Neuraminidase: Another Piece of the Influenza Vaccine Puzzle

Eckard, Laura; Webby, Richard J.

doi:10.1093/infdis/jiv196

Cited by 6 publications

(5 citation statements)

References 8 publications

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“…While there has been an increase in the number of clinical studies aimed at determining the efficacy and/or effectiveness of current vaccines, there has not been a corresponding increase in the number of laboratory-based studies to determine what underpins these measures. Neutralization antibody and cytotoxic T cell response have been postulated for decades as the major components of influenza immunity, validated by experiments in mouse models and in humans39414243. We revealed two more critical factors for influenza immunity with our study here.…”

Section: Discussionsupporting

confidence: 60%

“…This measurement has been applied for licensure of inactivated human seasonal influenza vaccines (TIV). However, the possibility of vaccine ineffectiveness always prompts the need to understand other relevant protection factors3940. In our experiments, both pre-infection with intranasal inoculation and intramuscular injection induced comparable levels of neutralizing antibodies and neutralization antibodies are associated with accelerated virus clearance and protection.…”

Section: Discussionmentioning

confidence: 65%

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Sterilizing immunity to influenza virus infection requires local antigen-specific T cell response in the lungs

Dutta

Huang

Lin

et al. 2016

Sci Rep

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Sterilizing immunity is a unique immune status, which prevents effective virus infection into the host. It is different from the immunity that allows infection but with subsequent successful eradication of the virus. Pre-infection induces sterilizing immunity to homologous influenza virus challenge in ferret. In our antigen-specific experimental system, mice pre-infected with PR8 influenza virus through nasal route are likewise resistant to reinfection of the same strain of virus. The virus is cleared before establishment of effective infection. Intramuscular influenza virus injection confers protection against re-infection with facilitated virus clearance but not sterilizing immunity. Pre-infection and intramuscular injection generates comparable innate immunity and antibody response, but only pre-infection induces virus receptor reduction and efficient antigen-specific T cell response in the lungs. Pre-infection with nH1N1 influenza virus induces virus receptor reduction but not PR8-specific T cell immune response in the lungs and cannot prevent infection of PR8 influenza virus. Pre-infection with PR8 virus induced PR8-specific T cell response in the lungs but cannot prevent infection of nH1N1 virus either. These results reveal that antigen-specific T cell immunity is required for sterilizing immunity.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 65%

Sterilizing immunity to influenza virus infection requires local antigen-specific T cell response in the lungs

Dutta

Huang

Lin

et al. 2016

Sci Rep

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“…Considering the potential of NA to serve as a universal target for the treatment of influenza virus infections, several compounds have been developed targeting this enzyme, aiming to become a universal antiviral drug. Many studies have been done, are currently being done and will be done in the future to achieve this remarkable milestone …”

