Hemagglutinin (influenza)

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Hemagglutinin
PDB 1hgd EBI.jpg
Identifiers
SymbolHemagglutinin
Pfam PF00509
InterPro IPR001364
SCOP2 1hgd / SCOPe / SUPFAM
OPM superfamily 109
OPM protein 6hjq
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
Influenza C hemagglutinin stalk
PDB 1flc EBI.jpg
x-ray structure of the haemagglutinin-esterase-fusion glycoprotein of influenza c virus
Identifiers
SymbolHema_stalk
Pfam PF08720
InterPro IPR014831
SCOP2 1flc / SCOPe / SUPFAM
OPM superfamily 277
OPM protein 2jrd
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

Influenza hemagglutinin (HA) or haemagglutinin [p] (British English) is a homotrimeric glycoprotein found on the surface of influenza viruses and is integral to its infectivity.

Contents

Hemagglutinin is a Class I Fusion Protein, having multifunctional activity as both an attachment factor and membrane fusion protein. Therefore, HA is responsible for binding Influenza virus to sialic acid on the surface of target cells, such as cells in the upper respiratory tract or erythrocytes, [1] causing as a result the internalization of the virus. [2] Secondarily, HA is responsible for the fusion of the viral envelope with the late endosomal membrane once exposed to low pH (5.0-5.5). [3]

The name "hemagglutinin" comes from the protein's ability to cause red blood cells (erythrocytes) to clump together ("agglutinate") in vitro . [4]

Subtypes

Hemagglutinin (HA) in influenza A has at least 18 different subtypes. [5] These subtypes are named H1 through H18. H16 was discovered in 2004 on influenza A viruses isolated from black-headed gulls from Sweden and Norway. H17 was discovered in 2012 in fruit bats. [6] [7] Most recently, H18 was discovered in a Peruvian bat in 2013. [8] The first three hemagglutinins, H1, H2, and H3, are found in human influenza viruses. By phylogenic similarity, the HA proteins are divided into 2 groups, with H1, H2, H5, H6, H8, H9, H11, H12, H13, H16, H17, and H18 belonging to group 1 and the rest in group 2. [9] The serotype of influenza A virus is determined by the Hemagglutinin (HA) and Neuraminidase (NA) proteins present on its surface. [10] Neuraminidase (NA) has 11 known subtypes, hence influenza virus is named as H1N1, H5N2 etc., depending on the combinations of HA and NA. [5]

Structure of influenza, showing neuraminidase marked as NA and hemagglutinin as HA. Flu und legende color c.jpg
Structure of influenza, showing neuraminidase marked as NA and hemagglutinin as HA.

A highly pathogenic avian flu virus of H5N1 type has been found to infect humans at a low rate. It has been reported that single amino acid changes in this avian virus strain's type H5 hemagglutinin have been found in human patients that "can significantly alter receptor specificity of avian H5N1 viruses, providing them with an ability to bind to receptors optimal for human influenza viruses". [11] [12] This finding seems to explain how an H5N1 virus that normally does not infect humans can mutate and become able to efficiently infect human cells. The hemagglutinin of the H5N1 virus has been associated with the high pathogenicity of this flu virus strain, apparently due to its ease of conversion to an active form by proteolysis. [13] [14]

Structure

HA is a homotrimeric integral membrane glycoprotein. It is shaped like a cylinder, and is approximately 13.5 nanometres long. [15] [16] HA trimer is made of three identical monomers. Each monomer is made of an intact HA0 single polypeptide chain with HA1 and HA2 regions that are linked by 2 disulfide bridges. [16] [17] Each HA2 region adopts alpha helical coiled coil structure and sits on top of the HA1 region, which is a small globular domain that consists of a mix of α/β structures. [18] The HA trimer is synthesized as inactive precursor protein HA0 to prevent any premature and unwanted fusion activity and must be cleaved by host proteases in order to be infectious. At neutral pH, the 23 residues near the N-terminus of HA2, also known as the fusion peptide that is eventually responsible for fusion between viral and host membrane, is hidden in a hydrophobic pocket between the HA2 trimeric interface. [19] The C-terminus of HA2, also known as the transmembrane domain, spans the viral membrane and anchors protein to the membrane. [20]

HA1
HA1 is mostly composed of antiparallel beta-sheets. [15]
HA2
HA2 domain contains three long alpha helices, one from each monomer. Each of these helices is connected by a flexible, loop region called Loop-B (residue 59 to 76). [21]

