2 alone had no effect on morbidity or mortality. Thus, there was no indication that M2 is immunogenic or protective. Furthermore, inclusion of NA in addition to HA in a vaccine preparation for chickens may not enhance the high level of protection provided by HA.

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Distinct Pathogenesis of Hong Kong-Origin H5N1 Viruses in Mice Compared to That of Other Highly Pathogenic H5 Avian Influenza Viruses

Journal of Virology ◽

10.1128/jvi.74.3.1443-1450.2000 ◽

2000 ◽

Vol 74 (3) ◽

pp. 1443-1450 ◽

Cited By ~ 97

Author(s):

Jody K. Dybing ◽

Stacey Schultz-Cherry ◽

David E. Swayne ◽

David L. Suarez ◽

Michael L. Perdue

Keyword(s):

Influenza Virus ◽

Hong Kong ◽

Avian Influenza ◽

Avian Influenza Virus ◽

Transforming Growth Factor ◽

Clinical Signs ◽

Influenza Viruses ◽

Rapid Weight Loss ◽

Avian Influenza Viruses ◽

Highly Pathogenic

ABSTRACT In 1997, an outbreak of virulent H5N1 avian influenza virus occurred in poultry in Hong Kong (HK) and was linked to a direct transmission to humans. The factors associated with transmission of avian influenza virus to mammals are not fully understood, and the potential risk of other highly virulent avian influenza A viruses infecting and causing disease in mammals is not known. In this study, two avian and one human HK-origin H5N1 virus along with four additional highly pathogenic H5 avian influenza viruses were analyzed for their pathogenicity in 6- to 8-week-old BALB/c mice. Both the avian and human HK H5 influenza virus isolates caused severe disease in mice, characterized by induced hypothermia, clinical signs, rapid weight loss, and 75 to 100% mortality by 6 to 8 days postinfection. Three of the non-HK-origin isolates caused no detectable clinical signs. One isolate, A/tk/England/91 (H5N1), induced measurable disease, and all but one of the animals recovered. Infections resulted in mild to severe lesions in both the upper and lower respiratory tracts. Most consistently, the viruses caused necrosis in respiratory epithelium of the nasal cavity, trachea, bronchi, and bronchioles with accompanying inflammation. The most severe and widespread lesions were observed in the lungs of HK avian influenza virus-infected mice, while no lesions or only mild lesions were evident with A/ck/Scotland/59 (H5N1) and A/ck/Queretaro/95 (H5N2). The A/ck/Italy/97 (H5N2) and the A/tk/England/91 (H5N1) viruses exhibited intermediate pathogenicity, producing mild to moderate respiratory tract lesions. In addition, infection by the different isolates could be further distinguished by the mouse immune response. The non-HK-origin isolates all induced production of increased levels of active transforming growth factor β following infection, while the HK-origin isolates did not.

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