Orthomyxovirus Receptors

Orthomyxovirus Receptors Background

The Orthomyxoviridae family comprises five genera;

• Influenzavirus A – pathogens of humans, horses, pigs, mink, seals, whales, and fowl
• Influenzavirus B – pathogens of humans only
• Influenzavirus C – infect humans and pigs, these viruses rarely cause serious disease
• Thogotovirus – tick-borne arboviruses infecting humans and livestock in Africa, Europe, and Asia
• Isavirus – named for its type species, infectious salmon anemia virus

The most important members of the family are the influenza viruses which cause worldwide annual epidemics estimated to result in about 3-5 million cases of severe illness, and about 290 000 to 650 000 respiratory deaths (WHO).

Influenza virions are spherical or pleomorphic, 80–120 nm in diameter and their envelope is derived from the cell membrane, incorporating virus glycoproteins and non-glycosylated proteins. The virus genome is segmented, has helical symmetry, and consists of different size ribonucleoproteins. The structural proteins common to all genera include three polypeptides; a nucleoprotein; a non-glycosylated matrix protein; and a hemagglutinin (HA), which is an integral, type I membrane glycoprotein involved in virus attachment, envelope fusion and neutralization. Viruses attach via the HA protein to sialic acid Orthomyxovirus receptors on the host cell surface. HA is a trimeric glycoprotein that is present in multiple copies in the membrane envelope of influenza virus. It contains a fusion peptide, a receptor binding site, a metastable structural motif and the transmembrane domain.

The first step of influenza virus entry is the recognition of the host cell receptor molecule, terminal α-sialic acid by HA, a homotrimer that forms spikes on the viral lipid membrane. This multivalent attachment by multiple copies of trimetric HA then triggers endocytosis of influenza virus towards the cell nucleus. The variety of sialylglycoconjugates differs substantially between viral host species as well as target tissues and cell types of the same species, leading to variations in the receptor-binding specificity of viruses circulating in these hosts. Therefore, receptor specificity plays an important role in the viral cell and tissue tropism, interspecies transmission and adaptation to a new host; this aids incompatibility of avian viruses to receptors in humans and reduces the emergence of new pandemic strains.

The emergence of the H7N9 avian influenza A virus and its ability to infect humans emphasizes the epidemic and pandemic potential of these viruses. Interspecies transmission is the result of many factors, which ultimately lead to a change in the host tropism of the virus. One of the key factors involved is a shift in the receptor-binding specificity of the virus, which is mostly determined by mutations in the viral haemagglutinin (HA). Inhibitors of virus entry are potentially effective antiviral drugs of influenza viruses.

References

• Virus Taxonomy. Ninth Report of the International Committee on Taxonomy of Viruses. 2012, Pages 749-761
• World Health Organisation. Influenza (Seasonal). 6 November 2018.
• Gabriele Neumanna and Yoshihiro Kawaoka (2015). Transmission of Influenza A Viruses. Virology. 0: 234–246.
• Pu et al. (2018). Potential Pandemic of H7N9 Avian Influenza A Virus in Human. Front Cell Infect Microbiol. 8: 414.
• Shi et al. (2014). Enabling the ‘host jump’: structural determinants of receptor-binding specificity in influenza A viruses. Nat Rev Microbiol. 12(12):822-31