Function

HA plays two key functions in viral entry. Firstly, it allows the recognition of target vertebrate cells, accomplished through the binding to these cells' sialic acid-containing receptors. Secondly, once bound it facilitates the entry of the viral genome into the target cells by causing the fusion of host endosomal membrane with the viral membrane. [22]

Specifically, the HA1 domain of the protein binds to the monosaccharide sialic acid which is present on the surface of its target cells, allowing attachment of viral particle to the host cell surface. HA17 and HA18 have been described to bind MHC class II molecules as a receptor for entry rather than sialic acid. [23] The host cell membrane then engulfs the virus, a process known as endocytosis, and pinches off to form a new membrane-bound compartment within the cell called an endosome. The cell then attempts to begin digesting the contents of the endosome by acidifying its interior and transforming it into a lysosome. Once the pH within the endosome drops to about 5.0 to 6.0, a series of conformational rearrangement occurs to the protein. First, fusion peptide is released from the hydrophobic pocket and HA1 is dissociated from HA2 domain. HA2 domain then undergoes extensive conformation change that eventually bring the two membranes into close contact.[ citation needed ]

This so-called "fusion peptide" that was released as pH is lowered, acts like a molecular grappling hook by inserting itself into the endosomal membrane and locking on. Then, HA2 refolds into a new structure (which is more stable at the lower pH), it "retracts the grappling hook" and pulls the endosomal membrane right up next to the virus particle's own membrane, causing the two to fuse together. Once this has happened, the contents of the virus such as viral RNA are released in the host cell's cytoplasm and then transported to the host cell nucleus for replication. [24]

As a treatment target

Since hemagglutinin is the major surface protein of the influenza A virus and is essential to the entry process, it is the primary target of neutralizing antibodies. [ citation needed ]These antibodies against flu have been found to act by two different mechanisms, mirroring the dual functions of hemagglutinin:

Head antibodies

Some antibodies against hemagglutinin act by inhibiting attachment. This is because these antibodies bind near the top of the hemagglutinin "head" (blue region in figure above) and physically block the interaction with sialic acid receptors on target cells. [25]

Stem antibodies

This group of antibodies acts by preventing membrane fusion (only in vitro; the efficacy of these antibodies in vivo is believed to be a result of antibody-dependent cell-mediated cytotoxicity and the complement system). [26]

The stem or stalk region of HA (HA2), is highly conserved across different strains of influenza viruses. The conservation makes it an attractive target for broadly neutralizing antibodies that target all flu subtypes, and for developing universal vaccines that let humans produce these antibodies naturally. [27] Its structural changes from prefusion to postfusion conformation drives fusion between viral membrane and host membrane. Therefore, antibodies targeting this region can block key structural changes that eventually drive the membrane fusion process, and therefore are able to achieve antiviral activity against several influenza virus subtypes. At least one fusion-inhibiting antibody was found to bind closer to the top of hemagglutinin, and is thought to work by cross-linking the heads together, the opening of which is thought to be the first step in the membrane fusion process. [28]

Examples are human antibodies F10, [29] FI6, [30] CR6261. They recognize sites in the stem/stalk region (orange region in figure at right), far away from the receptor binding site. [31] [32]

In 2015 researchers designed an immunogen mimicking the HA stem, specifically the area where the antibody ties to the virus of the antibody CR9114. Rodent and nonhuman primate models given the immunogen produced antibodies that could bind with HAs in many influenza subtypes, including H5N1. [33] When the HA head is present, the immune system does not generally make bNAbs (broadly neutralizing antibodies). Instead, it makes the head antibodies that only recognize a few subtypes. Since the head is responsible for holding the three HA units together, a stem-only HA needs its own way to hold itself together. One team designed self-assembling HA-stem nanoparticles, using a protein called ferritin to hold the HA together. Another replaced and added amino acids to stabilize a mini-HA lacking a proper head.[ citation needed ]

A 2016 vaccine trial in humans found many broadly neutralizing antibodies targeting the stem produced by the immune system. Three classes of highly similar antibodies were recovered from multiple human volunteers, suggesting that a universal vaccine that produces reproducible antibodies is indeed possible. [34]

Other agents

There are also other hemagglutinin-targeted influenza virus inhibitors that are not antibodies: [35]

  1. Arbidol
  2. Small Molecules
  3. Natural compounds
  4. Proteins and peptides

See also

Notes

[p] ^Hemagglutinin is pronounced /he-mah-Glue-tin-in/. [36] [37]

Related Research Articles

<i>Influenza A virus</i> Species of virus

Influenza A virus (IAV) is a pathogen that causes the flu in birds and some mammals, including humans. It is an RNA virus whose subtypes have been isolated from wild birds. Occasionally, it is transmitted from wild to domestic birds, and this may cause severe disease, outbreaks, or human influenza pandemics.

