Neuraminidase Stalk Length and Additional Glycosylation of the Hemagglutinin Influence the Virulence of Influenza H5N1 Viruses for Mice

Matsuoka, Yumiko; Swayne, David E.; Thomas, Colleen J.; Rameix‐Welti, Marie‐Anne; Naffakh, Nadia; Warnes, Christine; Altholtz, Melanie; Donis, Ruben O.; Subbarao, Kanta

doi:10.1128/jvi.01987-08

Cited by 212 publications

(199 citation statements)

References 25 publications

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“…Segment-specific regulation is particularly important for the HA and NA genes, because balancing the relative activity levels of these two molecules is key to maintaining optimal fitness across different host contexts (20,21,29). Previously described mechanisms of NA regulation in response to selective pressure entail cis-acting mutations that modulate NA activity in cells or virions (22,(30)(31)(32). NA activity on virions also can be influenced in trans by M1 and the viral polymerase proteins PB2 and PB1, although the specific mechanisms involved are uncertain (33,34).…”

Section: Discussionmentioning

confidence: 99%

Influenza A virus nucleoprotein selectively decreases neuraminidase gene-segment packaging while enhancing viral fitness and transmissibility

Brooke

Ince

Wei

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The influenza A virus (IAV) genome is divided into eight distinct RNA segments believed to be copackaged into virions with nearly perfect efficiency. Here, we describe a mutation in IAV nucleoprotein (NP) that enhances replication and transmission in guinea pigs while selectively reducing neuraminidase (NA) gene segment packaging into virions. We show that incomplete IAV particles lacking gene segments contribute to the propagation of the viral population through multiplicity reactivation under conditions of widespread coinfection, which we demonstrate commonly occurs in the upper respiratory tract of guinea pigs. NP also dramatically altered the functional balance of the viral glycoproteins on particles by selectively decreasing NA expression. Our findings reveal novel functions for NP in selective control of IAV gene packaging and balancing glycoprotein expression and suggest a role for incomplete gene packaging during host adaptation and transmission.influenza virus | genome segmentation | genome packaging | nucleoprotein | host adaptation S easonal influenza A virus (IAV) remains a major public health threat, causing tens of thousands of deaths each year in the United States alone (1). Morbidity and mortality rates can increase dramatically when a zoonotic strain adapts to circulate in humans, triggering a pandemic. The continuing toll exerted by IAV stems from its remarkable adaptability, which enables it to move between widely divergent host species and also evade herd immunity within each species. Defining the specific mechanisms that mediate IAV adaptation is essential to improving anti-IAV vaccines, therapeutics, and pandemic surveillance.The IAV genome consists of eight negative-sense RNA segments, each of which is required for productive infection. Genome segmentation complements the high mutation rate of IAV by facilitating reassortment, which can maximize positive intergenic epistasis (2-5) and allow selective elimination of segments with deleterious mutations (6, 7). Although reassortment is the most obvious and best-characterized benefit of segmentation, there are likely additional evolutionary advantages.Genome segmentation imposes the substantial constraint of maintaining a gene-packaging mechanism to produce fully infectious virions (8). For IAV, it is widely believed that a single copy of each segment is packaged into progeny virions with nearly perfect efficiency, resulting in an equimolar ratio of the segments at the population level (9-12). Confounding this model, we recently demonstrated that most IAV virions fail to express one or more gene products (13). This finding raises the possibility that in some circumstances incomplete influenza gene packaging is evolutionarily neutral and possibly even advantageous (14).The viral glycoproteins HA and neuraminidase (NA) are encoded by separate genome segments. HA attaches IAV to terminal sialic acid residues on the host cell surface, enabling viral entry. By hydrolyzing sialic acids, NA detaches budding virions and neutralizes HA-inhibiting glyco...

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Section: Discussionmentioning

confidence: 99%

Influenza A virus nucleoprotein selectively decreases neuraminidase gene-segment packaging while enhancing viral fitness and transmissibility

Brooke

Ince

Wei

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…The NA stalk of SC-H5N1 viruses had a 20 aa deletion (positions 49-68), which might enhance virus adaptation to domestic fowl and increase virulence in mammals (Cauldwell et al, 2014;Matsuoka et al, 2009;Zhou et al, 2009). This 20 aa deletion was not found in the NA stalk of SC-H5N6 and the human-H5N6 strain.…”

mentioning

confidence: 97%

Two novel reassortants of avian influenza A (H5N6) virus in China

Shi

et al. 2015

Journal of General Virology

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“…Neuraminidase (NA) is crucial for virus release and replication. Studies indicated that a deletion of five amino acids (residues 69 -73) in NA stalk may be associated with its increased virulence in mammals (22,23). The isolated H7N9 virus had a same deletion in the stalk region of NA, which may explain an adaptation of H7N9 viruses from aquatic birds to terrestrial poultry such as chickens.…”

Section: Discussionmentioning

confidence: 91%

“…The length of its stalk is associated with the virulence. It had been reported that a deletion of five amino acids (residues 69 -73) in its stalk may be associated with its increased virulence in mammals (22,23). All four human H7N9 virus strains and the novel isolate H7N9 virus have this deletion, suggesting that the novel isolated H7N9 virus may have the same virulence in mammals as four human H7N9 viruses.…”

Section: Molecular Characterization Of H7n9 Virus Isolated From Chickmentioning

confidence: 99%

Detection and Molecular Characterization of the Avian Influenza A (H7N9) Virus in Eastern China in 2013

Zhu

Pei

Jiang

et al. 2016

Jundishapur J Microbiol

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Background: On March 31, 2013, human infections with a novel avian influenza A (H7N9) virus were firstly reported in China. By February 7, 2015, a total of 562 laboratoryconfirmed human cases of H7N9 infection were reported in mainland China. Objectives: This study aimed to determine whether there is a novel H7N9 virus infection in human and animals in Taizhou city, China, in 2013. Methods: In this study, we developed real-time reverse transcription-polymerase chain reaction (RT-PCR) assays to detect H7N9 virus infection in human and animals (chicken, pig, and pigeon) in Taizhou city in the beginning of H7N9 epidemics of 2013. Also, we studied the novel isolated H7N9 virus strain by using genome sequencing and phylogenetic analysis.Results: Of 150 samples tested, 7 were detected to be H7N9 positive which all were collected from chickens. Also, a novel H7N9 virus strain (A/chicken/jiangsu/1021/2013) was isolated and studied. Phylogenetic analysis showed the novel isolated H7N9 virus had high identity to the four novel human H7N9 viruses (A/Shanghai/1/2013, A/Shanghai/2/2013, A/Anhui/1/2013, and A/Hangzhou/1/2013). Conclusions: Our results demonstrated a novel H7N9 virus in chickens in Taizhou city in 2013 that may pose a potential risk to public health.

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Neuraminidase Stalk Length and Additional Glycosylation of the Hemagglutinin Influence the Virulence of Influenza H5N1 Viruses for Mice

Cited by 212 publications

References 25 publications

Influenza A virus nucleoprotein selectively decreases neuraminidase gene-segment packaging while enhancing viral fitness and transmissibility

Influenza A virus nucleoprotein selectively decreases neuraminidase gene-segment packaging while enhancing viral fitness and transmissibility

Two novel reassortants of avian influenza A (H5N6) virus in China

Detection and Molecular Characterization of the Avian Influenza A (H7N9) Virus in Eastern China in 2013

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