Glycosylation of HxNx Avian Flu HA Protein

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 Glycosylation of HxNx Avian Flu HA Protein

     Recently, there is great concern regarding the repeated occurrence of highly pathogenic avian influenza virus (HPAIV) in domestic poultry and increasingly in humans worldwide. Specifically, the H5N1,H5N6, and H7N7 avian viruses have come into focus as having a high potential of becoming virulent in humans (Gao et al., 2019; Igarashi et al. 2019; Yang et al., 2009). Human cases of HPAIV have occurred frequently in China, Indonesia, and Vietnam over the last couple of decades but recently new cases have begun to appear worldwide (Gao et al., 2019). In April of 2021 a male in Colorado was reported to have contracted an H5 influenza strain, presumably H5N1 (Centers for Disease Control and Prevention [CDC], 2021d). Countries worldwide have culled countless flocks of affected poultry in an effort to stem the potential cross-over of the disease to humans and recently, record numbers of poultry are dying from avian flu (Polansek, 2022; Stanbrough & Horne, 2021).

     Influenza viruses are grouped by antigen types into four varieties: A, B,C, & D. Types A and B are the common types humans are affected by seasonally. Type C causes mild symptoms in humans and Type D is typically only found in cattle. There are two surface proteins that cover the influenza virus, hemagglutinin and neuraminidase, designated as H and N respectively. These surface proteins perform multiple functions, including the promotion of attachment to host cell surface molecules containing sialic acid, and contain exposed antigen molecules that are detectable by host antibodies that have been adapted to recognize them. Currently there are 18 known types of hemagglutinin (H1 - H18) and 11 known types of neuraminidase (N1 - N11). Thus H5N1 contains the fifth known type of hemagglutinin spike protein and the first known type of neuraminidase protein (CDC, 2021c) (Please see Figure 1 and Figure 2).

Figure 1: Influenza surface proteins and receptors (CDC, 2019). 















Figure 2: Influenza Virus Anatomy (CDC, 2019).

     There are multiple antigen sites on each head of the hemagglutinin and neuraminidase proteins. These sites are used as target molecules for vaccine development which promote the development of antibodies which recognize these antigens (Igarashi et al., 2019). These locations and others on the spike protein can or are also glycosylated with N-linked oligosaccharides. Glycosylation of hemagglutinin and neuraminidase frequently help to mask the antigen sites from host antibodies, increasing the virulence of such a strain (Vigerust & Shepherd, 2007). During replication, genetic modifications to the type of hemagglutinin and neuraminidase, antigen locations and formation, and areas of glycosylation occur. Often these are the result of small mutations in the genetic code, but occasionally even a small change can sometimes cause a major change in host antibody recognition of the virus, thus lending to pandemic outbreaks where the host organisms have no immunity across the species (CDC, 2021b; (Gao et al., 2019).

     Genetic mutations in the above mentioned areas, including glycosylation, can also allow a strain of influenza to jump hosts and survive in a new host organism. Changes in glycosylation can cause many different changes in viral function including masking and unmasking antigens, promoting or diminishing attachment to host cells, folding behavior of viral proteins, and survival within a host (Gao et al., 2019). The two prominent receptors on host cell surfaces are influenza-α-2,3 sialic and α-2,6 sialic acid receptor. α-2,6 sialic acid is the main receptor in mammals, including humans, and influenza-α-2,3 sialic is the main avian receptor(Yang et al. 2012). Glycosylation changes at the heads of surface proteins, significantly hemagglutinin, can enhance attachment to host receptor types. This is a major concern regarding future changes to these HPAIV, that changes in glycosylation will boost attachment rates to human α-2,6 sialic acid (Vigerust & Shepherd, 2007). If the glycosylation changes also diminish viral protein folding in the endoplasmic reticulum (ER), this could cause further fatality by inducing cytokine storms due to ER stress (Yin et al, 2020). This was the case with the 2009 H1N1 outbreak (CDC, 2021a), as this author can attest after having spent six days in the ICU at the end of December 2009 after contracting the new H1N1 strain.

References

Centers for Disease Control and Prevention. (2019). Images of Influenza Viruses. Influenza (Flu). Retrieved on October 30, 2022 from https://www.cdc.gov/flu/resource-center/freeresources/graphics/images.htm

Centers for Disease Control and Prevention. (2021a). How Flu Viruses Can Change: “Drift” and “Shift”. Influenza (Flu). Retrieved on October 30, 2022 from https://www.cdc.gov/flu/about/viruses/change.htm

Centers for Disease Control and Prevention. (2021b). Influenza Virus Genome Sequencing and Genetic

Characterization. Influenza (Flu). Retrieved on October 30, 2022 from https://www.cdc.gov/flu/about/professionals/genetic-characterization.htm

Centers for Disease Control and Prevention. (2021c). Types of Influenza Viruses. Influenza (Flu). Retrieved on October 30, 2022 from https://www.cdc.gov/flu/about/viruses/types.htm

Centers for Disease Control and Prevention. (2021d). U.S. Case of Human Avian Influenza A(H5) Virus Reported. CDC Newsroom. Retrieved on October 30, 2022 from https://www.cdc.gov/media/releases/2022/s0428-avian-flu.html

Gao, R., Gu, M., Shi, L., Liu, K., Li, X., Wang ,X., Hu, J., Liu, X., Hu, S., Chen, S., Peng, D., Jiao, X., Liu, X. (2021). N-Linked Glycosylation at Site 158 of the HA Protein of H5N6 Highly Pathogenic Avian Influenza Virus is Important for Viral Biological Properties and Host Immune Responses. Vet Res., 52(1), 8. doi: 10.1186/s13567-020-00879-6.

Igarashi, M., Ito, K., Takada, A. (2009). Prediction of N-glycosylation Potential of Influenza Virus Hemagglutinin by a Bioinformatic Approach. Glycoforum, 13(A3). Retrieved on October 29, 2022 from https://www.glycoforum.gr.jp/article/13A3.html

Polansek, T. (2022, October 18) Bird Flu Kills Close to a Record Number of Poultry in the U.S. Reuters. Retrieved on October 30, 2022 from https://www.reuters.com/world/us/us-nears-record-poultry-deaths-bird-flu-virus-type-complicates-fight-2022-10-18/

Stanbrough, L. & Horne, A. (2021). Avian Influenza on the Horizon: The Wolf in the Hen House. WTW. Retrieved on October 30, 2022 from https://www.wtwco.com/en-US/Insights/2021/08/avian-influenza-on-the-horizon-the-wolf-in-the-hen-house

Vigerust, D.J. & Shepherd V.L. (2007). Virus Glycosylation: Role in Virulence and Immune Interactions. Trends Microbiol. 15(5), 211-8. doi: 10.1016/j.tim.2007.03.003.

Yang, H., Carney, P.J., Donis, R.O., Stevens, J. (2012). Structure and Receptor Complexes of the Hemagglutinin from a Highly Pathogenic H7N7 Influenza Virus. J Virol. 86(16), 8645-52. doi: 10.1128/JVI.00281-12.

Yin, Y., Yu, S., Sun, Y., Qin, T., Chen, S., Ding, C., Peng, D., Liu, X. (2020). Glycosylation deletion of Hemagglutinin Head in the H5 Subtype Avian Influenza Virus Enhances its Virulence in Mammals by Inducing Endoplasmic Reticulum Stress. Transbound Emerg Dis., 67(4), 1492-1506. doi: 10.1111/tbed.13481.

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