<span class="mw-page-title-main">Avian influenza</span> Influenza caused by viruses adapted to birds

Avian influenza, also known as avian flu or bird flu, is a disease caused by the influenza A virus, which can infect both birds and people. It is similar to other types of animal flu in that it is caused by a virus strain that has adapted to a specific host. The type with the greatest risk is highly pathogenic avian influenza (HPAI).

<i>Orthomyxoviridae</i> Family of RNA viruses including the influenza viruses

Orthomyxoviridae is a family of negative-sense RNA viruses. It includes seven genera: Alphainfluenzavirus, Betainfluenzavirus, Gammainfluenzavirus, Deltainfluenzavirus, Isavirus, Thogotovirus, and Quaranjavirus. The first four genera contain viruses that cause influenza in birds and mammals, including humans. Isaviruses infect salmon; the thogotoviruses are arboviruses, infecting vertebrates and invertebrates. The Quaranjaviruses are also arboviruses, infecting vertebrates (birds) and invertebrates (arthropods).

Antigenic drift is a kind of genetic variation in viruses, arising from the accumulation of mutations in the virus genes that code for virus-surface proteins that host antibodies recognize. This results in a new strain of virus particles that is not effectively inhibited by the antibodies that prevented infection by previous strains. This makes it easier for the changed virus to spread throughout a partially immune population. Antigenic drift occurs in both influenza A and influenza B viruses.

<span class="mw-page-title-main">Influenza A virus subtype H5N1</span> Subtype of influenza A virus

Influenza A virus subtype H5N1 (A/H5N1) is a subtype of the influenza A virus, which causes influenza (flu), predominantly in birds. It is enzootic in many bird populations, and also panzootic. A/H5N1 virus can also infect mammals which have been exposed to infected birds; in these cases symptoms are frequently severe or fatal.

Virus-like particles (VLPs) are molecules that closely resemble viruses, but are non-infectious because they contain no viral genetic material. They can be naturally occurring or synthesized through the individual expression of viral structural proteins, which can then self assemble into the virus-like structure. Combinations of structural capsid proteins from different viruses can be used to create recombinant VLPs. Both in-vivo assembly and in-vitro assembly have been successfully shown to form virus-like particles. VLPs derived from the Hepatitis B virus (HBV) and composed of the small HBV derived surface antigen (HBsAg) were described in 1968 from patient sera. VLPs have been produced from components of a wide variety of virus families including Parvoviridae, Retroviridae, Flaviviridae, Paramyxoviridae and bacteriophages. VLPs can be produced in multiple cell culture systems including bacteria, mammalian cell lines, insect cell lines, yeast and plant cells.

<span class="mw-page-title-main">Hemagglutinin esterase</span> Glycoprotein present in some enveloped viruses

Hemagglutinin esterase (HEs) is a glycoprotein that certain enveloped viruses possess and use as an invading mechanism. HEs helps in the attachment and destruction of certain sialic acid receptors that are found on the host cell surface. Viruses that possess HEs include influenza C virus, toroviruses, and coronaviruses of the subgenus Embecovirus. HEs is a dimer transmembrane protein consisting of two monomers, each monomer is made of three domains. The three domains are: membrane fusion, esterase, and receptor binding domains.

<i>Influenza C virus</i> Genus of viruses in the family Orthomyxoviridae

Influenza C virus is the only species in the genus Gammainfluenzavirus, in the virus family Orthomyxoviridae, which like other influenza viruses, causes influenza.

<span class="mw-page-title-main">H5N1 genetic structure</span>

H5N1 genetic structure is the molecular structure of the H5N1 virus's RNA.

<span class="mw-page-title-main">Spanish flu research</span> Scientific research of the 1918 influenza pandemic

Spanish flu research concerns studies regarding the causes and characteristics of the Spanish flu, a variety of influenza that in 1918 was responsible for the worst influenza pandemic in modern history. Many theories about the origins and progress of the Spanish flu persisted in the literature, but it was not until 2005, when various samples of lung tissue were recovered from American World War I soldiers and from an Inupiat woman buried in permafrost in a mass grave in Brevig Mission, Alaska, that significant genetic research was made possible.