Section: Introductionmentioning

confidence: 99%

Studies on neuraminidase inhibition

Paiva

Costa

Ferreira

et al. 2018

Int J of Quantum Chemistry

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Neuraminidase (NA) inhibitors are a class of antiviral drugs developed to target the influenza virus a highly contagious virus that can cause severe respiratory illness and death. Although several NA inhibitors have been developed in the last decade, it is still poorly understood how they interact in the active site of the enzyme and which chemical and structural features potentiate their inhibitory activity. Taking this into account, we analyze in this article the inhibitory activity of 236 known NA inhibitors using molecular docking simulations. The protocol performed in this work, based on AutoDock, demonstrated to be very efficient in differentiating NA inhibitors with DG binding above 211.7 kcalÁmol 21 . The results have shown that the best inhibitors are those that closely resemble the structure of the natural substrate, but explore additional areas of the active site with which they interact strongly and, therefore, potentiate their inhibitory activity. The best NA inhibitors are characterized by a central saturated six-member ring filling almost completely the space available in the active site pocket. In addition, they contain both a carboxylate and an acetamide group, bound to the central ring structure, which allow them to interact with five arginines, organized in a triad (Arg371, Arg118, Arg292) and a pair (Arg151, Arg152). These interactions are very strong and act as two anchors that fix the compounds in the active site. The inhibitory activity of the compounds is improved if they have hydrophobic groups pointing toward a hydrophobic region of the active site, where Ile222 is located, and when they have amine or guanidine groups pointing toward three glutamates (Glu277, Glu276, Glu227). The studies performed here lay the foundations for the rational design of new and more efficient drugs to fight the influenza virus. K E Y W O R D SAutoDock, inhibitors, molecular docking, neuraminidase 1 | I N TR ODU C TI ON Influenza virus infections account for significant morbidity, mortality, and healthcare expenditures worldwide. [1,2] The Influenza virus is an RNA virus (single strand) that belongs to the Orthomyxoviridae family. The pathogen has a segmented negative-strand RNA genome that codes for two glycoproteins: hemagglutinin (HA) and neuraminidase (NA). These proteins are located in the virus capsid and play a key role in the interaction with the host cell during infection [3] HA is responsible for virus attachment to the cell sialic acid receptors. After virus replication, NA then cuts the link between HA and the receptors to facilitate the release and spread of the influenza virus.Considering that the A/H1N1 influenza virus pandemic in 2009 caused as many as ten times more deaths than originally estimated, these two proteins have become important drug targets and catalyzed an unprecedented drug discovery/development effort to stem future epidemics. [4] However, this process is far from being simple. As in many other viruses, the genome of influenza viruses is continuously changing by mutations or by ...

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“…Point mutations in the antigenic domains of the NA protein were considered as a way to escape host immune system for viruses [3]. Eckard suggested that NA may be another piece of the influenza vaccine, while European Pharmacopeia suggest to maximize vaccine NA content to induce protective immunity against influenza infection at the same time [4]. So the big question now is how virus protein NA triggered the immune response.…”

Section: Introductionmentioning

confidence: 99%

“…For example, miR451 regulates a subset of pro-inflammatory cytokine to combat with influenza virus in mice DCs [14]. In addition, there are now solid data to suggest a protective role for NA immunity and to prove that contribution of antibody production against neuraminidase to the protection afforded by influenza vaccines [4, 15]. The purpose of our study was to figure out how miRNAs regulate the immune response of DCs stimulated by virus protein NA.…”

Section: Introductionmentioning

confidence: 99%

MiR674 inhibits the neuraminidase-stimulated immune response on dendritic cells via down-regulated Mbnl3

et al. 2016

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Neuraminidase (NA), a structural protein of the H9N2 avian influenza virus (H9N2 AIV), can facilitate viral invasion of the upper airway by cleaving the sialic acid moieties on mucin. Dendritic cells (DCs) are major antigen-presenting cells whose immune functions, such as presenting antigens and activating lymphocytes, can be regulated by microRNAs. Here, we studied the molecular mechanism of miRNA-induced repression of immune responses in mouse DCs. First, we screened for and verified the miRNAs induced by NA. Then, we showed that, consistent with the H9N2 virus treatment, the viral NA up-regulated the expression of miR-155, miR-674, and miR-499 in DCs; however, unlike H9N2 virus treatment, the presence of NA was associated with reduced expression of miR-181b1. Our results suggest that NA significantly increased DC surface markers CD80 and MHCII and enhanced the ability of activating lymphocytes and secreting cytokines compared with HA, NP and M2. Meanwhile, we found that miR-674 and miR-155 over-expression increased all surface markers of DC. Nevertheless, by inhibiting the expression of miR-674 and miR-155, NA lost the ability to promote DC maturation. Furthermore, we predicted and demonstrated that Pgm2l1, Aldh18a1, Camk1d, and Mbnl3 were the target genes of miR-674. Among them, Mbnl3 interference strongly blocked the mature DCs. Collectively, our data shed new light on the roles of and mechanisms involved in the repression of DCs by miRNAs, which may contribute to efforts to develop a prophylaxis for the influenza virus.

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Neuraminidase: Another Piece of the Influenza Vaccine Puzzle

Cited by 6 publications

References 8 publications

Sterilizing immunity to influenza virus infection requires local antigen-specific T cell response in the lungs

Sterilizing immunity to influenza virus infection requires local antigen-specific T cell response in the lungs

Studies on neuraminidase inhibition

MiR674 inhibits the neuraminidase-stimulated immune response on dendritic cells via down-regulated Mbnl3

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