Antigenic variation or antigenic alteration refers to the mechanism by which an infectious agent such as a protozoan, bacterium or virus alters the proteins or carbohydrates on its surface and thus avoids a host immune response, making it one of the mechanisms of antigenic escape. It is related to phase variation. Antigenic variation not only enables the pathogen to avoid the immune response in its current host, but also allows re-infection of previously infected hosts. Immunity to re-infection is based on recognition of the antigens carried by the pathogen, which are "remembered" by the acquired immune response. If the pathogen's dominant antigen can be altered, the pathogen can then evade the host's acquired immune system. Antigenic variation can occur by altering a variety of surface molecules including proteins and carbohydrates. Antigenic variation can result from gene conversion, site-specific DNA inversions, hypermutation, or recombination of sequence cassettes. The result is that even a clonal population of pathogens expresses a heterogeneous phenotype. Many of the proteins known to show antigenic or phase variation are related to virulence.

<span class="mw-page-title-main">Influenza</span> Infectious disease

Influenza, commonly known as "the flu" or just "flu", is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These symptoms begin one to four days after exposure to the virus and last for about two to eight days. Diarrhea and vomiting can occur, particularly in children. Influenza may progress to pneumonia from the virus or a subsequent bacterial infection. Other complications include acute respiratory distress syndrome, meningitis, encephalitis, and worsening of pre-existing health problems such as asthma and cardiovascular disease.

<span class="mw-page-title-main">Viral neuraminidase</span> InterPro Family

Viral neuraminidase is a type of neuraminidase found on the surface of influenza viruses that enables the virus to be released from the host cell. Neuraminidases are enzymes that cleave sialic acid groups from glycoproteins. Viral neuraminidase was discovered by Alfred Gottschalk at the Walter and Eliza Hall Institute in 1957. Neuraminidase inhibitors are antiviral agents that inhibit influenza viral neuraminidase activity and are of major importance in the control of influenza.

<span class="mw-page-title-main">Hemagglutinin</span>

In molecular biology, hemagglutinins are receptor-binding membrane fusion glycoproteins produced by viruses in the Paramyxoviridae and Orthomyxoviridae families. Hemagglutinins are responsible for binding to receptors on red blood cells to initiate viral attachment and infection. The agglutination of red cells occurs when antibodies on one cell bind to those on others, causing amorphous aggregates of clumped cells.

CR6261 is a monoclonal antibody that binds to a broad range of the influenza virus including the 1918 "Spanish flu" (SC1918/H1) and to a virus of the H5N1 class of avian influenza that jumped from chickens to a human in Vietnam in 2004 (Viet04/H5). In contrast to most antibodies generated by exposure to influenza, which can only neutralize a few strains from within a single virus subtype, CR6261 neutralizes numerous strains from multiple subtypes. CR6261 recognizes a highly conserved helical region in the membrane-proximal stem of hemagglutinin, the predominant protein on the surface of the influenza virus. Based upon the conservation of the amino acid sequence on this part of hemagglutinin, CR6261 is predicted to neutralize roughly 50% of all flu viruses. It was found by The Scripps Research Institute and the Dutch biopharmaceutical company, Crucell.

FI6 is an antibody that targets a protein found on the surface of all influenza A viruses called hemagglutinin. FI6 is the only known antibody found to bind all 16 subtypes of the influenza A virus hemagglutinin and is hoped to be useful for a universal influenza virus therapy.

<span class="mw-page-title-main">H5N1 vaccine</span> Vaccine designed to provide immunity against H5N1 influenza

A H5N1 vaccine is an influenza vaccine intended to provide immunization to influenza A virus subtype H5N1.

<span class="mw-page-title-main">Universal flu vaccine</span> Vaccine that prevents infection from all strains of the flu

A universal flu vaccine is a flu vaccine that is effective against all influenza strains regardless of the virus sub type, antigenic drift or antigenic shift. Hence it should not require modification from year to year. As of 2021 no universal flu vaccine had been approved for general use, several were in development, and one was in clinical trial.

<i>Influenza D virus</i> Species of virus

Influenza D virus is a species in the virus genus Deltainfluenzavirus, in the family Orthomyxoviridae, that causes influenza.

Type A influenza vaccine is for the prevention of infection of influenza A virus and also the influenza-related complications. Different monovalent type A influenza vaccines have been developed for different subtypes of influenza A virus including H1N1 and H5N1. Both intramuscular injection or intranasal spray are available on market. Unlike the seasonal influenza vaccines which are used annually, they are usually used during the outbreak of certain strand of subtypes of influenza A. Common adverse effects includes injection site reaction and local tenderness. Incidences of headache and myalgia were also reported with H1N1 whereas cases of fever has also been demonstrated with H5N1 vaccines. It is stated that immunosuppressant therapies would reduce the therapeutic effects of vaccines and that people with egg allergy should go for the egg-free preparations.

References

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